Consumer medicine information

Saphnelo

Anifrolumab

BRAND INFORMATION

Brand name

Saphnelo

Active ingredient

Anifrolumab

Schedule

SUMMARY CMI

SAPHNELO^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about taking this medicine, speak to your doctor or nurse.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I taking SAPHNELO?

SAPHNELO contains the active ingredient anifrolumab. SAPHNELO is used to treat moderate to severe lupus (systemic lupus erythematosus or SLE) in adults whose disease is not well controlled by standard treatment.

For more information, see Section 1. Why am I taking SAPHNELO? in the full CMI.

2. What should I know before I am given SAPHNELO?

Talk to your doctor if you have ever had an allergic reaction to anifrolumab or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, are pregnant or plan to become pregnant, or are breastfeeding.

For more information, see Section 2. What should I know before I'm given SAPHNELO? in the full CMI.

3. What if I am taking other medicines?

Tell your doctor or nurse if you are taking, have recently taken, or might take any other medicines.

For more information, see Section 3. What if I am taking other medicines? in the full CMI.

4. How is SAPHNELO given to you?

SAPHNELO will be given to you in a hospital or clinic by a doctor or nurse.

More instructions can be found in Section 4. How is SAPHNELO given to you? in the full CMI.

5. What should I know while taking SAPHNELO?

Things you should do	Remind any doctor, dentist or nurse you visit that you are taking SAPHNELO. Keep your appointments with your doctor so that you do not miss a dose and your progress is monitored.
Things you should not do	Do not stop taking this medicine suddenly, unless you have discussed this with your doctor.
Driving or using machines	Be careful before you drive or use any machines or tools until you know how SAPHNELO affects you.
Call your doctor straight away if you	Become pregnant while taking SAPHNELO Have an infection while you are being treated with SAPHNELO, have had a serious allergic reaction to SAPHNELO (anaphylaxis), plan to have an immunisation (vaccine), or are diagnosed with cancer
Looking after your medicine	SAPHNELO will be stored by your healthcare providers at the hospital or clinic where you receive treatment.

For more information, see Section 5. What should I know while taking SAPHNELO? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. The most common side effects are headache, feeling sick, being sick, feeling tired or weak and dizziness (infusion-related reaction), rash, redness, itching or swelling of the skin where you have received SAPHNELO (hypersensitivity). The more serious side effects are fever or flu-like symptoms, body aches, cough, chest pain, shortness of breath, wheezing or sore throat (infection of the nose, throat, airways or chest, sinuses or lungs), red skin rash that can cause pain and burning (shingles).

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

FULL CMI

SAPHNELO^®

Active ingredient: anifrolumab

Consumer Medicine Information (CMI)

This leaflet provides important information about taking SAPHNELO. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking SAPHNELO.

Where to find information in this leaflet:

1. Why am I taking SAPHNELO?
2. What should I know before I am given SAPHNELO?
3. What if I am taking other medicines?
4. How is SAPHNELO given to you?
5. What should I know while taking SAPHNELO?
6. Are there any side effects?
7. Product details

1. Why am I taking SAPHNELO?

SAPHNELO contains the active ingredient anifrolumab. SAPHNELO is a monoclonal antibody (a type of specialised protein) that blocks the action of a group of proteins called Type I Interferons (IFN). Type I interferons are found at high levels in people with lupus and blocking them can reduce the inflammation in your body that causes the signs and symptoms of lupus.

SAPHNELO is used to treat moderate to severe lupus (systemic lupus erythematosus or SLE) in adults whose disease is not well controlled by standard treatment. You will be given SAPHNELO as well as your usual treatment for lupus.

Lupus is a disease in which the immune system (the system in the body that fights infections) attacks your own cells and tissues, causing inflammation and organ damage. It can affect almost any organ in the body, including skin, joints, kidneys, brain and other organs, and can cause pain, rashes, fatigue, swelling in joints, and fevers.

2. What should I know before I am given SAPHNELO?

Warnings

Do not take SAPHNELO if:

you are allergic to anifrolumab or any of the ingredients listed at the end of this leaflet

Check with your doctor if you:

have any other medical conditions
take any medicines for any other conditions
have a long term infection or if you have an infection that keeps coming back
get an infection or have symptoms of an infection.
Symptoms may include fever or flu-like symptoms, muscle or joint aches, cough, shortness of breath, stinging or burning while urinating, diarrhoea or stomach pain, shingles (a red skin rash that can cause pain and burning)
think you have had an allergic reaction. Symptoms may include swelling of your face, tongue or mouth, breathing difficulties, feeling faint, dizzy or lightheaded
have recently had or plan to have an immunisation (vaccine)
have, or have had, cancer
if your lupus affects your kidneys or nervous system
if you are receiving another biologic medicinal product (such as belimumab for your lupus)

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. It is not known if SAPHNELO can harm your unborn baby. Your doctor will decide if you can be given SAPHNELO.

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is not known whether SAPHNELO is passed into breast milk. Your doctor will discuss with you whether you should stop treatment with SAPHNELO while you are breastfeeding or if you should stop breastfeeding.

Children and adolescents

SAPHNELO should not be used in children and adolescents below 18 years of age.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect SAPHNELO.

4. How is SAPHNELO given to you?

SAPHNELO will be given to you in a hospital or clinic.

A doctor or nurse will give you SAPHNELO through a drip in your vein (intravenous infusion) over 30 minutes, every 4 weeks
The recommended dose is 300 mg

If you miss an appointment to get SAPHNELO

Call your doctor as soon as possible to reschedule your appointment
It is important that you do not miss a dose of SAPHNELO

If you stop taking SAPHNELO

Do not stop treatment with SAPHNELO unless you have discussed this with your doctor
If you have any further questions about your treatment, ask your doctor

5. What should I know while taking SAPHNELO?

Things you should do

Remind your doctor, dentist or nurse you visit that you are taking SAPHNELO
Keep your appointments with your doctor so that you do not miss a dose and your progress is monitored

Call your doctor straight away if you:

become pregnant while taking SAPHNELO
have an infection while you are being treated with SAPHNELO. Your doctor will want to check that your infection is being properly treated. Symptoms may include fever or flu-like symptoms, muscle or joint aches, cough, shortness of breath, stinging or burning while urinating, shingles (a red skin rash that can cause pain and burning)
have had a serious allergic reaction to SAPHNELO.
Symptoms may include swelling of your face, tongue or mouth, breathing difficulties, feeling faint, dizzy or lightheaded
plan to have an immunisation (vaccine)
are diagnosed with cancer

Things you should not do

Do not stop taking this medicine suddenly, unless you have discussed this with your doctor

Driving or using machines

Be careful before you drive or use any machines or tools until you know how SAPHNELO affects you.

It is not expected that SAPHNELO will affect your ability to drive or use any machines or tools. Be careful if you feel tired, dizzy, or have a headache.

Looking after your medicine

SAPHNELO will be stored by your healthcare providers at the hospital or clinic where you receive treatment.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Other side effects	What to do
rash, redness, itching or swelling of the skin where you have received SAPHNELO as they may be symptoms of a less severe allergic reaction (hypersensitivity) headache, feeling sick (nausea), being sick (vomiting), feeling tired or weak (fatigue) and dizziness as they may be symptoms of an infusion-related reaction joint pain (arthralgia)	Speak to your doctor if you have any of these less serious side effects and they worry you.

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Serious side effects

Serious side effects

What to do

swelling of your face, tongue or mouth, breathing difficulties, feeling faint, dizzy or lightheaded as these may be symptoms of a serious allergic reaction (anaphylaxis)
fever or flu-like symptoms, body aches, cough, chest pain, shortness of breath, wheezing or sore throat as they may be symptoms of an infection of the nose, throat, airways or chest (bronchitis), sinuses (sinusitis) or lungs
red skin rash that can cause pain and burning as this may be a symptom of shingles (herpes zoster)

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

The above list includes serious side effects that require medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What SAPHNELO contains

Active ingredient (main ingredient)	anifrolumab
Other ingredients (inactive ingredients)	histidine, histidine hydrochloride monohydrate, lysine hydrochloride, trehalose dihydrate, polysorbate 80, and water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What SAPHNELO looks like

SAPHNELO (AUST R 350930) is a clear to opalescent, colourless to slightly yellow concentrated solution supplied in a clear vial closed by a rubber stopper with an aluminium seal. There is 1 vial in each pack.

Who distributes SAPHNELO

AstraZeneca Pty Ltd
ABN 54 009 682 311
66 Talavera Road
Macquarie Park NSW 2113
Telephone: 1800 805 342

This leaflet was prepared in June 2024.

SAPHNELO is a registered trade mark of the AstraZeneca group of companies.

VV-RIM-04931514 V2.0

Published by MIMS August 2024

BRAND INFORMATION

Brand name

Saphnelo

Active ingredient

Anifrolumab

Schedule

1 Name of Medicine

Anifrolumab.

2 Qualitative and Quantitative Composition

Each mL of concentrate for solution for infusion contains 150 mg of anifrolumab.
One vial of 2.0 mL of concentrate contains 300 mg of anifrolumab.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Concentrate for solution for infusion (sterile concentrate).
Clear to opalescent, colourless to slightly yellow solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Saphnelo (anifrolumab) is indicated as add on treatment of adult patients with moderate to severe, active systemic lupus erythematosus (SLE), despite standard therapy.
The safety and efficacy of Saphnelo have not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus.

4.2 Dose and Method of Administration

Treatment should be initiated and supervised by a physician experienced in the treatment of SLE.
Discontinuation of treatment with Saphnelo should be considered if there is no improvement in disease control after 6 months of treatment.

Dosage.

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

Missed dose.

If a planned infusion is missed, administer Saphnelo as soon as possible. A minimum interval of 14 days should be maintained between doses.

Method of administration.

Saphnelo is for intravenous (IV) use.
Following dilution with sodium chloride (0.9%) solution for injection, Saphnelo is administered as an IV infusion over a 30 minute period. Do not administer as an intravenous push or bolus injection.
The infusion rate may be slowed or interrupted if the patient develops an infusion reaction.
Saphnelo is supplied as a single-dose vial. The solution for infusion should be prepared and administered by a healthcare professional, using aseptic technique as follows:

Preparation of solution.

1. Visually inspect the vial for particulate matter and discolouration. Saphnelo is a clear to opalescent, colourless to slightly yellow solution. Discard the vial if the solution is cloudy, discoloured or visible particles are observed. Do not shake the vial.
2. Withdraw and discard 2.0 mL from an infusion bag containing 50 mL or 100 mL of sodium chloride 9 mg/mL (0.9%) solution for injection.
3. Withdraw 2.0 mL from the vial of Saphnelo and add it to the infusion bag. Mix the solution by gentle inversion. Do not shake.
4. The concentrate does not contain any preservatives. Product is for single use in one patient only. Any concentrate remaining in the vial must be discarded.

Administration.

1. It is recommended that the solution for infusion be administered immediately after preparation. If the solution for infusion has been stored in a refrigerator (see Section 6.3 Shelf Life), allow it to reach room temperature (15 to 25°C) prior to administration.
2. Administer the infusion solution intravenously over 30 minutes through an IV line containing a sterile, low-protein binding 0.2 to 15 micron in-line or add-on filter.
3. To ensure the complete dose of Saphnelo has been administered, flush the infusion set with 25 mL sodium chloride 9 mg/mL (0.9%) solution for injection at the end of the infusion.
4. Do not co-administer other medicinal products through the same infusion line.

Special populations.

Renal impairment.

No specific studies with Saphnelo have been conducted in patients with renal impairment. Based on population pharmacokinetic analysis no dose adjustment is required in patients with mild (eGFR 60-89 mL/min/1.73 m²) renal impairment. There is no experience in patients with severe active lupus nephritis, severe renal impairment or end-stage renal disease who were all excluded from the clinical studies (see Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

No specific studies have been conducted in patients with hepatic impairment. Based on population pharmacokinetic analysis no dose adjustment is required for patients with mild to moderate hepatic impairment.

Use in the elderly.

No dose adjustment is required. There is limited information in subjects aged ≥ 65 years (see Section 5.2 Pharmacokinetic Properties).

Paediatric use.

The safety and efficacy of Saphnelo in children and adolescents (aged < 18 years old) have not yet been established. No data are available.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed, see Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

Hypersensitivity.

Serious hypersensitivity reactions including anaphylaxis have been reported following Saphnelo administration (see Section 4.8 Adverse Effects (Undesirable Effects)).
In the placebo-controlled 52-week clinical trials, serious hypersensitivity events (including angioedema) were reported for 0.6% (3/459) of patients receiving anifrolumab. There was one event of anaphylactic reaction in the SLE development program following the administration of anifrolumab.
If a serious infusion-related or hypersensitivity reaction (e.g. anaphylaxis) occurs, administration of Saphnelo should be interrupted immediately, and appropriate therapy initiated.

Infections.

Saphnelo increases the risk of respiratory infections and herpes zoster (disseminated herpes zoster events have been observed), see Section 4.8 Adverse Effects (Undesirable Effects). SLE patients also taking immunosuppressants may be at higher risk of herpes zoster infections.
In the placebo-controlled 52-week clinical trials, serious and sometimes fatal infections have occurred in patients receiving anifrolumab.
In the placebo-controlled long-term extension (LTE), up to an additional 3 years on treatment, serious infections in patients receiving anifrolumab and placebo were similar to those observed in the 52-week trials.
Due to the mechanism of action, Saphnelo should be used with caution in patients with a chronic infection, a history of recurrent infections, or known risk factors for infection. Treatment with Saphnelo should not be initiated in patients with any clinically significant active infection until the infection resolves or is adequately treated. Instruct patients to seek medical advice if signs or symptoms of clinically significant infection occur. If a patient develops an infection, or is not responding to standard therapy, monitor the patient closely and consider interrupting Saphnelo therapy until the infection resolves.
Studies in patients with a history of primary immunodeficiency have not been conducted.
The placebo-controlled clinical trials excluded patients with a history of active tuberculosis (TB) or latent TB in whom an adequate course of treatment could not be confirmed. Anti-tuberculosis (anti-TB) therapy should be considered prior to initiation of anifrolumab in patients with untreated latent TB. Anifrolumab should not be administered to patients with active TB.

Immunisations.

No data are available on the response to vaccines.
Prior to initiating therapy with Saphnelo, consider completion of all appropriate immunisations according to current immunisation guidelines. Avoid concurrent use of live or attenuated vaccines in patients treated with Saphnelo.

Malignancy.

There is an increased risk of malignancies with the use of immunomodulating agents. The impact of Saphnelo treatment on the potential development of malignancies is not known. Caution should be exercised when considering anifrolumab therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop malignancy.
In the placebo-controlled 52-week clinical trials, at any dose, malignant neoplasm (including non-melanoma skin cancers) was reported for 1.2% patients receiving Saphnelo, compared to 0.6% patients receiving placebo (corresponding to exposure-adjusted incidence rates [EAIRs]: 1.2 and 0.7 events per 100 patient years, respectively). Malignancies excluding non-melanoma skin cancers were observed in 0.7% and 0.6% of patients receiving anifrolumab and placebo, respectively. In patients receiving Saphnelo, breast and squamous cell carcinoma were the malignancies observed in more than one patient.
The EAIRs for malignancy over 4 years (3-year long-term extension combined with the 52-week trials) were 0.8 and 0.7 events per 100 patient years for anifrolumab (at any dose) and placebo, respectively.

Concomitant use with B-cell targeted 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.

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Use in the elderly.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed with Saphnelo.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effects of anifrolumab on human fertility.
Animal studies show no adverse effects of anifrolumab treatment on indirect measures of fertility.
Effects on male and female fertility have not been directly evaluated in animal studies. In the 9 month repeat dose study, there were no anifrolumab-related adverse effects on indirect measures of male or female fertility, based on semen analysis, spermatogenesis staging, menses cycle, organ weights and histopathological findings in the reproductive organs, in cynomolgus monkeys at doses up to 50 mg/kg IV once weekly (approximately 58 times the maximum recommended human dose [MRHD] on an area under the plasma drug concentration over time curve [AUC] basis).
(Category C)
There is a limited amount of data from the use of anifrolumab in pregnant women. The data are insufficient to inform on drug associated risk.
In a pre- and postnatal development study, conducted in cynomolgus monkeys, there were no maternal, embryofetal, or postnatal developmental effects observed for anifrolumab doses 30 or 60 mg/kg administered intravenously from Gestation Day 20, once every 2 weeks thereafter, throughout gestation to 1 month postpartum (approximately Lactation Day 28). Exposures were up to approximately 28 times the exposure at the MRHD on an AUC basis. Anifrolumab could be detected in infant circulation, likely due to placental transfer. A higher risk of certain viral infections could theoretically occur in infants exposed to anifrolumab during the later stage of the gestational period; however, there is no data to support this.
Saphnelo should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.
It is not known whether anifrolumab is excreted in human milk. Anifrolumab was detected in the milk of female cynomolgus monkeys administered, 30 or 60 mg/kg, intravenously every 2 weeks.
A risk to the breast-fed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Saphnelo therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.

4.7 Effects on Ability to Drive and Use Machines

Saphnelo has no or negligible influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The most commonly reported adverse drug reactions (> 5%) during anifrolumab treatment were upper respiratory tract infection (32.9%), bronchitis (10.5%), infusion-related reaction (9.4%) and herpes zoster (6.1%) (see Table 1). The most common serious adverse drug reaction was herpes zoster (0.4%).

Adverse drug reactions.

The data described in Table 1 reflect the exposure to Saphnelo 300 mg administered by IV infusion every 4 weeks compared to placebo in 925 patients with moderate or severe SLE, in the 52 week Phase II and Phase III placebo-controlled trials (Trials 1, 2, and 3).
Adverse drug reactions (ADRs) are organised by MedDRA System Organ Class (SOC). Within each SOC, preferred terms are arranged by decreasing frequency and then by decreasing seriousness. Frequencies of occurrence of adverse reactions are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data).

Description of selected adverse reactions.

Hypersensitivity and infusion-related reactions.

Hypersensitivity reactions were predominantly mild to moderate in intensity and did not lead to discontinuation of anifrolumab. Following treatment with anifrolumab, serious hypersensitivity was reported in 0.6% of patients in the controlled clinical-trials and one event of anaphylactic reaction was reported in the SLE development program (see Section 4.4 Special Warnings and Precautions for Use).
Infusion-related reactions were mild or moderate in intensity, the most common symptoms were headache, nausea, vomiting, fatigue, and dizziness.

Respiratory infections (upper respiratory tract infection, respiratory tract infection and bronchitis).

Infections were predominantly non-serious, mild or moderate in intensity and resolved without discontinuation of anifrolumab (see Section 4.4 Special Warnings and Precautions for Use).

Herpes zoster.

Herpes zoster infections were predominantly of localised cutaneous presentation, mild or moderate in intensity and resolved without discontinuation of anifrolumab. Cases with multidermatomal involvement and disseminated presentation have been reported (see Section 4.4 Special Warnings and Precautions for Use).
In the LTE, the EAIR of herpes zoster in patients treated with Saphnelo declined over time relative to the 52-week trials. By year 4 on treatment the EAIR of herpes zoster in patients treated with Saphnelo and placebo were similar.

Adverse events.

Adverse events were reported in 86.9% of patients receiving anifrolumab and 79.4% of patients receiving placebo. The most commonly reported adverse events (≥ 5%) during anifrolumab treatment, irrespective of causality, were nasopharyngitis, upper respiratory tract infection, urinary tract infection, bronchitis, infusion related reaction, headache, herpes zoster, back pain, sinusitis and cough.
During the placebo-controlled 52-week clinical trials, the proportion of patients with serious adverse events was 11.8% for anifrolumab and 16.7% for placebo.
The proportion of patients who discontinued treatment due to adverse events was 4.1% for anifrolumab and 5.2% for placebo.
Table 2 presents the most common adverse events regardless of causality occurring in at least ≥ 3% treated with Saphnelo 300 mg administered by IV infusion every 4 weeks plus standard of care in the 52-week Phase II and Phase III placebo-controlled trials (Trials 1, 2, and 3).

Long-term safety.

Patients who completed Trials 2 and 3 (Phase III feeder trials) through Week 52 were eligible to continue on treatment in a randomised, double-blind, placebo-controlled LTE for an additional 3 years (Trial 4, see Section 5.1 Pharmacodynamic Properties). The long-term safety of Saphnelo was assessed in 257 patients who received anifrolumab 300 mg administered by intravenous infusion once every 4 weeks, compared to 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 anifrolumab was consistent with the 52-week trials.
During Trial 4, the EAIR of adverse events leading to discontinuation was 1.9 and 2.1 per 100 patient years for patients receiving anifrolumab and placebo, respectively. The EAIR of serious adverse events was 8.6 per 100 patient years for anifrolumab and 11.4 per 100 patient years for placebo.

Summary of post-marketing data.

The following adverse reactions have been identified during post-approval use of Saphnelo. It is generally not possible to reliably determine the frequency because such reactions have been reported spontaneously from a population of uncertain size and therefore represent reporting rates. The frequency of these adverse reactions is therefore 'not known' (cannot be estimated from available data).

Musculoskeletal and connective tissue disorders.

Arthralgia.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

In clinical trials, doses of up to 1000 mg have been administered intravenously in patients with SLE with no evidence of dose limiting toxicities.
There is no specific treatment for an overdose with anifrolumab. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Anifrolumab is a human immunoglobulin G1 kappa monoclonal antibody that binds to subunit 1 of the type I interferon receptor (IFNAR1) with high specificity and affinity. This binding inhibits type I IFN signalling thereby blocking the biological activity of type I IFNs. Anifrolumab also induces the internalisation of IFNAR1, thereby reducing the levels of cell surface IFNAR1 available for receptor assembly. Blockade of receptor mediated type I IFN signalling inhibits IFN responsive gene expression as well as downstream inflammatory and immunological processes. Inhibition of type I IFN blocks plasma cell differentiation and normalises peripheral T cell subsets, restoring the balance between adaptive and innate immunity that is dysregulated in multiple autoimmune disorders.
Type I IFNs play an important role in the pathogenesis of SLE. Most adult patients with SLE (approximately 60-80%) express elevated levels of type I IFN inducible genes, which are associated with increased disease activity and severity.

Pharmacodynamic effects.

In adult patients with SLE, administration of anifrolumab at doses ≥ 300 mg, via IV infusion every 4 weeks, demonstrated consistent neutralisation (≥ 80%) of a 21 gene type I interferon pharmacodynamic (PD) signature in blood. This suppression occurred as early as 4 weeks post-treatment and was either maintained or further suppressed over the 52-week treatment period. Anifrolumab 150 mg IV, showed < 20% suppression of the gene signature at early timepoints, that reached a maximum of < 60% by the end of the treatment period.
Neutralisation (≥ 70%) of the type I IFN PD signature has also been observed in skin tissue as shown in a Phase I trial in patients with scleroderma (anifrolumab ≥ 1.0 mg/kg).
Following withdrawal of anifrolumab at the end of the 52-week treatment period in the SLE clinical trials, the type I IFN PD signature in blood samples returned to baseline levels within 8 to 12 weeks.
In the Phase III trials in SLE patients positive for anti-dsDNA antibodies at baseline, treatment with anifrolumab 300 mg led to numerical reductions in anti-dsDNA antibodies over time (median change from baseline at Week 52: -14.82 U/mL anifrolumab vs -5.37 U/mL placebo). At Week 52, 7.8% (13/167) of patients treated with anifrolumab and 5.8% (9/155) of patients receiving placebo had converted to anti-dsDNA negative.
In patients with low C3 levels at baseline, treatment with anifrolumab 300 mg led to greater numerical increases in C3 over the 52-week treatment period (mean change from baseline at Week 52: 0.13 g/L anifrolumab vs 0.04 g/L placebo). For patients with an abnormal C4 level at baseline, small increases were observed over the 52 weeks in both treatment groups (mean change from baseline at Week 52: 0.02 g/L anifrolumab vs 0.02 g/L placebo). In patients with low complement levels at baseline, normalisation of C3 and C4 was observed in 16.2% (21/130) and 22.6% (19/84) of patients receiving anifrolumab and in 9.5% (13/137) and 7.1% (6/85) of patients receiving placebo, respectively, at Week 52.
Treatment with anifrolumab 300 mg led to significantly (p < 0.05) increased numbers of T-cell subsets in patients with a high interferon gene signature. Normalised T-cell subset counts were observed as early as Week 12 and through Week 52.
Compared with placebo, anifrolumab 300 mg inhibited the production of proteins involved in B cell survival and recruitment (CXCL13, BAFF). Inhibition was observed as early as Week 12 and maintained through Week 52, which is consistent with the down regulation of certain autoantibody levels by anifrolumab.

Immunogenicity.

In the Phase III trials, treatment-emergent anti-drug antibodies were detected in 6 out of 352 (1.7%) patients treated with Saphnelo at the recommended dosing regimen during the 60 week study period. A total of 0.3% (1/351) of patients treated with Saphnelo developed in-vitro detected neutralising antibodies. Anti-anifrolumab antibodies were not associated with increased clearance of anifrolumab or loss of pharmacodynamic activity compared to anti-drug antibody negative patients. No evidence of an association of anti-drug antibodies with efficacy or safety was observed.
In the LTE (years 2 through 4 on treatment), treatment-emergent anti-drug antibodies were detected in an additional 5 patients treated with Saphnelo, no neutralising antibodies were detected.

Clinical trials.

The safety and efficacy of Saphnelo were evaluated in three 52 week treatment period, multicentre, randomised, double-blind, placebo-controlled trials (Trial 1 [MUSE], Trial 2 [TULIP 1] and Trial 3 [TULIP 2]). Patients were diagnosed with SLE according to the American College of Rheumatology (1997) classification criteria.
All patients were ≥18 years of age and had moderate to severe disease, with a SLE Disease Activity Index 2000 (SLEDAI-2K) score ≥ 6 points, organ level involvement based on BILAG assessment, and a Physician's Global Assessment [PGA] score ≥ 1, despite receiving standard SLE therapy consisting of either one or any combination of oral corticosteroids (OCS), antimalarials and/or immunosuppressants at baseline. Patients continued to receive their existing SLE therapy at stable doses during the clinical trials, with the exception of OCS (prednisone or equivalent) where tapering was a component of the protocol. Patients who had severe active lupus nephritis and patients who had severe active central nervous system lupus were excluded. The use of other biologic agents and cyclophosphamide were not permitted during the clinical trials; patients receiving other biologic therapies were required to complete a wash-out period of at least 5 half-lives prior to enrolment. All three trials were conducted in North America, Europe, South America and Asia. Patients received anifrolumab or placebo, administered by intravenous infusion, every 4 weeks.
In Trial 1, 305 patients were randomised (1:1:1) and received anifrolumab 300 mg or 1000 mg, or placebo. The primary endpoint was a combined assessment of the SLE Responder Index (SRI-4, a composite endpoint) and the sustained reduction in OCS (< 10 mg/day and ≤ OCS dose at week 1, sustained for 12 weeks) measured at Week 24; a significantly higher proportion of anifrolumab 300 mg-treated patients achieved SRI-4 response and sustained OCS reduction (anifrolumab: placebo 34.3% vs 17.6%). Pre-specified analysis of disease activity measured by the British Isles Lupus Assessment Group based Composite Lupus Assessment (BICLA) was 53.5% for anifrolumab and 25.1% for placebo at Week 52. The dose-response modelling and benefit-risk profile supported the evaluation of the 300 mg dose in the subsequent trials; the 1000 mg dose is not recommended.
The Phase III trials, Trial 2 (N=457) and Trial 3 (N=362), were similar in design, the primary endpoint was improvement in disease activity evaluated at 52 weeks, measured by the composite endpoints SRI-4 and BICLA, respectively. The common secondary efficacy endpoints included in both trials were maintenance of OCS reduction, improvement in cutaneous SLE activity measured by Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), joint activity and annualised flare rate. Both trials evaluated the efficacy of anifrolumab 300 mg versus placebo; a dose of 150 mg was also evaluated for dose-response in Trial 2. There was no consistent pattern of efficacy across the endpoints or over time in patients receiving anifrolumab 150 mg. The 150 mg dose is not recommended. The results summarised below are those for the recommended dosing regimen (see Section 4.2 Dose and Method of Administration).
Patient demographics were generally similar in both trials; the median age was 41.3 and 42.1 years (range 18-69), 4.4% and 1.7% were ≥ 65 years of age, 92% and 93% were female, 71% and 60% were White, 14% and 12% were Black/African American, and 5% and 17% were Asian, in Trials 2 and 3, respectively. In both trials, 72% of patients had high disease activity (SLEDAI 2K score ≥ 10). In Trials 2 and 3, respectively, 48% and 49% had severe disease (BILAG A) in at least 1 organ system and 46% and 47% of patients had moderate disease (BILAG B) in at least 2 organ systems. The most commonly affected organ systems (BILAG A or B at baseline) were the mucocutaneous (Trial 2: 87%, Trial 3: 85%) and musculoskeletal (Trial 2: 89%, Trial 3: 88%) systems; 7.4% and 8.8% of patients had cardiorespiratory, and 7.9% and 7.5% had renal manifestations at baseline, in Trials 2 and 3, respectively.
In Trials 2 and 3, 90% of patients (both trials) were seropositive for anti-nuclear antibodies (ANA), and 45% and 44% for anti-double-stranded DNA (anti-dsDNA) antibodies; 34% and 40% of patients had low C3, and 21% and 26% had low C4. In both trials, the majority of patients were classified as interferon gene signature test-high at baseline (Trial 2: 82%, Trial 3: 83%).
Baseline concomitant standard therapy medications included oral corticosteroids (Trial 2: 83%, Trial 3: 81%), antimalarials (Trial 2: 73%, Trial 3: 70%) and immunosuppressants (Trial 2: 47%, Trial 3: 48%; including azathioprine, methotrexate, mycophenolate and mizoribine). For those patients taking OCS (prednisone or equivalent) at baseline, the mean daily dose was 12.3 mg in Trial 2 and 10.7 mg in Trial 3. During Weeks 8-40, patients with a baseline OCS ≥ 10 mg/day were required to taper their OCS dose to ≤ 7.5 mg/day, unless there was worsening of disease activity.
Randomisation was stratified by disease severity (SLEDAI 2K score at baseline, < 10 vs ≥ 10 points), OCS dose on Day 1 (< 10 mg/day vs ≥ 10 mg/day prednisone or equivalent) and interferon gene signature test results (high vs low). The results are presented in Table 3. For consistency, the results presented for Trial 2 represent the post hoc analysis using the restricted medication thresholds as defined in Trial 3.

In Trial 3, clinically meaningful differences in BICLA response rate was observed as early as Week 8 and were maintained through to Week 52 (Figure 1). Similar findings were seen in Trial 2.

Treatment with anifrolumab reduced the time to the first visit at which BICLA response was attained and subsequently sustained up to, and including, Week 52. At any time during Trial 3, patients treated with anifrolumab were 55% more likely to achieve a sustained BICLA response, relative to patients receiving placebo (hazard ratio [HR] = 1.55, 95% CI 1.11, 2.18). Separation between the treatment arms began at approximately Week 4 (Figure 2). Similar findings were seen in Trial 2.

The treatment effect of anifrolumab relative to placebo, as measured by BICLA response, was consistent across subgroups (by age, gender, race, ethnicity, disease severity [SLEDAI-2K at baseline] and baseline OCS use).
In patients with a baseline OCS use ≥ 10 mg/day, the cumulative OCS dose was lower in patients treated with anifrolumab. The median (min, max) cumulative OCS dose at Week 52 was 3229 mg (718, 9893) versus 3697 mg (988, 11988) in Trial 2 and 3197 mg (309, 13265) versus 3640 mg (1745, 10920) in Trial 3 for the anifrolumab and placebo groups, respectively.
In patients with moderate to severe skin disease (CLASI score ≥ 10 at baseline), the improvement in cutaneous SLE lesions measured at Week 12 (Table 2) was maintained through Week 52. At any time during the treatment period, respectively in Trials 2 and 3, patients receiving anifrolumab were 91% and 55% more likely to achieve a sustained CLASI response (defined as a ≥ 50% reduction in CLASI activity score, in the subgroup of subjects with baseline CLASI activity score ≥ 10, that was attained at any time during the study and subsequently sustained at all visits through to Week 52), relative to patients receiving placebo (Trial 2 HR = 1.91, 95% CI 1.14, 3.27; Trial 3 HR = 1.55, 95% CI 0.87, 2.85).
In Trials 2 and 3, respectively, 63.9% (115/180) and 68.9% (124/180) of patients receiving anifrolumab experienced no SLE flares compared to 56.5% (104/184) and 57.7% (105/182) of patients receiving placebo, during the 52-week treatment period. The time to first flare was longer in the anifrolumab group, at any time during the study patients had a 35% lower risk of experiencing a first flare relative to patients receiving placebo (Trial 2 HR = 0.76, 95% CI 0.55, 1.06; Trial 3 HR = 0.65, 95% CI 0.46, 0.91).
The proportion of patients who reported improvement in fatigue, as measured by FACIT-F responder rate (improvement from baseline at Week 52 of > 3 points), was 35.4% versus 28.4% in Trial 2 (difference 7.1%, 95% CI 2.6, 16.7) and 33.2% versus 24.7% in Trial 3 (difference 8.5%, 95% CI 0.9, 17.9) for the anifrolumab and placebo groups, respectively.

Phase III long-term extension.

Patients who completed Trials 2 and 3 (feeder trials) were eligible to continue on treatment in a randomised, double-blind, placebo-controlled, 3-year LTE (Trial 4). Patients who had received anifrolumab, either 150 mg or 300 mg, in Trials 2 and 3 received anifrolumab 300 mg in Trial 4. Patients who had received placebo in Trials 2 and 3 were re-randomised 1:1 to receive either anifrolumab 300 mg or placebo, giving an approximate anifrolumab 300 mg: placebo ratio of 4:1 in Trial 4.
The long-term efficacy of anifrolumab was evaluated in patients who received anifrolumab 300 mg or placebo in both a feeder trial and the LTE. The long-term data for patients receiving anifrolumab 300 mg indicate a sustained reduction in disease activity over time, as measured by mean SLEDAI-2K. In Trial 4, investigators were permitted to change a patients' use of OCS according to best clinical judgment and there was no protocol mandated OCS taper; during Trial 4 the overall use of OCS continued to decrease in the anifrolumab 300 mg group, compared to placebo.

5.2 Pharmacokinetic Properties

The pharmacokinetics (PK) of anifrolumab was studied in adult patients with SLE following IV doses ranging from 100 to 1000 mg, once every 4 weeks, and healthy volunteers following a single dose.
Anifrolumab exhibits nonlinear PK in the dose range of 100 mg to 1000 mg. PK exposure decreased more rapidly at doses lower than 300 mg every 4 weeks (the recommended dosage).

Absorption.

Saphnelo is administered by intravenous infusion.

Distribution.

Based on population pharmacokinetic analysis, the estimated central and peripheral volumes of distribution for anifrolumab were 2.93 L (with 26.9% CV inter-individual variability) and 3.3 L, respectively for a 69.1 kg patient.

Metabolism.

Anifrolumab is a protein, therefore specific metabolism studies have not been conducted.
Anifrolumab is expected to be degraded, into small peptides and individual amino acids, by proteolytic enzymes that are widely distributed in the body and not restricted to hepatic tissues.

Excretion.

There was a greater-than-dose-proportional increase in drug exposure due to IFNAR1-mediated drug clearance.
From population PK modelling the estimated typical systemic clearance (CL) was 0.193 L/day with a 33.0% CV inter individual variability. The median CL decreases slowly over time, with 8.4% after 1 year of treatment. Following long-term observations, the clearance of anifrolumab was found to be stable in years 2 through 4 on treatment.
Based on population PK analysis, serum concentrations were below detection in 95% of patients approximately 16 weeks after the last dose of anifrolumab, when anifrolumab has been dosed for one year.