Fremanezumab

AJOVY is indicated for prophylaxis of migraine in adults who have at least 4 migraine days per month.

The treatment should be initiated by a physician experienced in the diagnosis and treatment of migraine. Posology Treatment is intended for patients with at least 4 migraine days per month when initiating treatment with fremanezumab.

Two subcutaneous dosing options are available: • 225 mg once monthly (monthly dosing) or • 675 mg every three months (quarterly dosing), which is administered as three consecutive subcutaneous injections of 225 mg each. When switching dosing regimens, the first dose of the new regimen should be administered on the next scheduled dosing date of the prior regimen.

1). The treatment benefit should be assessed within 3 months 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 a fremanezumab 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. Special Populations Elderly There is limited data available on the use of fremanezumab in patients ≥65 years of age.

2). 2). 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. Method of administration Subcutaneous use. AJOVY is for subcutaneous injection only.

It should not be administered by the intravenous or intramuscular route. AJOVY can be injected into areas of the abdomen, thigh, or upper arm that are not tender, bruised, red, or indurated. For multiple injections, injection sites should be alternated.

Patients may self-inject if instructed in subcutaneous self-injection technique by a healthcare professional. 6.

Summary of the safety profile A total of over 2,500 patients (more than 1,900 patient years) have been treated with AJOVY in registration studies. More than 1,400 patients were treated for at least 12 months. Commonly reported adverse drug reactions (ADRs) were local reactions at the injection site (pain [24%], induration [17%], erythema [16%] and pruritus [2%]).

The adverse reactions that most commonly led to discontinuations were injection site reactions (1%). Table 1 summarizes adverse reactions reported in the 3-month placebo-controlled studies (Study 1 and Study 2), and the 1-month follow-up period after those studies.

Tabulated list of adverse reactions ADRs from clinical studies and post-marketing reports are presented according to MedDRA system organ classification. Within each frequency grouping, ADRs 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). Within each system organ class, ADRs are ranked by frequency, most frequent reactions first.

Table 1:

Adverse reactions occurring with an incidence of at least 2% for either dosing regimen of fremanezumab and at least 2% greater than placebo in Studies 1 and 2 Fremanezumab 225 mg Monthly (n = 290) % Fremanezumab 675 mg Quarterly (n = 667) % Placebo Monthly (n = 668) % Injection site reactionsa 43 45 38 a Injection site reactions include multiple related adverse event terms, such as injection site pain, induration and erythema.

The following ADRs have been identified for AJOVY (Table 2).

Table 2:

Adverse reactions MedDRA System Organ Class Frequency Adverse Reaction Uncommon Hypersensitivity reactions such as rash, pruritus, urticaria and swelling Immune system disorders Rare Anaphylactic reaction Injection site pain Injection site induration Very common Injection site erythema Common Injection site pruritus General disorders and administration site conditions Uncommon Injection site rash Description of selected adverse reactions Serious hypersensitivity reactions Anaphylactic reactions have been reported rarely.

These reactions mostly occurred within 24 hours of administration although some reactions have been delayed. Injection site reactions The most frequently observed local reactions at the injection site were pain, induration and erythema.

All local injection site reactions were transient and 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. 4 % of patients (6 out of 1,701) treated with fremanezumab developed anti-drug antibodies (ADA).

The antibody responses were of low titer. One of these 6 patients developed neutralising antibodies. 95% of the patients developing neutralising antibodies. The safety and efficacy of fremanezumab were not affected by ADA development.

Reporting of suspected adverse reactions 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. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

1.

PrAJOVY® (fremanezumab solution for subcutaneous injection) is indicated for: • the prevention of migraine in adults who have at least 4 migraine days per month. • the prevention of episodic migraine (fewer than 15 migraine days per month) in pediatric patients aged 6 to 17 years and weighing at least 45 kg.

AJOVY should be initiated by healthcare professionals experienced in the diagnosis and treatment of migraine. 1 Pediatrics Pediatrics (6 to 17 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of AJOVY in pediatric patients 6-17 years, weighing at least 45 kg and with a clinical diagnosis of episodic migraine (fewer than 15 migraine days per month) have been established (see Recommended Dose and Dosage Adjustment).

Therefore, Health Canada has authorized an indication for pediatric use in these patients. The safety and efficacy of AJOVY in children below 6 years of age have not been established. 2 Geriatrics Geriatrics (≥ 65 years of age): Clinical studies of AJOVY did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

(See WARNINGS AND PRECAUTIONS, Geriatrics)

1 Dosing Considerations AJOVY is administered subcutaneously through single dose prefilled syringes or single dose prefilled autoinjectors. AJOVY may be self-administered by patients 13 years of age and older, or administered by healthcare professionals and/or adult caregivers.

In pediatric patients 6 to 12 years of age, AJOVY must be administered by a healthcare professional or adult caregiver. Administration should be performed by an individual who has been trained to administer the product. 2 Recommended Dose and Dosage Adjustment • Adults Two subcutaneous dosing options of AJOVY are available to administer the recommended dosage (See Clinical Trials): • 225 mg (1 subcutaneous injection) once a month (monthly dosing), or • 675 mg (3 separate subcutaneous injections of 225 mg one after another) every 3 months (quarterly dosing).

The dose regimen must be followed as prescribed. Patients should be advised that monthly dosing consists of a single subcutaneous injection. When switching dosage options, the first dose of the new regimen should be given on the next scheduled dosing date of the prior regimen.

• Pediatrics (6 to 17 years of age) and weighing at least 45 kg The recommended dosage in pediatric patients aged 6 to 17 years, weighing at least 45 kg is: - 225 mg (1 subcutaneous injection) once a month (monthly dosing) Do not administer AJOVY to pediatric patients weighing less than 45 kg as an appropriate strength presentation is not available.

(see CLINICAL TRIALS). For both adult and pediatric patients, the treatment benefit should be assessed within 3 months after initiation of the 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. (See CLINICAL TRIALS). 4 Administration AJOVY is for subcutaneous use only. AJOVY may be administered by healthcare professionals, patients and/or caregivers.

Only healthcare professionals and/or caregivers may administer AJOVY to pediatric patients aged 12 years and younger. Prior to use, provide proper training to patients and/or caregivers on the preparation and administration of AJOVY prefilled syringe or prefilled autoinjector, including aseptic technique [see respective Instructions for Use].

• Remove AJOVY from the refrigerator. Prior to use, allow AJOVY to sit at room temperature for 30 minutes protected from direct sunlight. Do not warm by using a heat source such as hot water or a microwave. Do not use AJOVY if it has been at room temperature for 7 days or longer.

(See STORAGE, STABILITY AND DISPOSAL). • Follow aseptic injection technique every time AJOVY is administered. Inspect AJOVY for particles or discolouration prior to administration. Do not use if the solution is cloudy, discoloured, or contains particles.

(See DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING). • 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, you may use the same body site, but not the exact location of the previous injection.

5 Missed Dose If an AJOVY injection is missed on the planned date, the missed dose should be administered as soon as possible. The regular dosing regimen should resume from the new dosing day. A double dose must not be administered to make up for a missed dose.

5 OVERDOSE 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 the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

1 Adverse Reaction Overview Adults Hypersensitivity reactions, including rash, pruritus and urticaria were reported with fremanezumab in less than 1% of patients in clinical trials. Most reactions were mild to moderate, but some led to discontinuation or required corticosteroid treatment.

Most reactions were reported from within hours to one month after administration. Hypersensitivity reactions, including urticaria, pruritus, rash and swelling/edema have also been reported with fremanezumab in post-marketing experience.

Very common reported adverse drug reactions (ADRs) from the clinical trials were local reactions at the injection site pain, induration, erythema and pruritus. The adverse reactions that most commonly led to discontinuations were injection site reactions.

Pediatrics No new clinical trial safety findings were noted for AJOVY use in the pediatric population compared to the known safety profile from the adult clinical trials. 2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions.

Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug. The safety of AJOVY was evaluated in 2512 adult patients with migraine who received at least one dose of AJOVY 225 mg monthly or AJOVY 675 mg quarterly for at least six months; 775 patients for at least 12 months; and 138 patients for at least 15 months.

In placebo- controlled clinical trials (Studies 1 and 2), 662 patients received AJOVY 225 mg monthly for 12 weeks (with or without a loading dose of 675 mg), and 663 patients received AJOVY 675 mg quarterly for 12 weeks (See CLINICAL TRIALS) .

In the controlled trials, 87% of patients were female, 80% were White, and the mean age was 41 years. The most common adverse reactions in the clinical trials for the preventive treatment of migraine were injection site reactions. The adverse reactions that most commonly led to discontinuations were injection site reactions.

Patients with significant cardiovascular disease, vascular ischemia, or thrombotic events, such as cerebrovascular accident, transient ischemic attacks, deep vein thrombosis, or pulmonary embolism were excluded from the clinical trials.

(See CLINICAL TRIALS) Table 2: Adverse Reactions Occurring with an Incidence of ≥ 1% and Greater Than Placebo in Episodic and Chronic Migraine Studies System Organ Class Preferred Term AJOVY 225 mg monthly N=290 AJOVY 675 mg quarterly N=667 Placebo N=668 Injection site reactions* 43 % 45 % 38 % *Injection site reactions include multiple related adverse event terms, such as injection site pain, induration, and erythema Table 3: Treatment Emergent adverse events occurring with an incidence of ≥1% in the Placebo Controlled Studies System Organ Class Preferred Term AJOVY 225 mg monthly N=290 n= (%) AJOVY 675 mg quarterly N=667 n= (%) Placebo N=668 n= (%) Patients with at least 1 AE 192 (66) 458 (69) 411 (62) System Organ Class Preferred Term AJOVY 225 mg monthly N=290 n= (%) AJOVY 675 mg quarterly N=667 n= (%) Placebo N=668 n= (%) Gastrointestinal Disorders Nausea 4 (1) 11 (2) 16 (2) Diarrhoea 2 (<1) 5 (<1) 8 (1) General disorders and administration site conditions Injection site pain 87 (30) 200 (30) 180 (27) Injection site induration 71 (24) 131 (20) 113 (17) Injection site erythema 52 (18) 135 (20) 101 (15) Injection site haemorrhage 3 (1) 16 (2) 16 (2) Injection site pruritus 4 (1) 10 (1) 2 (<1) Fatigue 2 (<1) 9 (1) 9 (1) Injection site rash 3 (1) 5 (<1) 0 Injection site swelling 3 (1) 4 (<1) 0 Infections and infestations Upper respiratory tract infection 16 (6) 29 (4) 30 (4) Nasopharyngitis 11 (4) 30 (4) 29 (4) Urinary tract infection 7 (2) 14 (2) 11 (2) Bronchitis 6 (2) 9 (1) 6 (<1) Sinusitis 4 (1) 12 (2) 18 (3) Influenza 2 (<1) 8 (1) (1) Gastroenteritis 4 (1) 4 (<1) 5 (<1) Cystitis 3 (1) 1 (<1) 1 (<1) System Organ Class Preferred Term AJOVY 225 mg monthly N=290 n= (%) AJOVY 675 mg quarterly N=667 n= (%) Placebo N=668 n= (%) Herpes zoster 3 (1) 0 1 (<1) Injury, poisoning and procedural complications Ligament sprain 1 (<1) 3 (<1) 2 (<1) Investigations Blood creatine phosphokinase increased 1 (<1) 3 (<1) 7 (1) Alanine aminotransferase increased 1 (<1) 3 (<1) 1 (<1) Aspartate aminotransferase increased 1 (<1) 3 (<1) 1 (<1) Musculoskeletal and connective tissue disorders Back pain 3 (1) 11 (2) 9 (1) Musculoskeletal pain 3 (1) 4 (<1) 0 Arthralgia 3 (1) 2 (<1) 1 (<1) Nervous system disorders Dizziness 3 (1) 9 (1) 9 (1) Paraesthesia 2 (<1) 9 (1) 4 (<1) Migraine 1 (<1) 6 (<1) 11 (2) Respiratory, thoracic and mediastinal disorders Cough 1 (<1) 8 (1) 6 (<1) Skin and subcutaneous tissue disorders Pruritus 0 8 (1) 1 (<1) Injection site reactions The most frequently observed local reactions at the injection site were pain, induration and erythema.

Most local injection site reactions were transient and 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.

Most injection site reactions resolved, generally within a few hours or days. If the intensity of Injection site reactions is severe, discontinuation of fremanezumab should be considered. 1 Clinical Trial Adverse Reactions – Pediatrics Over 400 pediatric patients with migraine, 6 to 17 years of age, have been treated with AJOVY in registration studies.

This included 123 pediatric patients in the placebo-controlled trial with episodic migraine (EM). The only adverse reactions of AJOVY observed in this study were injection site reactions, which is similar to the overall safety profile observed in adult clinical studies.

The injection site reactions reported were injection site erythema, injection site pain, and injection site swelling. Table 4 summarizes adverse reactions reported in the 3- month […]

AJOVY (fremanezumab) is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, (see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING).

AJOVY is indicated for prophylaxis of migraine in adults who have at least 4 migraine days per month.

The treatment should be initiated by a physician experienced in the diagnosis and treatment of migraine. Posology 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.

1). The treatment benefit should be assessed within 3 months 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.

3 Missed dose If a fremanezumab 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. Special populations Elderly There is limited data available on the use of fremanezumab in patients ≥65 years of age.

2). 2). 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. Method of administration Subcutaneous use. AJOVY is for subcutaneous injection only.

AJOVY can be injected into areas of the abdomen, thigh, or upper arm that are not tender, bruised, red, or indurated. For multiple injections, injection sites should be alternated. Patients may self-inject if instructed in subcutaneous self-injection technique by a healthcare professional.

6.

Summary of the safety profile A total of over 2,500 patients (more than 1,900 patient years) have been treated with AJOVY in registration studies. More than 1,400 patients were treated for at least 12 months. Commonly reported adverse drug reactions (ADRs) were local reactions at the injection site (pain [24%], induration [17%], erythema [16%] and pruritus [2%]).

Tabulated list of adverse reactions ADRs from clinical studies and post-marketing reports are presented according to MedDRA system organ classification. Within each frequency grouping, ADRs 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). Within each system organ class, ADRs are ranked by frequency, most frequent reactions first.

The following ADRs have been identified for AJOVY (Table 1). 5 Table 1: Adverse reactions MedDRA System Organ Class Frequency Adverse reaction Immune system disorders Uncommon Hypersensitivity reactions such as rash, pruritus, urticaria and swelling Rare Anaphylactic reaction General disorders and administration site conditions Very common Injection site pain Injection site induration Injection site erythema Common Injection site pruritus Uncommon Injection site rash Description of selected adverse reactions Injection site reactions The most frequently observed local reactions at the injection site were pain, induration and erythema.

All local injection site reactions were transient and 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. Serious hypersensitivity reactions Anaphylactic reactions have been reported rarely.

These reactions mostly occurred within 24 hours of administration although some reactions have been delayed. 4 % of patients (6 out of 1,701) treated with fremanezumab developed anti-drug antibodies (ADA). The antibody responses were of low titer.

One of these 6 patients developed neutralising antibodies. 95% of the patients developing neutralising antibodies. The safety and efficacy of fremanezumab were not affected by ADA development. Reporting of suspected adverse reactions 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 via the national reporting system listed in Appendix V.

1.