Consumer medicine information

Ajovy

Fremanezumab

BRAND INFORMATION

Brand name

Ajovy

Active ingredient

Fremanezumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ajovy.

SUMMARY CMI

AJOVY®

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 AJOVY?

AJOVY contains the active ingredient fremanezumab. AJOVY is used to prevent migraine in adults.

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

2. What should I know before I use AJOVY?

Do not use if you have ever had an allergic reaction to AJOVY 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 AJOVY? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with AJOVY 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 AJOVY?

  • Follow all directions given to you by your doctor or pharmacist carefully.
  • AJOVY must only be given by subcutaneous injection.

More instructions can be found in Section 4. How do I use AJOVY? in the full CMI.

5. What should I know while using AJOVY?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using AJOVY.
  • Keep all of your doctor's appointments so that your progress can be checked.
Things you should not do
  • Do not take AJOVY to treat any other complaints unless your doctor tells you to.
  • Do not administer AJOVY by any other method or route other than subcutaneous injection.
Driving or using machines
  • Be careful driving or operating machinery until you know how AJOVY affects you.
Looking after your medicine
  • Store in a refrigerator (2°C to 8°C). Do not freeze.
  • AJOVY may be stored unrefrigerated for up to 7 days at a temperature up to 30°C.

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

6. Are there any side effects?

Less serious side effects: Local skin reactions at the injection site: pain, hardening or redness; itching; rash.

Serious side effects: Symptoms of an allergic or hypersensitivity reaction may include: chest tightness, cough, wheezing or difficulty breathing; drop in blood pressure (fainting, dizziness, feeling lightheaded); swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin; stomach pain or discomfort; vomiting.

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

AJOVY® (A-JO-VEE) Solution for Injection

Active ingredient(s): Fremanezumab (Fre-ma-nay-zoo-mab)

Consumer Medicine Information (CMI)

This leaflet provides important information about using AJOVY. 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 AJOVY.

Where to find information in this leaflet:

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

1. Why am I using AJOVY?

AJOVY is a medicine containing the active substance fremanezumab, a monoclonal antibody, a type of protein that recognises and binds to a specific target in the body.

AJOVY is used to prevent migraine in adults.

Do not give this medicine to a child or adolescent under the age of 18 years.

AJOVY is not recommended for children and adolescents below the age of 18 years because it has not been studied in this age group.

Fremanezumab binds to the calcitonin gene-related peptide (CGRP) thereby blocking it from binding to the CGRP receptor. CGRP plays an important role in migraine.

AJOVY has been shown to reduce the frequency of migraine attacks and days with headache. This medicine also decreases important migraine-associated symptoms like nausea, vomiting, sensitivity to light and sound.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

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

This medicine is not expected to affect your ability to drive a car or operate machinery.

2. What should I know before I use AJOVY?

Warnings

Do not use AJOVY if:

  • you are allergic to fremanezumab, or any of the ingredients listed at the end of this leaflet.
  • you are using any other similar medicines (such as medicines of the same class or with a similar structure).
  • Always check the ingredients to make sure you can use this medicine.

Some of the symptoms of an allergic reaction may include:

  • chest tightness, cough, wheezing or difficulty breathing
  • drop in blood pressure (fainting, dizziness, feeling lightheaded)
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin
  • stomach pain or discomfort
  • vomiting

Tell your doctor if you have or have had cardiovascular disease (problems affecting the heart and blood vessels) before using this medicine, because AJOVY has not been studied in patients with certain cardiovascular diseases.

Do not take this medicine if the packaging is torn or shows signs of tampering.

Check the pre-filled syringe or autoinjector label and the box. Make sure the name AJOVY appears on the label.

If you are not sure whether you should start taking this medicine, talk to your doctor.

If you have not told your doctor about any of the above, tell him/her before you start taking AJOVY.

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.

It is preferable to avoid the use of AJOVY during pregnancy as the effects of this medicine in pregnant women are not known.

Your doctor can discuss with you the risks and benefits involved.

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.

It is not yet known whether some medicines and AJOVY may interfere with each other and affect how each might work.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

Tell your doctor if you are taking any medication to prevent migraines.

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

4. How do I use AJOVY?

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

AJOVY is given by single use needle injection using a pre-filled syringe or autoinjector, into the tissues just below the skin.

This is called a subcutaneous injection and it is a simple procedure.

AJOVY must only be given by subcutaneous injection in areas such as:

  • the stomach area (abdomen)
  • front of your thighs
  • the back of your upper arms

AJOVY can be given by your doctor and/or caregivers. You may also be able to inject yourself once you have received the correct training and are confident in doing so.

It is important that neither you nor a caregiver try to administer the injection unless you have received training from your doctor or nurse.

If you and/or your caregiver do not understand the instructions in this leaflet or the "Instructions for Use" leaflet, ask your doctor or pharmacist for help.

Each pre-filled syringe or autoinjector is for single use in one patient only.

Wait for 30 minutes to let AJOVY reach room temperature to reduce discomfort during injection.

Do NOT leave the pre-filled syringe or autoinjector in direct sunlight.

Do NOT warm up the pre-filled syringe or autoinjector using a microwave or any other heat source.

Do NOT pull back the plunger at any time as this can break the pre-filled syringe.

Do NOT shake the pre-filled syringe or autoinjector.

Do NOT use this medicine if you notice that the pre-filled syringe or autoinjector is damaged, or that the medicine is cloudy, discoloured or there are particles in it.

Do NOT use this medicine after the expiry date which is stated on the outer carton and on the label of the pre-filled syringe or autoinjector after EXP. The expiry date refers to the last day of that month.

How much to take / When to take AJOVY

AJOVY can be given as either:

  • 225 mg once monthly (monthly dosing) equivalent to one pre-filled syringe or autoinjector; or
  • 675 mg every three months (quarterly dosing) equivalent to three pre-filled syringes or autoinjector given in a single sitting at three different injection sites.

Your doctor will advise which dosing regimen is right for you.

If your doctor advises you that they are switching dosing regimens, the first dose of the new regimen should be administered on the next scheduled dosing date of the prior regimen.

If you or a caregiver is administering AJOVY refer to the "Instructions for Use" leaflet for correct clean injection technique and preferred injection sites.

It may be helpful to use a reminder method such as a calendar or diary to help you remember your next dose so that you avoid missing or repeating doses.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

You should see your doctor after you have been using AJOVY for 8-12 weeks to discuss whether you should keep using AJOVY.

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

How to Administer AJOVY

Choose an injection area from the following areas:

  • Your stomach area (abdomen), avoid about 5 cm around the belly button

  • The front of your thighs, about 5 cm above the knee and 5 cm below the groin

  • The back of your upper arms, in the fleshy areas of the upper back portion

If multiple injections are required, they may be given in the same or different area (abdomen, thigh, upper arm) but you should avoid injecting in exactly the same place.

If you forget to use AJOVY

If you have missed a dose of AJOVY, inject your missed dose as soon as you can.

Do not take a double dose to make up for a forgotten dose.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your doctor or pharmacist for some hints.

If you use too much AJOVY

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

You should immediately:

  • phone the Poisons Information Centre
    (In Australia by calling 13 11 26 and in New Zealand 0800 POISON [0800 764 766]), 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 AJOVY?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking AJOVY.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

It may affect or be affected by other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine.

It may interfere with the results of some tests.

Keep all of your doctor's appointments so that your progress can be checked.

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

Things you should not do

Do not take AJOVY to treat any other complaints unless your doctor tells you to.

Do not co-administer AJOVY with other injectable drugs at the same injection site.

Do not administer AJOVY by any other method or route other than subcutaneous injection using the technique as demonstrated by your doctor in accordance with this leaflet or the separate "Instructions for Use guide". Speak to your doctor if you are unsure.

Do not administer AJOVY by subcutaneous injection into areas of the abdomen, thigh, or upper arm that are:

  • tender
  • bruised
  • sunburnt
  • hardened
  • red
  • infected
  • tattooed
  • calloused
  • scarred; or
  • contain stretch marks
  • For multiple injections, do not use the same injection site.

Refer to the "Instructions for Use" leaflet with this medicine for helpful hints on where you should inject if you are unsure.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine without checking with your doctor.

Driving or using machines

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

Looking after your medicine

Storage

Store in a refrigerator (2°C to 8°C).

Do not freeze.

AJOVY may be stored unrefrigerated for up to 7 days at a temperature up to 30°C.

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

Store in the original carton in order to protect from light.

Do not store AJOVY:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Disposal

Once you have injected AJOVY, do not put the needle cap back on the used syringe.

Discard the used pre-filled syringe or autoinjector right away into an approved, puncture-resistant sharps container and keep it out of the reach of children.

Never put the used pre-filled syringes/autoinjectors or sharps disposal container into your normal household rubbish bin or recycling container.

Dispose of the full puncture-resistant sharps container as instructed by your doctor, nurse or pharmacist.

When to discard your medicine

AJOVY must be discarded if not used within 7 days of removal from refrigeration.

Getting rid of any unwanted medicine

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

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 printed on the pack.

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. The side effects caused by AJOVY are usually mild to moderate.

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 effectsWhat to do
Local skin reactions at the injection site:
  • pain, hardening or redness
  • itching
  • rash
Gut-related
  • constipation
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Symptoms of an allergic or hypersensitivity reaction may include:
  • chest tightness, cough, wheezing or difficulty breathing
  • drop in blood pressure (fainting, dizziness, feeling lightheaded)
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin
  • stomach pain or discomfort
  • vomiting
If you think you are having an allergic reaction to AJOVY, stop using this medicine and contact your doctor or nurse immediately or go to the accident and emergency department at your nearest hospital.

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 or Medsafe at www.medsafe.govt.nz/safety/report-a-problem.asp#Medicine. 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 AJOVY contains

Active ingredient
(main ingredient)		Each pre-filled syringe of AJOVY contains 225 mg of fremanezumab as the active ingredient in 1.5 mL of solution (150 mg/mL).
Each autoinjector of AJOVY contains 225 mg of fremanezumab as the active ingredient in 1.5 mL of solution (150 mg/mL).
Other ingredients
(inactive ingredients)
  • Histidine
  • Histidine hydrochloride monohydrate
  • Sucrose
  • Disodium edetate
  • Polysorbate 80
  • Water for injections

AJOVY does not contain lactose or gluten.

AJOVY does not contain any preservatives.

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

What AJOVY looks like

AJOVY is a solution for injection. It is supplied in a pre-filled syringe with a fixed injection needle in a blister, or in an autoinjector.

AJOVY is a clear, colourless to slightly yellow solution.

Each pre-filled syringe contains 1.5 mL solution.

Pre-filled Syringe:

AJOVY is available in packs containing 1 or 3 pre-filled syringes.

225 mg/1.5 mL pre-filled syringe: Aust R 308630

Autoinjector:

AJOVY is available in packs containing 1 or 3 autoinjector(s) containing an integrated pre-filled syringe.

225 mg/1.5 mL autoinjector: Aust R 342612

Not all pack sizes may be marketed

Autoinjector not currently available in New Zealand.

Who distributes AJOVY

AJOVY is supplied in Australia by:

Teva Pharma Australia Pty Ltd
Level 1, 37 Epping Rd
Macquarie Park, NSW, 2113
Toll Free Number: 1800 288 382

Distributed in New Zealand by:

Teva Pharma New Zealand Ltd
PO Box 128 244, Remuera
Auckland 1541,
New Zealand
Telephone: 0800 800 097

This leaflet was prepared in May 2024.

Published by MIMS August 2024

BRAND INFORMATION

Brand name

Ajovy

Active ingredient

Fremanezumab

Schedule

S4

 

1 Name of Medicine

Fremanezumab.

2 Qualitative and Quantitative Composition

One pre-filled syringe contains 225 mg fremanezumab in 1.5 mL (150 mg/mL). One autoinjector contains 225 mg fremanezumab in 1.5 mL (150 mg/mL).
Fremanezumab is a fully humanised monoclonal antibody produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ajovy is a sterile, preservative-free solution for injection available as follows:
225 mg/1.5 mL in a single-dose autoinjector;
225 mg/1.5 mL in a single-dose pre-filled syringe.
Ajovy is a clear to opalescent, colourless to slightly yellow solution with a pH of 5.5 and an osmolality of 300-450 mOsm/kg.

4 Clinical Particulars

4.1 Therapeutic Indications

Ajovy is indicated for the preventive treatment of migraine in adults.

4.2 Dose and Method of Administration

Dosage.

Ajovy should be initiated by a physician experienced in the diagnosis and treatment of migraine.
Ajovy should only be administered by subcutaneous injection.
Two dosing options are available:
225 mg once monthly (monthly dosing); or
675 mg every three months (quarterly dosing).
When switching dosing regimens, the first dose of the new regimen should be administered on the next scheduled dosing date of the prior regimen.
The treatment benefit should be assessed 8-12 weeks after initiation of treatment. Any further decision to continue treatment should be taken on an individual patient basis. Evaluation of the need to continue treatment is recommended regularly thereafter.

Missed dose.

If an Ajovy injection is missed on the planned date, dosing should resume as soon as possible on the indicated dose and regimen. A double dose must not be administered to make up for a missed dose.

Method of administration.

Subcutaneous use.

Instructions for use.

Ajovy may be administered by healthcare professionals, patients, and/or caregivers. Provide proper training to patients and/or caregivers on the preparation and administration of Ajovy pre-filled syringe or autoinjector prior to use according to the Instructions for use. Instruct patients and/or caregivers to read and follow the Instructions for use each time they use Ajovy pre-filled syringe or autoinjector.
Ajovy is for single use in one patient only. Discard any residue. Follow clean injection technique every time Ajovy is administered.
Remove Ajovy from the refrigerator. Prior to use, allow Ajovy to reach room temperature for 30 minutes. Do not use Ajovy if it has been stored unrefrigerated for longer than 7 days, or at temperatures higher than 30°C.
The pre-filled syringe and autoinjector should not be shaken.
Visually inspect Ajovy for particles or discolouration prior to administration. Ajovy is a clear to opalescent, colourless to slightly yellow solution. Do not use if the solution is cloudy, discoloured, or contains particles. Do not use if Ajovy is frozen.
Administer Ajovy by subcutaneous injection into areas of the abdomen, thigh, or upper arm that are not tender, bruised, red, or indurated. For multiple injections, do not use the same injection site.
Do not co-administer Ajovy with other injectable drugs at the same injection site.

Dosage adjustments.

Renal or hepatic impairment.

No dose adjustment is required in patients with renal or hepatic impairment.

Paediatric population.

The safety and efficacy of Ajovy in children and adolescents below the age of 18 years have not yet been established. No data are available.

Elderly.

There is limited data available on the use of Ajovy in patients ≥ 65 years of age. Based on the results of population pharmacokinetic analysis, no dose adjustment is required.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1.

4.4 Special Warnings and Precautions for Use

In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Identified precautions.

Hypersensitivity.

Hypersensitivity reactions, including rash, pruritus, drug hypersensitivity and urticaria, were reported with fremanezumab in clinical trials and in the post-marketing setting. Hypersensitivity reactions were reported with Ajovy in less than 1% of patients in clinical trials. If a hypersensitivity reaction occurs, discontinuation of Ajovy administration should be considered and appropriate therapy should be initiated.
Anaphylactic reactions have been reported rarely with fremanezumab. These reactions mostly occurred within 24 hours of administration although some reactions have been delayed.
In the post-marketing period, one patient who was taking multiple concomitant medications including lamotrigine, and treated with fremanezumab, was reported to have Stevens-Johnson Syndrome. This reaction has also been rarely reported to occur in patients taking other anti-CGRP monoclonal antibodies, along with concomitant medications including lamotrigine.

Major cardiovascular diseases.

Patients with certain major cardiovascular diseases were excluded from clinical studies (see Section 5.1). No safety data are available in these patients.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal clinical drug interaction studies have been performed with Ajovy.
The safety and efficacy of Ajovy has been evaluated in patients concurrently taking acute migraine treatments (specifically analgesics, ergots, and triptans) and preventive migraine medications. In population pharmacokinetic analysis, concomitant use of these medications was not found to influence fremanezumab exposure.

CYP450 substrates.

Monoclonal antibodies are not metabolised by cytochrome P450 (CYP) enzymes. Fremanezumab is expected to be metabolised in the same manner as other endogenous proteins; degraded into small peptides and amino acids via catabolic pathways. Therefore, direct pharmacokinetic interactions via the CYP pathway are not expected between Ajovy and co-administered small molecular weight medicinal products.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no fertility data in humans. Available non-clinical data do not suggest an effect on fertility. In a combined fertility/embryofetal development study in rats, fremanezumab had no effect on fertility at exposures corresponding to 22 (females) to 45 (males) times those achieved clinically at a 225 mg/month dose (based on AUC).
(Category B1)
There are limited data from the use of Ajovy in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. In embryo-fetal development (EFD) studies in NZW rabbits and SD rats fremanezumab was administered subcutaneously (achieving exposures approximately 20 times those achieved clinically at a 225 mg/month dose) during the organogenesis period of the pregnancy and was well tolerated and did not induce any maternal or embryo-fetal toxicity at any dose level in either animal species.
Data from an embryo-fetal development study in rabbits demonstrated that fremanezumab crossed the placenta. Concentrations of fremanezumab in newborns were about 9% to 23% exposure relative to the maternal exposure.
In a pre- and postnatal development study in rats (achieving fremanezumab exposures 20 times that achieved clinically at a 225 mg/month dose), no maternal effects were noted as well no effects on F1 offspring following subcutaneous weekly dosing.
Fremanezumab has a long half-life (see Section 5.2 Pharmacokinetic Properties). This should be taken into consideration for women who are pregnant or intend to become pregnant while using Ajovy. Monoclonal antibodies, such as Ajovy, are transported across the placenta in a linear fashion as pregnancy progresses. Therefore, exposure of the fetus is likely to be greater during the second and third trimester of pregnancy.
 It is unknown whether fremanezumab is excreted in human milk. A risk to the breastfed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Ajovy therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after authorisation 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.

Summary of the safety profile.

The most frequently reported adverse events were local reactions at the injection site [pain (24%), induration (17%), erythema (16%) and pruritus (2%)].
The safety of Ajovy was evaluated in all completed and ongoing clinical studies for all indications. In the four placebo controlled trials and the single long-term study for migraine, a total of 2,512 patients received at least 1 dose of Ajovy with the mean (standard deviation [SD]) duration of exposure of 244.8 (121.24) days. A total of 2,289 patients (91%) received treatment with Ajovy for ≥ 3 months, 1,731 patients (69%) received treatment with Ajovy for ≥ 6 months, and 775 patients (31%) received treatment with Ajovy for ≥ 12 months.
Table 1 presents the occurrence rates of treatment-emergent adverse events (TEAEs) observed in the double-blind, placebo-controlled trials (phase II and phase III) of the Ajovy clinical development programme. All the adverse events occurring in ≥ 2% of patients who received Ajovy, at any proposed dose, is presented in the table.

Tabulated list of adverse reactions.

Adverse drug reactions from clinical studies are presented according to the MedDRA system organ classification. Within each system organ class, events are ranked by frequency, most frequent events first. Within each frequency grouping, adverse drug reactions are presented in the order of decreasing seriousness. Frequency categories are based on the following convention: 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).
The following adverse drug reactions have been identified in the Ajovy clinical development programme.
Table 2 depicts the relative frequencies of adverse drug reactions in Ajovy and placebo treated patients.

Description of selected adverse events.

Injection site reactions.

The most frequently observed local reactions at the injection site were pain, induration and erythema. These reactions were predominantly mild to moderate in severity. Pain, induration and erythema were typically observed immediately after injection while pruritus and rash appeared within a median of 24 and 48 hours, respectively. All injection site reactions resolved, mostly within a few hours or days. Injection site reactions generally did not necessitate discontinuation of the medicinal product.

Immunogenicity.

Clinical immunogenicity of Ajovy was monitored by analysing anti-drug antibodies (ADA) and neutralising antibodies in drug-treated patients. In placebo-controlled studies, 0.4% of patients (6 out of 1,701) treated with Ajovy developed anti-drug antibodies (ADA). The antibody responses were of low titer. One of these 6 patients developed neutralising antibodies. With 12 months of treatment, in the long-term study [Study 3], ADA were detected in 2.3% of patients (43 out of 1,888) with 0.95% of the patients developing neutralising antibodies. There were no significant adverse events related to ADA development in patients with treatment-emergent ADA. The safety and efficacy of fremanezumab were not affected by ADA development.

Adverse reactions from post-marketing reports.

The following are additional adverse drug reactions that have been reported since the introduction of fremanezumab to the market. Frequency categories are based on the following convention: Very common (≥ 10%); common (≥ 1% to < 10%); uncommon (≥ 0.1% to < 1%); rare (≥ 0.01% to < 0.1%); very rare (< 0.01% including isolated reports).

Immune system disorders.

Uncommon: Hypersensitivity reactions such as rash, pruritus, urticaria and swelling.
Rare: Anaphylactic reaction.

Gastrointestinal disorders.

Unknown: Constipation*.
*Causal relationship not established.

4.9 Overdose

Doses up to 2000 mg have been administered intravenously in clinical trials without dose-limiting toxicity. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse effects and given appropriate symptomatic treatment if necessary.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Analgesics, antimigraine preparations, ATC code: N02CD03.

Mechanism of action.

Fremanezumab is a fully humanised IgG2Δa/kappa monoclonal antibody produced by recombinant DNA technology that is derived from a murine precursor. Fremanezumab potently and selectively binds the calcitonin gene-related peptide (CGRP) ligand and blocks both CGRP isoforms (α-and β-CGRP) from binding to the CGRP receptor preventing the activation of the trigeminal system. While the precise mechanism of action by which fremanezumab prevents migraine attacks is unknown, it is believed that prevention of migraine is obtained by its effect modulating the trigeminal system.
Fremanezumab is highly specific for CGRP and does not bind to closely related family members (e.g. amylin, calcitonin, intermedin and adrenomedullin).

Pharmacodynamic effects.

Fremanezumab binds to the C-terminus of CGRP preventing interaction with the CGRP receptor and thereby inhibits physiological signalling of the CGRP receptor. The relationship between the pharmacodynamic activity and the mechanism(s) by which fremanezumab exerts its clinical effects is unknown.

Clinical trials.

Patients with certain major cardiovascular diseases were excluded from clinical studies. No safety data are available in these patients.

Efficacy.

The efficacy of Ajovy was assessed in two randomised, 12-week, double-blind, placebo-controlled phase III studies in adult patients with episodic (Study 1) and chronic migraine (Study 2).
Episodic migraine. Study 1 included adults with a history of episodic migraine (patients with less than 15 headache days per month). All patients were randomised to one of three arms: 675 mg fremanezumab every three months (quarterly), 225 mg fremanezumab once a month (monthly), or monthly administration of placebo administered via subcutaneous injection. Patients were allowed to use acute headache treatments during the study. A sub-set of patients (21%) were also allowed to use one concomitant, preventive medication, consistent with patient treatment outside of controlled clinical settings.
In Study 1, a total of 875 patients (742 females, 133 males), ranging in age from 18 to 70 years, were randomised. A total of 791 patients completed the 12-week double-blind treatment period.
The primary efficacy endpoint was the mean change from baseline in the monthly average number of migraine days during the 12-week treatment period. Both monthly and quarterly dosing regimens of Ajovy demonstrated statistically significant and clinically meaningful improvement from baseline compared to placebo at all time points over the 12-week treatment period (see Figure 1).
Ajovy treatment demonstrated statistically significant and clinically meaningful improvements from baseline compared to placebo for all key efficacy variables (see Table 3).
On average in a given month, more than 67% of episodic migraine patients treated with Ajovy achieved at least a 25% reduction in monthly migraine days (compared to 53% of placebo), while more than 25% of patients achieved at least a 75% reduction in monthly migraine days (compared to 15% of placebo), and more than 8% of patients achieved a 100% reduction in monthly migraine days (compared to 4% of placebo).
Chronic migraine. Study 2 included adults with a history of chronic migraine (patients with 15 headache days or higher per month). All patients were randomised to one of three arms: 675 mg fremanezumab for the starting dose, followed by 225 mg fremanezumab once a month (monthly), 675 mg fremanezumab every three months (quarterly), or monthly administration of placebo administered via subcutaneous injection. Patients were allowed to use acute headache treatments during the study. A sub-set of patients (21%) were also allowed to use one concomitant, preventive medication, consistent with patient treatment outside of controlled clinical settings.
In Study 2, a total of 1,130 patients (991 females, 139 males), ranging in age from 18 to 70 years, were randomised. A total of 1,034 patients completed the 12-week double-blind treatment period.
The primary efficacy endpoint was the mean change from baseline in the monthly average number of headache days of at least moderate severity during the 12-week treatment period (see Table 4). Both monthly and quarterly dosing regimens of Ajovy demonstrated statistically significant and clinically meaningful improvement from baseline compared to placebo at all time points over the 12-week treatment period (see Figure 2).
Ajovy treatment demonstrated statistically significant and clinically meaningful improvements from baseline compared to placebo for all key efficacy variables.
On average in a given month, more than 61% of chronic migraine patients treated with Ajovy achieved at least a 25% reduction in monthly headache days of at least moderate severity (compared to 46% of placebo), while more than 20% of patients achieved at least a 75% reduction in monthly headache days of at least moderate severity (compared to 10% of placebo), and more than 7% of patients achieved a 100% reduction in monthly headache days of at least moderate severity (compared to 4% of placebo).

Long-term open label study (study 3).

For all episodic and chronic migraine patients, efficacy was sustained for up to 12 additional months in the long-term open label study (Study 3), in which patients received 225 mg fremanezumab monthly or 675 mg quarterly. 79% of patients completed the 12-month treatment period of Study 3. Pooled across the two dosing regimens, a reduction of 6.6 monthly migraine days was observed after 15 months relative to Study 1 and Study 2 baseline. 61% of patients completing Study 3 achieved a 50% response in the last month of the study. No safety signal was observed during the 15-month combined treatment period.
Intrinsic and extrinsic factors. The efficacy and safety of Ajovy was demonstrated regardless of age, gender, race, use of concomitant preventive medications, use of topiramate for migraine in the past, and use of onabotulinumtoxin A for migraine in the past.
Difficult to treat migraine. The efficacy and safety of fremanezumab in a total of 838 episodic and chronic migraine patients with documented inadequate response to two to four classes of prior migraine preventive medicinal products was assessed in a randomised study (Study 4), which was composed of a 12-week double-blind, placebo-controlled treatment period followed by a 12-week open-label period.
The primary efficacy endpoint was the mean change from baseline in the monthly average number of migraine days during the 12-week double-blind treatment period. Key secondary endpoints were the achievement of at least 50% reduction from baseline in monthly migraine days, the mean change from baseline in the monthly average number of headache days of at least moderate severity and change from baseline in monthly average number of days of acute headache medicinal product use. Both monthly and quarterly dosing regimens of fremanezumab demonstrated statistically significant and clinically meaningful improvement from baseline compared to placebo for key endpoints. Therefore, the results of Study 4 are consistent with the main findings of the previous efficacy studies, and in addition, demonstrate efficacy in difficult to treat migraine, including mean reduction in monthly migraine days (MMD) of -3.7 (95% CI: -4.38, -3.05) with fremanezumab quarterly and -4.1 (95% CI: -4.73, -3.41) with fremanezumab monthly compared to -0.6 (95% CI: -1.25, 0.07) in placebo-treated patients. 34% of the patients treated with fremanezumab quarterly and 34% of the patients treated with fremanezumab monthly achieved at least 50% reduction in MMD, compared to 9% in placebo-treated patients (p < 0.0001) during the 12-week treatment period. The effect also occurred from as early as the first month and was sustained over the treatment period (see Figure 3). No safety signal was observed during the 6-month treatment period.

5.2 Pharmacokinetic Properties

Absorption.

After single subcutaneous administrations of 225 mg, 675 mg, and 900 mg fremanezumab, median time to maximum concentrations (tmax) was 5 to 7 days. The absolute bioavailability of fremanezumab after subcutaneous administration was about 55% as determined by subcutaneous vs. intravenous administrations of 225 mg and 900 mg. Dose proportionality, based on population pharmacokinetics, was observed between 225 mg to 900 mg. Steady state was achieved by approximately 168 days (about 6 months) following 225 mg subcutaneous monthly and 675 mg subcutaneous quarterly dose regimens. Median accumulation ratio, based on once monthly and once quarterly dosing regimens, is approximately 2.3 and 1.2, respectively.

Distribution.

Fremanezumab has an apparent volume of distribution of approximately 6 litres (for a patient at a weight of 71 kg), suggesting minimal distribution to the extravascular tissues.

Metabolism.

Similar to other monoclonal antibodies, fremanezumab is expected to be degraded by enzymatic proteolysis into small peptides and amino acids (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Elimination.

As fremanezumab binds to a soluble target, it is not expected to be eliminated through a target-mediated clearance. Fremanezumab has an apparent clearance of approximately 0.141 L/day (for a patient at a weight of 71 kg). Fremanezumab has an estimated half-life of 31 days.

Special populations.

A population pharmacokinetic analysis looking at age, race, gender, and weight was conducted on data from 2,287 subjects. No dose adjustments are required for Ajovy.

Renal or hepatic impairment.

Since monoclonal antibodies are not known to be eliminated via renal pathways or metabolised in the liver, renal and hepatic impairment are not expected to impact the pharmacokinetics of fremanezumab. No clinical studies were conducted to assess the effect of renal or hepatic impairment on the pharmacokinetics of fremanezumab.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity or toxicity to reproduction and development in studies conducted in rats and monkeys.
Intravenous and subcutaneous repeated administrations to rats (up to 3 months) and monkeys (up to 6 months) did not induce toxic effect and no target organs were identified (including injection sites). In the pivotal 6-month chronic toxicity study in monkeys at the NOAEL (No Observed Adverse Effects Level) dose of 300 mg/kg/week (at least 158 times the exposure achieved at MRHD (Maximum Recorded Human Dose) on an AUC (Area Under the Curve) basis) subcutaneous weekly dosing was well tolerated.
Safety pharmacology studies to assess cardiovascular (CV) effects in cynomolgus monkeys demonstrated no CV effects following single and repeated administrations. No effect on CNS and respiratory function was noted following a single administration to SD (Sprague Dawley) rats.

Genotoxicity.

As fremanezumab is a monoclonal antibody, no genotoxicity studies have been conducted.

Carcinogenicity.

As fremanezumab is a monoclonal antibody no carcinogenicity studies have been conducted.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each pre-filled syringe or autoinjector contains the following excipients: histidine, histidine hydrochloride monohydrate, sucrose, disodium edetate, polysorbate 80, water for injections.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store in a refrigerator (2°C to 8°C). Do not freeze.
Store in the original carton in order to protect from light.
Ajovy may be stored unrefrigerated for up to 7 days at a temperature up to 30°C. Ajovy must be discarded if not used within 7 days of removal from refrigeration.

6.5 Nature and Contents of Container

Ajovy is supplied as follows:

Autoinjector.

Autoinjector containing an integrated 1.5 mL solution in a 2.25 mL Type I glass pre-filled syringe with plunger stopper (bromobutyl rubber) and needle.
Pack sizes of 1 or 3 autoinjectors. Not all pack sizes may be marketed.

Pre-filled syringe.

1.5 mL solution in a 2.25 mL Type I glass syringe with plunger stopper (bromobutyl rubber) and needle. The pre-filled syringe cap is not made with natural rubber latex.
Pack sizes of one 225 mg/1.5 mL or three 225 mg/1.5 mL pre-filled syringes. Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

Dispose of carefully in a sharps container. Do not throw away (dispose of) loose needles, syringes, prefilled syringes or autoinjectors in your household rubbish.
Do not recycle used sharps disposal container.

6.7 Physicochemical Properties

Chemical structure.

C6470H9952N1716O2016S46.

CAS number.

1655501-53-3.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only.

Summary Table of Changes