Consumer medicine information

Kesimpta

Ofatumumab

BRAND INFORMATION

Brand name

Kesimpta

Active ingredient

Ofatumumab

Schedule

SUMMARY CMI

Kesimpta^®

Consumer Medicine Information (CMI) summary

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

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

1. Why am I using Kesimpta?

Kesimpta contains the active ingredient ofatumumab. Kesimpta is used for the treatment of adults with relapsing forms of multiple sclerosis. For more information, see Section 1. Why am I using Kesimpta? in the full CMI.

2. What should I know before I use Kesimpta?

Do not use if you have ever had an allergic reaction to Kesimpta 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, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Kesimpta? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Kesimpta and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Kesimpta?

Inject 20mg under the skin on week 0, week 1 and week 2. There is no injection at week 3.
At week 4 and then every month, inject 20mg under the skin.

More instructions can be found in Section 4. How do I use Kesimpta? in the full CMI. Your health professional will give you or your caregiver training in the right way to prepare and inject. Do not try to inject Kesimpta until you or your caregiver have been shown the right way by your health professional.

5. What should I know while using Kesimpta?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using Kesimpta. Have a blood test to check for Hepatitis B Tell your doctor if you have any type of infection Tell your doctor if you plan to receive a vaccine Avoid becoming pregnant while using Kesimpta and for 6 months after you stop using it
Things you should not do	Do not stop using this medicine suddenly.
Driving or using machines	It is not known if Kesimpta will influence your ability to drive and use machines
Drinking alcohol	There are no known interactions between Kesimpta and alcohol
Looking after your medicine	Refrigerate, do not freeze. Store between 2°C – 8°C. Keep out of reach of children

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

6. Are there any side effects?

Common side effects include upper chest infections (sore throat and runny nose), local injection site reactions such as redness, pain, itching and swelling and general injection site reactions such as fever, headache, muscle pain, chills and tiredness. 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

Kesimpta^®

Active ingredient(s): ofatumumab

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

1. Why am I using Kesimpta?
2. What should I know before I use Kesimpta?
3. What if I am taking other medicines?
4. How do I use Kesimpta?
5. What should I know while using Kesimpta?
6. Are there any side effects?
7. Product details

1. Why am I using Kesimpta?

Kesimpta contains the active ingredient ofatumumab. Ofatumumab is a type of protein called a monoclonal antibody designed to recognize and attach to a target called CD20 on the surface of certain types of white blood cells which are part of the immune system (so called B-cells).

Kesimpta is used for the treatment of adults with relapsing forms of multiple sclerosis.

By targeting and removing the B-cells, Kesimpta helps to reduce their activity and thereby reduces the chance of having a relapse, relieves symptoms and slows down the progression of multiple sclerosis.

2. What should I know before I use Kesimpta?

Warnings

Do not use Kesimpta if:

you are allergic to ofatumumab, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

are at risk of hepatitis B infection (all patients will have a blood test before starting Kesimpta)
have an infection, especially if it is severe. Kesimpta must not be used until a severe infection is better
have a weakened immune system and are at a higher risk of getting an infection. Kesimpta must not be used until your immune system is stronger
take any medicines for any other condition.

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.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

You should avoid becoming pregnant while using Kesimpta and for 6 months after you stop using it.

If you become pregnant or think you are pregnant, tell your doctor right away.

Contraception

To avoid becoming pregnant, you should use contraception while using Kesimpta and for 6 months after you stop using it.

Use in children

It is not known whether Kesimpta is safe and effective in children.

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.

Some medicines may interfere with Kesimpta and affect how it works.

Medicines that lower or modify the immune system including other medicines used to treat multiple sclerosis such as ocrelizumab, cladribine, fingolimod, natalizumab, teriflunomide, mitoxantrone, or dimethyl fumarate
vaccines

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

4. How do I use Kesimpta?

How much to use

Inject 20mg under the skin on week 0, week 1 and week 2. There is no injection at week 3.
At week 4 and then every month, inject 20mg under the skin.
Follow the instructions provided and use Kesimpta until your doctor tells you to stop.

When to use Kesimpta

Kesimpta is injected under the skin on week 0, week 1 and week 2. There is no injection at week 3. At week 4 and then every month inject under the skin.

How to use Kesimpta

Kesimpta is injected under the skin.
Follow the “Instructions for Use” leaflet in the pack.

If you forget to use Kesimpta

Kesimpta should be used regularly at the same time each week on weeks 0, 1 and 2 and then each month from week 4 onwards.

If you have missed a dose of Kesimpta, you should inject your missed dose as soon as possible without waiting until the next scheduled dose. Any following doses should be administered as per the recommended schedule.

Do not inject a double dose to make up for the dose you missed.

If you use too much Kesimpta

If you think that you have used too much Kesimpta, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Kesimpta?

Things you should do

Have a blood test to check for Hepatitis B
Tell your doctor if you plan to receive a vaccine
Avoid becoming pregnant while using Kesimpta and for 6 months after you stop using it

Call your doctor straight away if you:

Have injection related reactions or injection site reactions
Have any type of infection
Believe your multiple sclerosis is getting worse (e.g. weakness or eye changes) or if you notice any new or unusual symptoms – this can be serious.
Have symptoms of an allergic reaction including rash, hives, trouble breathing, swelling of the face, eyelids, lips, mouth, tongue or throat, chest tightness, feeling faint.
If any of these symptoms become worse or you have new serious symptoms after more injections.

Remind any doctor, dentist or pharmacist you visit that you are using Kesimpta.

Things you should not do

Do not stop using this medicine suddenly.

Driving or using machines

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

The effects of Kesimpta on a person's ability to drive and use machines has not been tested.

Looking after your medicine

Store between 2 to 8°C. Refrigerate. Do not freeze. Keep in the original package.
If necessary, Kesimpta may be stored unrefrigerated for a single period of up to 7 days at room temperature (not above 30°C). If not used during this period, Kesimpta can then be returned to the refrigerator for a maximum of 7 days.

Follow the instructions in the carton on how to take care of your medicine properly.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

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

Less serious side effects

What to do

Upper chest infections such as:

sore throat
runny nose

Local injection site reactions such as:

redness
pain
itching
swelling at injection site

General injection site reactions such as:

fever
headache
muscle pain
chills
tiredness

Infections such as:

urinary tract infection

Speak to your doctor if you have any of these less serious side effects and they worry you.
If these side effects become severe, please tell your doctor, pharmacist or healthcare provider.

Serious side effects

Serious side effects

What to do

Worsening of multiple sclerosis symptoms such as:

muscle weakness, muscle stiffness, muscle spasms
eye changes such as blurred vision, double vision
tremor
general weakness or
any unusual or different symptoms

Allergic reaction symptoms such as:

rash
hives
trouble breathing
swelling of the face, eyelids, lips, mouth, tongue or throat
chest tightness
feeling faint

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.

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.

Some side effects (for example decrease in specific proteins in the blood (immunoglobulins M) which help protect against infection) can only be found when your doctor does tests from time to time to check your progress.

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 Kesimpta contains

Active ingredient (main ingredient)	Each injection contains ofatumumab 20 mg
Other ingredients (inactive ingredients)	arginine sodium acetate trihydrate sodium chloride polysorbate 80 disodium edetate hydrochloric acid water for injection

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

What Kesimpta looks like

Kesimpta is supplied as a 20 mg/0.4 mL pre-filled syringe or a 20 mg/0.4 mL pre-filled pen.*

This product contains only one pre-filled pen or pre-filled syringe per pack.

The single-use solution for injection is sterile, preservative-free, clear to slightly opalescent, and colorless to slightly brownish-yellow (Aust R 330617; AUST R 330601).

*Not all products may be marketed

Who distributes Kesimpta

Kesimpta is supplied in Australia by:

Novartis Pharmaceuticals Australia Pty Limited
(ABN 18 004 244 160)
54 Waterloo Road
Macquarie Park NSW 2113
Telephone 1 800 671 203
Website: www.novartis.com.au

This leaflet was prepared in October 2023.

(kes230924c based on PI kes230924i)

Published by MIMS November 2024

BRAND INFORMATION

Brand name

Kesimpta

Active ingredient

Ofatumumab

Schedule

1 Name of Medicine

Ofatumumab.

2 Qualitative and Quantitative Composition

Ofatumumab is a recombinant fully human monoclonal immunoglobulin G1 (IgG1) antibody against human CD20 expressed on B-cells. Ofatumumab is produced in a murine cell line (NS0) by recombinant DNA technology.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Each pre-filled syringe and pre-filled pen contains 20 mg ofatumumab solution for injection (0.4 mL of 50 mg/mL solution).
20 mg/0.4 mL Solution for injection in a pre-filled syringe.
20 mg/0.4 mL Solution for injection in a pre-filled pen.
The single-use solution for injection is sterile, preservative-free, clear to slightly opalescent, and colourless to slightly brownish-yellow.

4 Clinical Particulars

4.1 Therapeutic Indications

Kesimpta is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (RMS) to delay the progression of physical disability and reduce the frequency of relapse (see Section 5.1).

4.2 Dose and Method of Administration

Dosage regimen.

The recommended dose is 20 mg Kesimpta administered by subcutaneous injection with:
initial dosing of 20 mg by subcutaneous injection at weeks 0, 1 and 2, followed by subsequent monthly dosing of 20 mg by subcutaneous injection, starting at week 4.

Missed doses.

If an injection of Kesimpta is missed, it should be administered as soon as possible without waiting until the next scheduled dose. Subsequent doses should be administered at the recommended intervals.

Method of administration.

Treatment with Kesimpta should be initiated by a physician experienced in the management of neurological conditions.
Kesimpta is intended for patient self-administration by subcutaneous injection. Administration should be performed by an individual who has been instructed to administer the product.
The usual sites for subcutaneous injections are the abdomen, the thigh and the upper outer arm.
The first injection of Kesimpta should be performed under the guidance of a healthcare professional (see Section 4.4 Special Warnings and Precautions for Use).
Comprehensive instructions for administration are provided in the instructions for use and handling.

Special populations.

Renal impairment.

No specific studies of ofatumumab in patients with renal impairment have been performed.
Patients with mild renal impairment were included in clinical studies. There is no experience in patients with moderate and severe renal impairment. However, as ofatumumab is not excreted via urine, it is not expected that patients with renal impairment require dose modification (see Section 5 Pharmacological Properties).

Hepatic impairment.

No studies of ofatumumab in patients with hepatic impairment have been performed.
Since hepatic metabolism of monoclonal antibodies such as ofatumumab is negligible, hepatic impairment is not expected to impact its pharmacokinetics. Therefore, it is not expected that patients with hepatic impairment require dose modification (see Section 5 Pharmacological Properties).

Paediatric patients (below 18 years).

The safety and effectiveness in paediatric MS patients below the age of 18 years have not yet been studied.

Elderly patients (aged 55 years and over).

No studies have been performed in elderly MS patients. Ofatumumab was studied in patients with RMS aged 18 to 55 years.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Injection-related reactions.

Injection site reaction (local) symptoms observed in clinical studies included erythema, swelling, itching and pain.
Systemic injection-related reactions (SIRRs) observed in clinical studies occurred predominantly with the first injection. Symptoms observed include fever, headache, myalgia, chills and fatigue and were predominantly (99.7%) non-serious and mild to moderate in severity. There were no life-threatening injection reactions in RMS clinical studies.
Additional SIRRs reported in the post-marketing setting include rash, urticaria, dyspnea, angioedema (e.g. tongue, pharyngeal or laryngeal swelling), and rare cases which were reported as anaphylaxis. Most of the cases were non-serious and occurred with first injection. While there were some cases which were serious and resulted in discontinuation of Kesimpta treatment, there were also serious cases where patients were able to continue Kesimpta treatment without further incidents.
Some SIRR symptoms may be clinically indistinguishable from Type 1 acute hypersensitivity reactions (IgE-mediated). Patients should be informed that SIRRs generally occur within 24 hours and predominantly following the first injection. SIRRs can be managed with symptomatic treatment, should they occur.
A hypersensitivity reaction may present with any injection, although typically would not present with the first injection. For subsequent injections, more severe symptoms than previously experienced, or new severe symptoms, should prompt consideration of a potential hypersensitivity reaction. Patients with known IgE mediated hypersensitivity to Kesimpta must not be treated with Kesimpta (see Section 4.3 Contraindications).
Only limited benefit of premedication with steroids, antihistamines, or paracetamol was seen in RMS clinical studies. Ofatumumab-treated patients who received premedication with methylprednisolone (or an equivalent steroid) experienced fewer symptoms such as fever, myalgia, chills, and nausea. However, the use of steroid premedication increased the occurrence of flushing, chest discomfort, hypertension, tachycardia, and abdominal pain even in the absence of ofatumumab treatment (i.e. in patients receiving placebo injections). Therefore, use of premedication is not required.
The first injection of Kesimpta should be performed under the guidance of an appropriately trained healthcare professional.

Infections.

It is recommended to evaluate the patient's immune status prior to initiating therapy with Kesimpta.
Serious, including life-threatening or fatal, bacterial, fungal, and new or reactivated viral infections have been observed during and following completion of treatment with anti-CD20 B-cell depleting therapies. Based on its mode of action and available clinical experience, ofatumumab has the potential for an increased risk of infections (see Section 4.8 Adverse Effects (Undesirable Effects)). Administration should be delayed in patients with a severe active infection until the infection is resolved.
Kesimpta should not be given to patients with severe immunosuppression (e.g. significant neutropenia or lymphopenia).
In RMS clinical studies, the proportion of patients with infections was similar in the ofatumumab and the teriflunomide treatment groups. In the Phase 3 pivotal clinical studies, 51.6% of ofatumumab-treated patients experienced at least one infection compared to 52.7% of teriflunomide-treated patients.

Progressive multifocal leukoencephalopathy.

No cases of progressive multifocal leukoencephalopathy (PML) have been reported for ofatumumab in the RMS clinical studies. However, since John Cunningham (JC) virus infection resulting in PML has been observed in patients treated with anti-CD20 antibodies (including ofatumumab at higher doses in other indications) and other MS therapies, physicians should be vigilant for any clinical symptoms or magnetic resonance imaging (MRI) findings that may be suggestive of PML. If PML is suspected, treatment with Kesimpta should be suspended until PML has been excluded. To establish or exclude a diagnosis of PML evaluation including MRI scan, CSF testing for JC viral DNA and repeat neurological assessments, should be considered. If PML is confirmed, treatment with Kesimpta should be discontinued.

Hepatitis B virus reactivation.

Patients with active hepatitis B disease should not be treated with Kesimpta. Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with Kesimpta. At a minimum screening should include Hepatitis B surface antigen (HBsAg) and Hepatitis B Core Antibody (HBcAb) testing. These can be complemented with other appropriate markers as per local guidelines. Patients who are negative for HBsAg and positive for Hepatitis B core antibody [HBcAb+] or are carriers of HBV [HBsAg+] should consult liver disease experts before starting and during treatment with Kesimpta.
No cases of HBV reactivation were identified in Kesimpta RMS clinical studies. However, hepatitis B reactivation has occurred in patients treated with anti-CD20 antibodies, which in some cases resulted in fulminant hepatitis, hepatic failure and death.

Treatment of severely immunocompromised patients.

Patients in a severely immunocompromised state must not be treated until the condition resolves. It is not recommended to use other immunosuppressants concomitantly with Kesimpta except corticosteroids for symptomatic treatment of relapses.

Vaccinations.

All immunizations should be administered according to immunization guidelines at least 4 weeks prior to initiation of Kesimpta for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of Kesimpta for inactivated vaccines.
Kesimpta may interfere with the effectiveness of inactivated vaccines.
The safety of immunization with live or live-attenuated vaccines following Kesimpta therapy has not been studied. Vaccination with live or live-attenuated vaccines is not recommended during treatment and after discontinuation until B-cell repletion (see Section 5 Pharmacological Properties).

Vaccination of infants born to mothers treated with Kesimpta during pregnancy.

In infants of mothers treated with Kesimpta during pregnancy, live or live-attenuated vaccines should not be administered until confirmed B-cell counts have reached the lower limit of normal. Depletion of B-cells in these infants may increase the risks from live or live-attenuated vaccines.
Inactivated vaccines may be administered as indicated prior to recovery from B-cell depletion, however, assessment of vaccine immune responses, including consultation with a qualified specialist, should be considered to determine whether a protective immune response was mounted (see Section 4.6 Fertility, Pregnancy and Lactation).

Malignancies.

An increased risk of breast cancer has been observed with other anti CD20 B cell-depleting therapies in MS. Patients with existing active malignancies (including patients actively monitored for relapse of a malignancy) must not be treated with ofatumumab. In patients with known risk factors for malignancies, the benefit-risk ratio of ofatumumab should be carefully considered and relevant tumour monitoring performed before and during treatment.

Use in hepatic impairment.

Since hepatic metabolism of monoclonal antibodies such as ofatumumab is negligible, hepatic impairment is not expected to impact its pharmacokinetics. Therefore, it is not expected that patients with hepatic impairment require dose modification.

Use in renal impairment.

Ofatumumab is not excreted via urine; therefore, it is not expected that patients with renal impairment require dose modification.

Use in the elderly.

No studies have been performed in elderly MS patients.

Paediatric use.

The safety and effectiveness in paediatric patients below the age of 18 years have not yet been established.

Effects on laboratory tests.

Immunoglobulins.

During the course of the RMS Phase 3 clinical studies, decrease in mean value of immunoglobulin M (IgM) was observed and was not associated with a risk of infections including serious infections. A decrease in mean IgM value of 30.9% after 48 weeks and 38.8% after 96 weeks was noted, while mean serum IgM levels remained well within reference ranges overall. In 14.3% of patients, treatment with ofatumumab resulted in a decrease in IgM that reached a value below 0.34 g/L. Ofatumumab was associated with a transient decrease of 4.3% in mean IgG levels after 48 weeks of treatment but an increase of 2.2% after 96 weeks.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Ofatumumab does not share a common clearance pathway with chemical drugs that are metabolized by the cytochrome P450 system or other drug metabolizing enzymes. Additionally, there is no evidence that CD20 monoclonal antibodies (mAbs) are involved in the regulation of the expression of drug metabolizing enzymes. Interactions between Kesimpta and other medicinal products have not been investigated in formal studies.

Vaccinations.

The safety of and the ability to generate a primary or anamnestic (recall) response to immunization with live, live-attenuated or inactivated vaccines during ofatumumab treatment has not been investigated. The response to vaccination could be impaired when B-cells are depleted. It is recommended that patients complete immunizations prior to the start of Kesimpta therapy (see Section 4.4 Special Warnings and Precautions for Use).

Other immunosuppressive or immune-modulating therapies.

The risk of additive immune system effects should be considered when co-administering immunosuppressive therapies with Kesimpta.
When initiating Kesimpta after other immunosuppressive therapies with prolonged immune effects or initiating other immunosuppressive therapies with prolonged immune effects after Kesimpta, the duration and mode of action of these medicinal products should be taken into account because of potential additive immunosuppressive effects.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effect of Kesimpta on human fertility. No effects on fertility parameters such as reproductive organs, menstrual cycle and semen analysis were observed in male and female cynomolgus monkeys that were administered ofatumumab at intravenous doses up to 100 mg/kg weekly followed by 20 mg/kg bi-weekly for 13 weeks (> 260 times the systemic exposure [based on AUC]).

Women of childbearing potential.

Females of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) while receiving Kesimpta and for 6 months after the last treatment of Kesimpta.
(Category C)
There are no studies of Kesimpta in pregnant women.
In the embryofetal development study in pregnant cynomolgus monkeys, ofatumumab was administered intravenously at doses up to 100 mg/kg/week (1280 times the systemic exposure [AUC] in patients). Ofatumumab did not cause maternal toxicity or embryofetal harm. In a separate pre- and postnatal development study, ofatumumab given intravenously at doses up to 100 mg/kg weekly followed by 20 mg/kg bi-weekly did not cause any adverse developmental effects on neonates (160 times the exposure in patients, based on AUC).
Ofatumumab, like other IgG antibodies, was shown to cross the placental barrier in cynomolgus monkeys. It is not known whether Kesimpta can cause fetal harm when administered to pregnant women. Kesimpta should be used in pregnancy only if the potential benefit justifies the potential risk to the mother or fetus.
Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. The potential duration of B-cell depletion in infants exposed to ofatumumab in utero, and the impact of B-cell depletion on the safety and effectiveness of vaccines, are unknown (see Section 4.4 Special Warnings and Precautions for Use; Section 5 Pharmacological Properties).
To help determine the effects of ofatumumab in pregnant women, healthcare professionals are encouraged to report all pregnancy cases and complications that happen during treatment or within 6 months after the last dose of Kesimpta to Novartis, in order to allow monitoring of these patients through the pregnancy outcomes intensive monitoring program (PRIM).
Epidemiologic studies from USA, Canada, major EU countries and South American countries have shown that the risk of birth defects in MS population is similar to that in the general population. For spontaneous abortions and still births, the background risk in the MS population in the US appears to be similar to that in the general US population.
The use of Kesimpta in women during lactation has not been studied. It is unknown whether ofatumumab is transferred into human milk; however, human IgG is present in human milk. There are no data on the effects of Kesimpta on the breastfed infant or on milk production. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Kesimpta and any potential adverse effects on the breastfed infant from Kesimpta.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of this registration.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

Approximately 1500 patients with RMS received ofatumumab in clinical studies. In the two Phase 3 pivotal studies comparing ofatumumab and teriflunomide, 1882 patients with RMS were randomized, 946 of whom were treated with ofatumumab for a median duration of 85 weeks; 33% of patients receiving ofatumumab were treated for more than 96 weeks (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The proportion of patients with adverse events (AEs) (83.6% versus 84.2%) and the AEs leading to drug discontinuation (5.7% versus 5.2%) were similar in the ofatumumab and teriflunomide groups.

Tabulated summary of adverse drug reactions from clinical trials.

Adverse drug reactions that have been reported in pivotal clinical studies are listed by MedDRA system organ class (see Table 1). Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Adverse drug reactions from spontaneous reports and literature cases (frequency not known).

The following adverse drug reactions have been derived from postmarketing experience with Kesimpta via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness. See Table 2.

Description of selected adverse drug reactions.

Upper respiratory tract infections.

A higher proportion of ofatumumab-treated patients experienced upper respiratory tract infections compared to teriflunomide-treated patients. In the RMS clinical studies, 39.4% of ofatumumab-treated patients experienced upper respiratory tract infections compared to 37.8% of teriflunomide-treated patients. The infections were predominantly mild to moderate and mostly consisted of nasopharyngitis, upper respiratory tract infection and influenza.

Injection related reactions and injection site reactions.

In patients treated with ofatumumab in the RMS Phase 3 clinical studies, injection related reactions (systemic) and injection-site reactions (local) were reported in 20.6% and 10.9% of patients treated with ofatumumab, respectively.
The incidence of injection-related reactions was highest with the first injection (14.4%), decreasing significantly with subsequent injections (4.4% with second, < 3% from third injection). Injection-related reactions were mostly (99.8%) mild to moderate in severity. Only two (0.2%) ofatumumab-treated MS patients reported serious injection-related reactions. There were no life-threatening injection-related reactions. The most frequently reported symptoms (≥ 2%) included fever, headache, myalgia, chills, and fatigue.
Local reactions at the administration site were very common. Injection-site reactions were all mild to moderate in severity and non-serious in nature. The most frequently reported symptoms (≥ 2%) included erythema, pain, itching, and swelling (see Section 4.4 Special Warnings and Precautions for Use).

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

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
No cases of overdose have been reported in RMS clinical studies.
Doses up to 700 mg have been administered intravenously in clinical studies with MS patients without dose-limiting toxicity. In the event of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted as necessary.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Selective immunosuppressants, ATC code: L04AG12.

B-cell depletion.

In the RMS Phase 3 studies, ofatumumab 20 mg every 4 weeks, after an initial dose regimen of 20 mg on days 1, 7 and 14, resulted in a rapid and sustained reduction of B-cells to below the lower limit of normal as early as two weeks after treatment initiation, and sustained for as long as 120 weeks while on treatment.
Similar results were observed in a study of bioequivalence using the same dosing regimen as in the Phase 3 studies. Before initiation of the maintenance phase starting at week 4, total B-cell levels < 10 cells/microL were reached in 94% of patients increasing to 98% of patients at week 12.

B-cell repletion.

Data from RMS Phase 3 studies indicate a median time to B-cell recovery to LLN or baseline value of 24.6 weeks post treatment discontinuation. PK-B-cell modelling and simulation for B-cell repletion corroborate this data, predicting median time to B-cell recovery to LLN of 23 weeks post treatment discontinuation.

Mechanism of action.

B-cells play an important role in MS pathogenesis due to production of pro-inflammatory cytokines, release of auto-reactive antibodies and activation of pathogenic T cells. Ofatumumab is a fully human anti-CD20 monoclonal antibody (IgG1). It binds to a distinct epitope encompassing both the small and large extracellular loops of the CD20 molecule giving rise to a slow off-rate and high binding affinity. The CD20 molecule is a transmembrane phosphoprotein expressed on B lymphocytes from the pre-B to mature B lymphocyte stage. The CD20 molecule is also expressed on a small fraction of activated T cells.
The binding of ofatumumab to CD20 induces lysis of CD20+ B-cells primarily through complement-dependent cytotoxicity (CDC) and to a lesser extent, through antibody-dependent cell-mediated cytotoxicity (ADCC). Ofatumumab has also been shown to induce cell lysis in both high and low CD20 expressing cells. CD20-expressing T cells are also depleted by ofatumumab.

Clinical trials.

The efficacy and safety of Kesimpta were evaluated in two randomized, double-blind, active-controlled Phase 3 pivotal studies of identical design (G2301 (ASCLEPIOS I) and G2302 (ASCLEPIOS II)) in patients with relapsing forms of MS (RMS), aged 18 to 55 years, a disability status at screening with an Expanded Disability Status Scale (EDSS) score from 0 to 5.5, and who had experienced at least one documented relapse during the previous year or two relapses during the previous two years or a positive gadolinium (Gd)-enhancing MRI scan during the previous year. Both newly diagnosed patients and patients switching from their current treatment were enrolled.
In the two studies, 927 and 955 patients with RMS, respectively, were randomized 1:1 to receive either Kesimpta 20 mg subcutaneous injections every 4 weeks starting at Week 4 after an initial dosing regimen of three weekly 20 mg doses in the first 14 days (on Days 1, 7 and 14) or teriflunomide 14 mg capsules orally once daily. Patients also received matching placebo corresponding to the other treatment arm to ensure blinding (double-dummy design).
The treatment duration for individual patients was variable based on when the end of study criteria were met. Across both studies, the median treatment duration was 85 weeks, 33.0% of patients in the Kesimpta group vs 23.2% of patients in the teriflunomide group were treated more than 96 weeks.
Demographics and baseline characteristics were well-balanced across treatment arms and both studies (see Table 3). Mean age was 38 years, mean disease duration was 8.2 years since onset of first symptom, and mean EDSS score was 2.9; 40% of patients had not been previously treated with a disease modifying therapy (DMT) and 40% had gadolinium (Gd)-enhancing T1 lesions on their baseline MRI scan.
The primary efficacy endpoint of both studies was the annualized rate of confirmed relapses (ARR) based on EDSS. Key secondary efficacy endpoints included the time to disability worsening on EDSS (confirmed at 3 months and 6 months), defined as an increase in EDSS of ≥ 1.5, ≥ 1, or ≥ 0.5 in patients with a baseline EDSS of 0, 1 to 5, or ≥ 5.5, respectively. Further key secondary endpoints were the number of Gd-enhancing T1 lesions per MRI scan and the annualized rate of new or enlarging T2 lesions. Disability-related key secondary endpoints were evaluated in a meta-analysis of combined data from studies G3201 and G2302, as defined in the study protocols.

The efficacy results for both studies are summarized in Table 4, and Figure 1.
In both Phase 3 studies (G2301 and G2302), Kesimpta demonstrated a significant reduction in the annualized relapse rate of 50.5% and 58.4%, respectively (both p < 0.001) compared to teriflunomide.
The pre-specified meta-analysis of combined data showed that Kesimpta significantly reduced the risk of 3-month confirmed disability worsening (CDW) (risk reduction = 34.3%, p = 0.003) and 6-month CDW (risk reduction = 32.4%, p = 0.012) compared to teriflunomide (see Figure 1).
Kesimpta significantly reduced the number of Gd-enhancing T1 lesions and the rate of new or enlarging T2 lesions by 95.9% and 83.5%, respectively (both studies combined).
Efficacy results were consistent across the two Phase 3 studies (G2301 and G2302) and across subgroups defined based on gender, age, prior MS therapy and baseline disability and disease activity.

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. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other ofatumumab products may be misleading.
Treatment-induced anti-drug antibodies (ADA) in the Phase 3 studies were detected in 2 of 946 (0.2%) Kesimpta treated patients; no patients with treatment enhancing or neutralizing ADAs were identified. There was no impact of positive ADA titers on PK, safety profile or B-cell kinetics in any patient, however, these data are not adequate to assess the impact of ADAs on the safety and efficacy of Kesimpta.

5.2 Pharmacokinetic Properties

Absorption.

Based on the 12 week bioequivalence study in RMS patients (COMB157G2102) a monthly subcutaneous dose of 20 mg leads to a mean AUC_tau of 483 microgram.h/mL and a mean C_max of 1.43 microgram/mL at steady state. The T_max was generally achieved within the first week of treatment.
After subcutaneous administration, ofatumumab is believed to be predominantly absorbed via the lymphatic system similarly to other therapeutic monoclonal antibodies.

Distribution.

The volume of distribution at steady state was estimated to be 5.42 litres following repeated subcutaneous administration of Kesimpta at a dose of 20 mg.

Metabolism.

Ofatumumab is a protein for which the expected metabolic pathway is degradation to small peptides and amino acids by ubiquitous proteolytic enzymes.

Excretion.

Ofatumumab exhibits a long half-life and low volume of distribution similar to that of other monoclonal antibodies. Ofatumumab is eliminated through a non-linear target-mediated route as well as a target-independent route mediated by non-specific endocytosis followed by intracellular catabolism. Higher baseline B-cell count results in greater component of target-mediated elimination clearance and shorter ofatumumab half-life at the start of therapy. Subsequent ofatumumab dosing leads to potent depletion of B-cells resulting in reduced overall clearance.
Ofatumumab is eliminated in two ways: a target-independent route mediated by non-specific endocytosis followed by intracellular catabolism, as with other IgG molecules and a target-mediated route that is related to binding to B-cells. B-cells present at baseline result in a greater component of target-mediated clearance of ofatumumab at the start of therapy. Ofatumumab dosing leads to potent depletion of B-cells resulting in reduced overall clearance. The half life at steady state was estimated to be approximately 16 days following repeated subcutaneous administration of ofatumumab at a dose of 20 mg.
Ofatumumab had non-linear pharmacokinetics related to its decreasing clearance over time.