Saphnelo (Anifrolumab-fnia Injection ) : Uses, Dosage, Side Effects, Interactions, Warning (2023)

Description of the medicine

DESCRIPTION

Anifrolumab-fnia is a type I interferon (IFN)-receptor.antagonist,immunoglobulinsG1 kappa (IgG1k)monoclonal antibodyproduced in mousemyelomacells (NS0) ofrecombinant-DNA-technologie. The molecular weight is about 148 kDa.

SAPHNELO (anifrolumab-fnia) is a sterile, preservative-free, clear to iridescent, colorless to pale yellow solution for intravenous use. SAPHNELO contains anifrolumab-fnia at a concentration of 150 mg/ml in a single dose vial.

Each vial contains 300 mg (150 mg/ml) anifrolumab-fnia, L-histidine(3 mg), L-histidine hydrochloride monohydraat (6 mg), L-lysinehydrochloride (18 mg), polysorbate 80 (1 mg), trehalose dihydrate (98 mg), and water for injection, USP. The pH is 5.9.

Indications & Dosage

INDICATIONS

SAPHNELO (anifrolumab-fnia) is indicated for the treatment of adult patients with moderate to severeSystemic lupus erythematosus(PAGE), who receive standard treatment [seeclinical studies].

Restrictions on use

The efficacy of SAPHNELO has not been evaluated in severely active patientswolf nephritisor seriously activeCentral nervous systemWolf. The use of SAPHNELO is not recommended in these cases.

DOSAGE AND ADMINISTRATION

Dosage recommendations

SAPHNELO must be diluted before intravenous administration [seeDOSAGE AND ADMINISTRATION].

The recommended dose of SAPHNELO is 300 mg administered as an intravenous infusion over a 30 minute period every 4 weeks.

Missed dose

If you miss a scheduled infusion, give SAPHNELO as soon as possible. Keep an interval of at least 14 days between injections.

Instructions for preparation and administration

SAPHNELO is available as a single dose vial. Prepare the diluted solution for infusion usingaseptictechnique, with the following procedure:

1. Visually inspect the vial for particulate matter and discoloration. SAPHNELO is a clear to iridescent, colorless to pale yellow solution. Discard the vial if the solution is cloudy or discolored or if visible particles are observed. Do not shake the vial.
2. Withdraw and discard 2 mL of solution from a 50 mL or 100 mL IV bag containing 0.9% Sodium Chloride, USP.
3. Withdraw 2 ml of solution from the SAPHNELO vial and add to the infusion bag. Mix the solution by gentle inversion. Don't shake.
4. Each vial is for single use only. Discard any unused portion remaining in the vial.
5. Administer the infusion solution immediately after preparation.
6. If the solution for infusion is not given immediately, store the diluted SAPHNELO solution for up to 4 hours at room temperature (59°F to 77°F, 15°C to 25°C) or in a refrigerator (36°F to 46°C). C). F, 2°C to 8°C) for up to 24 hours. Do not freeze. Protect from light. If refrigerated, allow the diluted SAPHNELO solution to reach room temperature prior to administration.
7. Administer the infusion solution intravenously over a 30 minute period through an infusion line containing a sterile, low protein, 0.2 to 15 micron in-line filter cartridge or supplemental filter.
8. To ensure the full dose of SAPHNELO has been administered, flush the entire IV line with 25 mL of 0.9% Sodium Chloride Injection, USP at the end of the infusion.
9. Do not administer other drugs simultaneously through the same infusion line.
10. Dispose of any unused drug or residue in accordance with local regulations.

HOW DELIVERED

Dosage forms and strengths

Injection: 300 mg/2 ml (150 mg/ml) as a clear to iridescent, colorless to pale yellow solution in a single dose vial.

Storage and handling

SAPHNELOInjection (anifrolumab-fnia) is a sterile, preservative-free, clear to iridescent, colorless to pale yellow solution for intravenous infusion. It is packaged in a 2 ml clear glass vial containing 300 mg/2 ml (150 mg/ml) anifrolomab-fnia.

SAPHNELOsupplied in a carton containing a single dose vial (NDC-0310-3040-00).

Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton in order to protect from light.

Do not freeze. Don't shake.

Manufacturer: AstraZeneca AB Sodertalje, Sweden SE-15185. Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850. Revised: September 2022

Side effects and drug interactions

side effects

The following clinically important adverse reactions are also listed elsewhere in the label:

• Serious infections [seeWARNINGS AND PRECAUTIONS]
• Hypersensitivity reactions IncludesAnaphylaxis[I seeWARNINGS AND PRECAUTIONS]
• Malice[I seeWARNINGS AND PRECAUTIONS]

Clinical trial experience

Because clinical trials are conducted under very different conditions, the rates of adverse reactions observed in clinical trials of one drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice .

The safety of SAPHNELO was evaluated for 52 weeks in patients with moderate to severe SLE who received anifrolumab-fnia 300 mg every 4 weeks as an intravenous infusion (N=459) compared to placebo (N=466) in controlled clinical trials (Tests). 1 , 2 and 3) [seeclinical studies]. The study population had a mean age of 41 years (range: 18 to 69), 93% female, 60% white, 13% black/African Americanand 10% Asian.

In controlled clinical trials, adverse reactions, regardless of etiology, were reported in 87% of SAPHNELO-treated patients and 79% of placebo-treated patients.

Adverse reactions occurring with a frequency greater than or equal to 2% are listed in Table 1.

Table 1 Adverse Reactions Occurring in ≥2% of Patients Receiving SAPHNELO 300 mg (Studies 1, 2, and 3) at Week 52

Specific side effects

Infections

In controlled clinical trials, infections were reported in a higher proportion of patients on SAPHNELO treatment compared to placebo (69.7% [320/459] vs. 55.4% [258/466]), consistent with incidence rates for exposure corrected (EAIR) 141.8 and 99.9 per 100 patient years (PY), respectively.

Serious infections

In controlled clinical trials, the incidence of serious infections during treatment was 4.8% (22/459) in patients treated with SAPHNELO compared to 5.6% (26/466) in patients treated with placebo, corresponding with EAIRs of 5.4 and 6.6 per 100 PY, respectively. The most common serious infection was pneumonia.

In controlled clinical trials, fatal infections occurred in 0.4% of patients receiving SAPHNELO and 0.2% of patients receiving placebo.

Shingles

In controlled clinical trials, the incidence of shingles in patients treated with SAPHNELO was 6.1% (28/459) and 1.3% (6/466) in patients treated with placebo, corresponding to EAIR 6.9, respectively. and 1.5 every 100 years. Cases with multicutaneous involvement and diffuse presentation have been reported. Of the 28 SAPHNELO-treated patients with herpes zoster, 2 developed disseminated disease requiring hospitalization, compared with none of the placebo-treated patients.

Hypersensitivity reactions including anaphylaxis

During the drug development program, there was one report of an anaphylactic reaction in a patient receiving 150 mg anifrolumab-fnia and two reports of angioedema after 300 mg. In general, hypersensitivity reactions were mostly mild or moderate in intensity and did not lead to discontinuation of SAPHNELO.

In controlled clinical trials, hypersensitivity reactions occurred in 2.8% (13/459) of patients treated with SAPHNELO and 0.6% (3/466) of patients treated with placebo, corresponding to an EAIR of 3.2 and 0.7 per 100 PY. . Serious hypersensitivity reactions were reported in 0.6% (3/459) of patients receiving SAPHNELO, including angioedema (n=2).

Infusion-related reactions

Infusion-related reactions were mild to moderate in severity. The most common symptoms were headache, nausea, vomiting, fatigue and dizziness.

In controlled clinical trials, the incidence of infusion-related reactions during treatment was 9.4% (43/459) in patients treated with SAPHNELO and 7.1% (33/466) in patients treated with placebo, corresponding to EAIRs of 11.1 and 8.7 per 100 PY, respectively.

Malignancies

In controlled clinical trials, malignancies (excluding non-melanoma skin cancer) were observed in 0.7% (3/459) and 0.6% (3/466) of patients receiving SAPHNELO and placebo, equivalent to EAIR 0.7 and 0.7 per 100 years. , respectively. Malignancy (including non-melanoma skin cancers) was reported in 1.3% (6/459) of SAPHNELO-treated patients compared to 0.6% (3/466) of placebo-treated patients (EAIR: 1, 3 and 0.7 per 100 years). ). Malignancies reported in more than one patient treated with SAPHNELO included breast cancer and squamous cell carcinoma.

immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. In addition, the observed incidence of antibody positivity (including neutralizing antibody) in an assay can be influenced by several factors, including assay methodology, sample handling, time of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to anifrolumab-fnia in the studies described below with the incidence of antibodies in other studies or other products may be misleading.

In studies 2 and 3, antibodies to anifrolomab-fnia were detected in 6 of 352 (1.7%) patients who received SAPHNELO at the recommended dosing regimen during the 60-week study period. The clinical significance of the presence of anti-anifrolumab fnia antibodies is not known.

INTERACTIONS WITH OTHER MEDICINES

No formal drug interaction studies have been performed.

Warnings and Precautions

WARNINGS

It is included as part of itPRECAUTIONARY MEASURESUnit.

PRECAUTIONARY MEASURES

Serious infections

Serious and sometimes fatal infections have occurred in patients receiving immunosuppressants, including SAPHNELO. In general, the incidence of serious infections in controlled trials was similar in patients treated with SAPHNELO compared to placebo, while fatal infections were more common in patients treated with SAPHNELO [seeUNWANTED ACTIONS].

In controlled trials, SAPHNELO increased the risk of respiratory infections and shingles (disseminated cases of shingles have been reported) [seeUNWANTED ACTIONS].

Consider the benefit and risk of administering SAPHNELO to patients with chronic infection, a history of recurrent infections, or known risk factors for infection. Avoid initiating SAPHNELO treatment in patients with a clinically significant active infection until the infection has resolved or has been adequately treated. Instruct patients to seek medical advice if signs or symptoms of clinically significant infection develop. If a patient develops an infection or does not respond to standard anti-infective therapy, monitor the patient closely and consider discontinuing SAPHNELO until the infection resolves.

Hypersensitivity reactions including anaphylaxis

Serious hypersensitivity reactions (including anaphylaxis) have been reported following administration of SAPHNELO [seeCONTRAINDICATIONS]. Cases of angioedema have also been reported [seeUNWANTED ACTIONS].

Other hypersensitivity and infusion-related reactions have occurred following administration of SAPHNELO [seeUNWANTED ACTIONS]. Consider premedication prior to infusion of SAPHNELO for patients with a history of these reactions.

SAPHNELO should be administered by healthcare professionals prepared to manage hypersensitivity reactions, including anaphylaxis, and infusion-related reactions. If a serious infusion-related reaction or hypersensitivity (e.g., anaphylaxis) occurs, discontinue SAPHNELO immediately and initiate appropriate treatment.

Malice

There is an increased risk of malignancies with the use of immunosuppressants. The effect of treatment with SAPHNELO on the potential development of malignancies is not known.

Consider the individual benefit-risk balance in patients with known risk factors for malignancy development or recurrence before prescribing SAPHNELO. In patients who develop malignancies, consider the benefit-risk balance of continuing SAPHNELO treatment.

Immunization

Be up to date with vaccinations, according to current immunization guidelines, before starting SAPHNELO therapy. Avoid concomitant use of live or live attenuated vaccines in patients treated with SAPHNELO.

Not recommended for simultaneous use with other biological treatments

SAPHNELO has not been studied in combination with other biologic therapies, including those targeting B cells. Therefore, the use of SAPHNELO is not recommended for use in combination with biologic therapies.

Patient counseling information

Advise patient to read FDA cleared patient labels (PATIENT INFORMATION).

Serious infections

Advise patients that SAPHNELO may impair their ability to fight infections and that serious infections, including fatal ones, have occurred in patients receiving SAPHNELO in clinical trials. Also inform patients that they are at increased risk of respiratory infections and herpes zoster during treatment with SAPHNELO [seeWARNINGS AND PRECAUTIONS]. Advise patients to contact their healthcare provider if they develop any symptoms of infection, including fever or flu-like symptoms. Muscle strain? cough; breathing difficulties; burning sensation when urinating or urinating more often than usual; diarrhea or stomach pain; shingles (a red skin rash that can be painful and burning).

Hypersensitivity reactions/anaphylaxis

Advise patients that serious hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving SAPHNELO. Instruct patients to immediately notify their healthcare provider or go to the nearest hospital emergency department if they develop symptoms of an allergic reaction (e.g., anaphylaxis) during or after administration of SAPHNELO [seeWARNINGS AND PRECAUTIONS]. Symptoms may include swelling of the face, tongue or mouth, difficulty breathing and/or fainting, dizziness, feeling light-headed (due to low blood pressure).

Vaccinations

Advise patients not to receive live or attenuated vaccines while receiving SAPHNELO. Advise patients to consult with their health care provider before seeking vaccinations themselves [seeWARNINGS AND PRECAUTIONS].

Pregnancy

Advise female patients to tell their healthcare provider if they plan to become pregnant during treatment, suspect they are pregnant, or become pregnant while receiving SAPHNELO [seeUse in specific populations].

Advise women that they can find information on a pregnancy exposure registry that tracks pregnancy outcomes in women exposed to SAPHNELO by calling AstraZeneca at 1-877-693-9268.

Nonclinical Toxicology

Carcinogenesis, mutagenesis, impaired fertility

The carcinogenic and genotoxic potential of anifrolumab-fnia has not been evaluated. An increased carcinogenic potential has been observed in IFNAR1 knockout rodent models. The clinical significance of these findings is unknown.

Effects on male and female fertility have not been directly evaluated in animal studies. No adverse reactions related to anifrolumab-fnia were observed in indirect measures of male or female fertility, based on semen analysis, staging of spermatogenesis, menstrual cycle, organ weight, and histopathological findings in reproductive organs in 9-month repeated dose toxicity studies in dosed cynomolgus monkeys to 50 mg/kg IV once weekly (approximately 58 times the MRHD based on AUC).

Use in specific populations

Pregnancy

Exposure registry during pregnancy

A pregnancy exposure registry tracks pregnancy outcomes in women exposed to SAPHNELO during pregnancy. For more information about the registry or to report a pregnancy while on SAPHNELO, contact AstraZeneca at 1-877-693-9268.

Risk summary

The limited human data on the use of SAPHNELO in pregnant women are insufficient to provide information on the drug-related risk of major congenital malformations, miscarriage, or adverse maternal or fetal outcomes. It is known that IgG monoclonal antibodies are actively transferred to the placenta as pregnancy progresses. Therefore, fetal exposure to anifrolumab may be greater during the third trimester of pregnancy.

In an enhanced pre- and post-natal study in pregnant cynomolgus monkeys receiving intravenous anifrolumab-fnia, there was no evidence of embryotoxicity or fetal malformations at exposures up to 28 times the exposure at the maximum recommended human dose. MRHD) based on area under the curve (AUC) (seeFacts).

All pregnancies carry a historical risk of birth defects, loss, or other adverse outcomes. The estimated historical risk of major birth defects and miscarriage for the indicated population is unknown. In the general US population, the estimated historical risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Risk to the mother and/or fetus associated with the disease

Pregnant women with SLE are at increased risk of adverse pregnancy outcomes, including worsening of the underlying disease, preterm delivery, miscarriage, and intrauterine growth retardation. Maternal lupus nephritis increases the risk of hypertension and preeclampsia/eclampsia. Passage of maternal autoantibodies across the placenta can lead to adverse neonatal outcomes, including neonatal lupus and congenital heart block.

Facts

Animal data

In a study of enhanced pre- and postnatal development, pregnant cynomolgus monkeys received anifrolumab-fnia at intravenous doses of 30 or 60 mg/kg once every 2 weeks from confirmation of pregnancy on day 20 of gestation, throughout gestation and up to 1 month after childbirth. (approximately Day 28 of Breastfeeding). There was no evidence of anifrolumab-related maternal toxicity, foetotoxicity, or effects on postnatal development. There was no anifrolomab-related effect on the T cell-dependent antibody response in infants up to postnatal day 180. The NOAEL (No Observed Adverse Effect Level) for maternal and developmental toxicity was determined to be 60 mg/kg (approximately 28 times the MRHD based on AUC). In infants, mean serum concentrations of anifrolumab-fnia at postnatal day 30 increased with dose and were approximately 4.2% to 9.7% of corresponding maternal concentrations. Concentrations of anifrolumab-fnia in infant serum were approximately 22 times higher than concentrations in breast milk, suggesting that anifrolumab-fnia was transferred across the placenta.

Breastfeeding

Risk summary

No data are available on the presence of SAPHNELO in human milk, effects on the suckling infant or effects on milk production. Anifrolumab-fnia was detected in the milk of female cynomolgus monkeys administered anifrolumab-fnia. Due to species-to-species differences in lactation physiology, animal data may not reliably predict drug levels in humans. Maternal IgG is known to be present in breast milk. If anifrolumab-phnia is excreted in human milk, the effects of local gastrointestinal exposure and the infant's limited systemic exposure to anifrolumab-phnia are unknown.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for anifrolumab-fnia and any adverse effects on the nursing infant from anifrolumab-fnia or the underlying maternal condition.

Use in children

The safety and efficacy of SAPHNELO in pediatric patients below 18 years of age have not been established.

Geriatric use

Of the 664 SLE patients exposed to anifrolumab-fnia in clinical trials, 3% (n=20) were 65 years of age or older. The number of patients aged 65 and over was not sufficient to determine whether they respond differently from younger adult patients.

Overdose & Contraindications

OVERDOSAGE

No information provided

CONTRAINDICATIONS

SAPHNELO is contraindicated in patients with a history of anaphylaxis with anifrolumab fnia [seeWARNINGS AND PRECAUTIONS].

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Action mechanism

Anifrolumab-fnia is a human IgG1κ monoclonal antibody that binds to type I interferon receptor (IFNAR) subunit 1 with high specificity and affinity. This binding inhibits type I IFN signaling, thereby blocking the biological activity of type I IFNs. Anifrolumab-fnia also induces the internalization of IFNAR1, reducing levels of cell surface IFNAR1 available for receptor assembly. Blockade of receptor-mediated type I IFN signaling inhibits IFN-responsive gene expression as well as downstream inflammatory and immune processes. Inhibition of type I IFN blocks plasma cell differentiation and normalizes peripheral T cell subsets.

Type I IFNs play a role in the pathogenesis of SLE. Approximately 60-80% of adult patients with active SLE express elevated levels of inducible type I IFN genes.

Pharmacodynamics

In patients with SLE, after administration of anifrolumab-fnia at a dose of 300 mg by intravenous infusion every 4 weeks for 52 weeks, neutralization (≥80%) of a type I IFN gene signature was observed from week 4 to week 52 in the blood samples of patients with elevated levels of inducible type I IFN genes and who returned to baseline within 8 to 12 weeks of discontinuing anifrolumab-fnia at the end of the 52-week treatment period. However, the clinical relevance of neutralizing the type I IFN gene signature is not clear.

In SLE patients with positive anti-dsDNA antibodies at baseline (Studies 2 and 3), treatment with anifrolumab-fnia 300 mg resulted in numerical reductions in anti-dsDNA antibodies over time through week 52.

In patients with low complement levels (C3 and C4), increases in complement levels were observed in patients receiving anifrolumab-fnia through week 52.

Pharmacokinetics

The pharmacokinetics of anifrolomab-fnia were studied in adult patients with SLE after intravenous doses ranging from 100 to 1000 mg every 4 weeks and in healthy volunteers after a single intravenous dose of 300 mg. Anifrolumab-fnia exhibits non-linear pharmacokinetics over the dose range of 100 mg to 1000 mg with greater than dose-proportional increases in exposure as measured by AUC. After intravenous administration of 300 mg anifrolumab-fnia every 4 weeks, steady state was reached by day 85. The accumulation ratio was approximately 1.36 for Cmax and 2.49 for Ctrough.

Distribution

Based on population pharmacokinetic analysis, the estimated steady-state volume of distribution for a typical SLE patient (69.1 kg) is 6.23 L.

Elimination

From population PK analysis, anifrolumab-fnia showed nonlinear PK due to IFNAR1-mediated drug clearance.

Following administration of anifrolumab-fnia at a dose of 300 mg by intravenous infusion every 4 weeks, the estimated systemic clearance (CL) for anifrolumab-fnia was 0.193 L/day.

Specific populations

There was no clinically significant difference in systemic clearance based on age, race, ethnicity, region, sex, IFN status, or body weight, requiring dose adjustment.

Age

Based on population pharmacokinetic analyses, age (range 18 to 69 years) did not affect the clearance of anifrolomab-fnia. Limited pharmacokinetic data are available in elderly patients. 3% (n=20) of patients included in the PK analysis were 65 years or older [seeUse in specific populations].

Kidney failure

No specific clinical studies have been conducted to investigate the effect of renal impairment on anifrolumab-fnia. Based on population pharmacokinetic analyses, clearance of anifrolumab-fnia was similar in SLE patients with mild (60-89 mL/min/1.73 m2) and moderate (30-59 mL/min/1.73 m2) reduction in eGFR values ​​and in patients with normal renal function (≥90 ml/min/1.73 m2). There were no SLE patients with severely decreased eGFR or end-stage renal disease (<30 ml/min/1.73 m2). Anifrolumab-fnia is not cleared via the kidneys.

Patients with UPCR >2 mg/mg were excluded from clinical studies. Based on population pharmacokinetic analyses, increased urinary protein to creatinine ratio (UPCR) did not significantly affect the clearance of anifrolomab-fnia.

Liver dysfunction

No specific clinical studies have been conducted to investigate the effect of hepatic impairment on anifrolumab-fnia. IgG1 monoclonal antibodies are eliminated primarily via catabolism and are not expected to undergo hepatic metabolism. changes in liver function are not expected to affect the clearance of anifrolomab-fnia. Based on population pharmacokinetic analyses, the major biomarkers of liver function (ALT and AST ≤2.0 × ULN and total bilirubin) had no clinically relevant effect on the clearance of anifrolumab-fnia.

Interactions with other medications

No formal drug interaction studies have been performed.

Based on population pharmacokinetic analysis, concomitant use of oral corticosteroids, antimalarials, immunosuppressants (azathioprine, methotrexate, mycophenolate mofetil, mycophenolic acid, and mizoribine), NSAIDs, ACE inhibitors, and HMG-CoA inhibitors did not significantly affect the PKF reduction of anifrolomab. fnia.

clinical studies

The safety and efficacy of SAPHNELO were evaluated in three 52-week treatment periods, multicenter, randomized, double-blind, placebo-controlled trials (Trial 1 [NCT01438489], Trial 2 [NCT02446912], and Trial 3 [NCT0244689]. Patients were diagnosed with SLE according to the classification criteria of the American College of Rheumatology (Revised 1982).All patients were ≥18 years of age and had moderate to severe disease, with SLE Disease Activity Index 2000 (SLEDAI-2K) score ≥6, organ level involvement based on BILAG assessment and Physician Global Assessment [PGA] score ≥1, receive standard SLE therapy consisting of one or a combination of oral corticosteroids (OCS), antimalarials, and/or immunosuppressants at baseline Patients continued to receive their existing fixed-dose SLE therapy during clinical trials, except for OCD (prednisone or equivalent) where tapering was part of the protocol Patients with severe active lupus nephritis and patients with severe active central nervous system lupus were excluded. The use of other biological agents and cyclophosphamide was not allowed during the tests. Patients receiving other biologic therapies were required to complete a washout period of at least 5 half-lives prior to admission. All three studies were conducted in North America, Europe, South America and Asia. Patients received anifrolumab-fnia or placebo every 4 weeks by intravenous infusion.

The efficacy of SAPHNELO was determined based on assessment of clinical response using the composite endpoints, the British Isles Lupus Composite Assessment (BICLA) and the SLE Response Index (SRI-4).

BICLA response at week 52 was defined as improvement in all organ domains with moderate or severe activity at baseline:

• Reduction of all baseline BILAG A to B/C/D and baseline BILAG B to C/D, and no worsening of BILAG in other organ systems, as defined by ≥1 new BILAG A or ≥2 new BILAG B.
• No deterioration from baseline on SLEDAI-2K, where deterioration is defined as an increase from baseline of >0 points on SLEDAI-2K.
• No worsening from baseline in patients' lupus disease activity, where worsening is defined by an increase of ≥0.30 points on a 3-point PGA VAS.
• No interruption of treatment.
• No use of restricted medication beyond the permissible limit of the protocol.

SRI-4 response was defined as meeting each of the following criteria at week 52 compared to baseline:

• A decrease from baseline of ≥4 points on the SLEDAI-2K.
• No new instrument system is affected as defined by 1 or more BILAG A items or 2 or more BILAG B items compared to baseline.
• No deterioration from baseline in patients' lupus disease activity defined by an increase of ≥0.30 points on a 3-point PGA visual analog scale (VAS).
• No interruption of treatment.
• No use of restricted medication beyond the permissible limit of the protocol.

Trial 1 randomized 305 patients (1:1:1) to anifrolumab-fnia, 300 mg or 1000 mg, or placebo for up to 52 weeks. The primary endpoint was a combined assessment of SRI-4 and sustained OCD reduction (<10 mg/day and ≤OCS dose at week 1, maintained for 12 weeks) measured at week 24.

Trials 2 and 3 were similar in design. Trial 2 randomized 457 patients to receive anifrolumab-fnia 150 mg, 300 mg, or placebo (1:2:2). Trial 3 randomized 362 patients (1:1) to anifrolumab-fnia 300 mg or placebo. The primary endpoints were improvement in disease activity assessed at 52 weeks as measured by SRI-4 in Trial 2 and BICLA in Trial 3 (defined above). Common secondary efficacy endpoints included in both studies were maintenance of OCD reduction, improvement in SLE skin activity, and flare frequency. During weeks 8-40, patients with baseline OCD ≥ 10 mg/day had their OCD dose reduced to ≤ 7.5 mg/day unless disease activity worsened. Both studies assessed the efficacy of anifrolumab-fnia 300 mg versus placebo. A dose of 150 mg was also assessed for dose response in Trial 2.

Patient demographics and disease characteristics were generally similar and well balanced across treatment arms (Table 2).

Table 2: Demographics and basic characteristics

Randomizationstratified by disease severity (SLEDAI-2K score at baseline, <10 vs. ≥10 points), OCD dose on day 1 (<10 mg/day vs. ≥10 mg/day prednisone or equivalent), and interferon genessignaturetest scores (high vs low);

The reduction in disease activity observed with BICLA and SRI-4 was mainly related to improvement of the mucosal and musculoskeletal organ systems. The number of flare-ups was reduced in patients receiving SAPHNELO compared to patients receiving placebo, although the difference was not statistically significant.

BICLA-responsanalyse

BICLA was the primary endpoint in study 3. Anifrolumab-fnia 300 mg demonstrated statistically significant and clinically meaningful efficacy in overall disease activity compared to placebo, with greater improvements in all components of the composite endpoint. In trials 1 and 2, the BICLA was a pre-specified assay. The BICLA results are presented in Table 3.

Tabel 3: BICLA-responspercentage in week 52

In Trial 3, examination of subgroups based on age, race, gender, ethnicity, disease severity [SLEDAI-2K at baseline] and OCD use at baseline revealed no differences in response to anifrolumab-fnia.

Figure 1 shows the percentage of subjects who responded to BICLA during the 52-week treatment period in Trial 3.

Figure 1: Trial 3: Percentage (%) of BICLA Responders by Visit*

* The same patients may not have responded at each time point.

SRI-4 responsanalyse

SRI-4 was the primary endpoint in Trial 2. Treatment with anifrolumab-fnia did not lead to statistically significant improvements over placebo. In Trials 1 and 3, the SRI-4 was a predetermined analysis. The SRI-4 results are presented in Table 4.

Table 4: SRI-4 Response Rate at Week 52

Effect on concomitant steroid treatment

In study 3, anifrolumab-fnia showed a statistically significant difference in the proportion of patients who were able to reduce OCD use by at least 25% to ≤7.5 mg/day in 47% of patients with baseline OCD use ≥10 mg/day day by day. Week 40 and maintain the reduction through Week 52 (p-value = 0.004). 52% (45/87) of patients in the anifrolumab-fnia group versus 30% (25/83) on placebo achieved this level of steroid reduction (difference 21% [95% CI 6.8, 35.7]). Consistent trends favoring anifrolumab-fnia compared to placebo in terms of the effect of reducing OCD use were observed in Trials 1 and 2, but the difference was not statistically significant.

Medication Guide

PATIENT INFORMATION

SAPHNELO®
(saf-NEH-low)
(anifrolumab-fnia) injection, for intravenous use

What is SAPHNELO?

• SAPHNELO is a prescription medicine used to treat adults with moderate to severe systemic lupus erythematosus (SLE or lupus) who are taking other medicines for lupus.
• SAPHNELO contains anifrolumab-fnia, which belongs to a group of medicines calledmonoclonalantibodies. Lupus is a disease of itimmune system(the body system that fights infections). In combination with other lupus drugs, SAPHNELO may help reduce the activity of lupus disease more than other lupus drugs alone.
• It is not known if SAPHNELO is effective in people with severe active lupus nephritis or central nervous system lupus.
• It is not known if SAPHNELO is safe and effective in children under 18 years of age.

Do not use SAPHNELO if:

• are allergic to anifrolumab-fnia or any of the ingredients in SAPHNELO. See the end of this Patient Information Leaflet for a full list of ingredients in SAPHNELO.

Before receiving SAPHNELO, tell your healthcare provider about all of your medical conditions, including if you:

• you think you have an infection or you have infections that keep coming back. You should not use SAPHNELO if you have an infection unless your healthcare provider tells you to. See "What are the possible side effects of SAPHNELO?"
• are scheduled to receive onevaccinationor if you think you need a vaccination. You may not receive livevaccinesduring treatment with SAPHNELO.
• you have or have had any form of cancer.
• other biological drugs or monoclonal antibodies.
• you are pregnant or planning to become pregnant. It is not known if SAPHNELO will harm your unborn baby. Tell your healthcare provider if you are pregnant, think you may be pregnant, or plan to become pregnant during your treatment with SAPHNELO.
  • Pregnancy exposure registry.If you become pregnant while taking SAPHNELO, call your healthcare provider. A pregnancy exposure registry tracks pregnancy outcomes in women exposed to SAPHNELO. You can find more information about the registry by calling AstraZeneca at 1-877-693-9268.
• breast-feeding or planning to breast-feed. It is not known if SAPHNELO passes into breast milk. Talk to your healthcare provider about the best way to feed your baby while taking SAPHNELO.

Tell your healthcare provider about all medications you are taking,including prescription and over-the-counter drugs, vitamins, and herbal supplements. SAPHNELO can affect the way other medicines work and other medicines can affect the way SAPHNELO works.

How do I get SAPHNELO?

• Your healthcare provider will give you SAPHNELO through a needle in a vein (IV or intravenous drip). It takes about 30 minutes for the full dose of SAPHNELO to be delivered to you.
• SAPHNELO is usually given once every 4 weeks.
• If you miss an appointment, call your healthcare provider as soon as possible to reschedule your appointment.

What are the possible side effects of SAPHNELO?

SAPHNELO can cause serious side effects such as:

• Serious infections.SAPHNELO may decrease your immune system's ability to fight infection. You may be at a higher risk of developing respiratory infections andherpes(Herpes zoster) during treatment with SAPHNELO. Infections can be serious and lead to hospitalization or death. Tell your healthcare provider right away if you have any of the following symptoms of infection:
  • fever, sweating or chills
  • burning during urination
  • muscle strain
  • urinate more often
  • cough
  • diarrhea or stomach pain
  • breathing difficulties
  • hot, red, or painful skin or sores on your body;
• Allergic (hypersensitivity) reactions, including anaphylaxis.Severe allergic reactions can occur during or after administration of SAPHNELO Injection. Tell your healthcare provider or get emergency help right away if you have any of the following symptoms of a severe allergic reaction:
  • swelling of your face, mouth, and tongue
  • pass outor dizziness
  • Breathing problems
  • Feeling dizzy (low bloodpressure)
• Cancer.SAPHNELO may decrease the activity of your immune system. Drugs that affect the immune system may increase the risk of certain cancers.

The most common side effects of SAPHNELO are:

• infections of the upper respiratory tract
• bronchitis
• infusion reactions
• shingles (herpesshingles)
• cough

These are not all the possible side effects of SAPHNELO.

Call your doctor for medical advice about side effects. You can report side effects to the FDA at 1-800-FDA-1088.

General information on the safe and effective use of SAPHNELO

Medicines are sometimes prescribed for purposes other than those stated in a package leaflet. If you want more information about SAPHNELO, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about SAPHNELO.

What are the ingredients of SAPHNELO?

Active Ingredient:anifrolomab-fnia

Inactive Ingredients:L-histidine, L-histidine hydrochloride monohydrate, L-lysine hydrochloride, trehalose dihydrate, polysorbate 80 and water for injections.

This patient information has been approved by the US Food and Drug Administration.