AJOVY 225mg 150mg / ml injection solution in pre-filled syringe medication leaflet

AJOVY 225 mg solution for injection in pre-filled syringe

AJOVY 225 mg solution for injection in pre-filled pen

One pre-filled syringe contains 225 mg fremanezumab.

Pre-filled pen

One pre-filled pen contains 225 mg fremanezumab.

Fremanezumab is a humanised monoclonal antibody produced in Chinese Hamster Ovary (CHO) cellsby recombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Clear to opalescent, colourless to slightly yellow solution with a pH of 5.5 and an osmolality of320-420 mOsm/kg.

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

The treatment should be initiated by a physician experienced in the diagnosis and treatment ofmigraine.

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 thenext scheduled dosing date of the prior regimen.

When initiating treatment with fremanezumab, concomitant migraine preventive treatment may becontinued, if considered necessary by the prescriber (see section 5.1).

The treatment benefit should be assessed within 3 months after initiation of treatment. Any furtherdecision to continue treatment should be taken on an individual patient basis. Evaluation of the need tocontinue treatment is recommended regularly thereafter.

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

There is limited data available on the use of fremanezumab in patients ≥65 years of age. Based on theresults of population pharmacokinetic analysis, no dose adjustment is required (see section 5.2).

No dose adjustment is necessary in patients with mild to moderate renal impairment or hepaticimpairment (see section 5.2).

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

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 sitesshould be alternated.

Patients may self-inject if instructed in subcutaneous self-injection technique by a healthcareprofessional. For further instructions on administration, see section 6.6.

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

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

Serious hypersensitivity reactions

Anaphylactic reactions have been reported rarely with fremanezumab (see section 4.8). Most reactionshave occurred within 24 hours of administration although some reactions have been delayed. Patientsshould be warned about the symptoms associated with hypersensitivity reactions. If a serioushypersensitivity reaction occurs, initiate appropriate therapy and do not continue treatment withfremanezumab (see section 4.3).

Major cardiovascular diseases

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

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., is essentially“sodium-free”.

No formal clinical drug interaction studies have been performed with AJOVY. No pharmacokineticdrug interactions are expected based on the characteristics of fremanezumab. Furthermore,concomitant use of acute migraine treatments (specifically analgesics, ergots, and triptans) andmigraine preventive medicinal products during the clinical studies did not affect the pharmacokineticsof fremanezumab.

There is a limited amount of data from the use of AJOVY in pregnant women. Animal studies do notindicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As aprecautionary measure, it is preferable to avoid the use of AJOVY during pregnancy.

It is unknown whether fremanezumab is excreted in human milk. Human IgG is known to be excretedin breast milk during the first days after birth, which is decreasing to low concentrations soonafterwards; consequently, a risk to breast-fed infants cannot be excluded during this short period.

Afterwards, use of fremanezumab could be considered during breast-feeding only if clinically needed.

There are no fertility data in humans. Available non-clinical data do not suggest an effect on fertility(see section 5.3).

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

A total of over 2,500 patients (more than 1,900 patient years) have been treated with AJOVY inregistration 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%]).

ADRs from clinical studies and post-marketing reports are presented according to MedDRA systemorgan classification. Within each frequency grouping, ADRs are presented in the order of decreasingseriousness. 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 reactionsfirst.

The following ADRs have been identified for AJOVY (Table 1).

Table 1: Adverse reactions

MedDRA System Organ Frequency Adverse reaction

Class

Immune system disorders Uncommon Hypersensitivity reactions suchas rash, pruritus, urticaria andswelling

Rare Anaphylactic reaction

General disorders and Very common Injection site painadministration site conditions Injection site induration

Injection site erythema

Common Injection site pruritus

Uncommon Injection site rash

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 rashappeared 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 discontinuationof the medicinal product.

Serious hypersensitivity reactions

Anaphylactic reactions have been reported rarely. These reactions mostly occurred within 24 hours ofadministration although some reactions have been delayed.

In placebo-controlled studies, 0.4 % of patients (6 out of 1,701) treated with fremanezumab developedanti-drug antibodies (ADA). The antibody responses were of low titer. One of these 6 patientsdeveloped neutralising antibodies. With 12 months of treatment, ADA were detected in 2.3% of thepatients (43 out of 1,888) with 0.95% of the patients developing neutralising antibodies. The safetyand efficacy of fremanezumab were not affected by ADA development.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Doses up to 2,000 mg have been administered intravenously in clinical trials without dose-limitingtoxicity. In case of overdose, it is recommended that the patient be monitored for any signs orsymptoms of adverse reactions and given appropriate symptomatic treatment if necessary.

Pharmacotherapeutic group: analgesics, calcitonin gene-related peptide (CGRP) antagonists. ATCcode: N02CD03.

Fremanezumab is a humanised IgG2Δa/kappa monoclonal antibody derived from a murine precursor.

Fremanezumab selectively binds the calcitonin gene-related peptide (CGRP) ligand and blocks both

CGRP isoforms (α-and β-CGRP) from binding to the CGRP receptor. While the precise mechanism ofaction by which fremanezumab prevents migraine attacks is unknown, it is believed that prevention ofmigraine is obtained by its effect modulating the trigeminal system. CGRP levels have been shown toincrease significantly during migraine and return to normal with headache relief.

Fremanezumab is highly specific for CGRP and does not bind to closely related family members (e.g.,amylin, calcitonin, intermedin and adrenomedullin).

The efficacy of fremanezumab 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).

The patients enrolled had at least a 12-month history of migraine (with and without aura) according tothe International Classification of Headache Disorders (ICHD-III) diagnostic criteria. Elderly patients(>70 years), patients using opioids or barbiturates on more than 4 days per month, and patients withpre-existing myocardial infarction, cerebrovascular accident, and thromboembolic events wereexcluded.

Episodic migraine study (Study 1)

The efficacy of fremanezumab was evaluated in episodic migraine in a randomised, multicentre,12-week, placebo-controlled, double-blind study (Study 1). Adults with a history of episodic migraine(less than 15 headache days per month) were included in the study. A total of 875 patients(742 females, 133 males) were randomised into one of three arms: 675 mg fremanezumab every threemonths (quarterly, n=291), 225 mg fremanezumab once a month (monthly, n=290), or monthlyadministration of placebo (n=294) administered via subcutaneous injection. Demographics andbaseline disease characteristics were balanced and comparable between the study arms. Patients had amedian age of 42 years (range: 18 to 70 years), 85% were female, and 80% were white. The meanmigraine frequency at baseline was approximately 9 migraine days per month. Patients were allowedto use acute headache treatments during the study. A sub-set of patients (21%) was also allowed to useone commonly used concomitant, preventive medicinal product (beta-blockers, calcium channelblocker/benzocycloheptene, antidepressants, anticonvulsants). Overall, 19% of the patients hadpreviously used topiramate. A total of 791 patients completed the 12-week double-blind treatmentperiod.

The primary efficacy endpoint was the mean change from baseline in the monthly average number ofmigraine days during the 12-week treatment period. Key secondary endpoints were the achievement ofat least 50% reduction from baseline in monthly migraine days (50% responder rate), mean changefrom baseline in the patient reported MIDAS score, and change from baseline in monthly averagenumber of days of acute headache medicinal product use. Both monthly and quarterly dosing regimensof fremanezumab demonstrated statistically significant and clinically meaningful improvement frombaseline compared to placebo for key endpoints (see Table 2). The effect also occurred from as earlyas the first month and sustained over the treatment period (see Figure 1).

Figure 1: Mean Change from Baseline in the Monthly Average Number of Migraine Days for

Study 1

Placebo AJOVY Quarterly AJOVY Monthly0.0

- 0.5

- 1.0

- 1.5

- 2.0

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- 3.0

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Visit: Baseline Week 1 Week 2 Week 3 Month 1 Month 2 Month 3

AJOVY Monthly <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.0002

AJOVY Quarterly <0.0001 <0.0001 0.0003 <0.0001 0.0009 0.0013

Mean at baseline (monthly average number of migraine days): Placebo: 9.1, AJOVY Quarterly: 9.2, AJOVY

Monthly: 8.9.

Table 2: Key Efficacy Outcomes in Study 1 in Episodic Migraine

Efficacy Endpoint Placebo Fremanezumab Fremanezumab(n=290) 675 mg quarterly 225 mg monthly(n=288) (n=287)

MMD

Mean changea (95% -2.2 (-2.68, -1.71) -3.4 (-3.94, -2.96) -3.7 (-4.15, -3.18)

CI) - -1.2 (-1.74, -0.69) -1.4 (-1.96, -0.90)

TD (95% CI)b 9.1 (2.65) 9.2 (2.62) 8.9 (2.63)

Baseline (SD)

P-value (vs. placebo)a - p<0.0001 p<0.0001

MHD

Mean changea (95% -1.5 (-1.88, -1.06) -3.0 (-3.39, -2.55) -2.9 (-3.34, -2.51)

CI) - -1.5 (-1.95, -1.02) -1.5 (-1.92, -0.99)

TD (95% CI)b 6.9 (3.13) 7.2 (3.14) 6.8 (2.90)

Baseline (SD)

P-value (vs. placebo)a - p<0.0001 p<0.000150% Responder Rate

MMD

Percentage [%] 27.9% 44.4% 47.7%

P-value (vs. placebo) - p<0.0001 p<0.000175% Responder Rate

MMD

Percentage [%] 9.7% 18.4% 18.5%

P-value (vs. placebo) - p=0.0025 p=0.0023

MIDAS total

Mean changea (95% -17.5 (-20.62, -14.47) -23.0 (-26.10, -19.82) -24.6 (-27.68, -21.45)

CI) 37.3 (27.75) 41.7 (33.09) 38 (33.30)

Baseline (SD)

P-value (vs. placebo)a - p=0.0023 p<0.0001

MAHMD

Mean changea (95% -1.6 (-2.04, -1.20) -2.9 (-3.34, -2.48) -3.0 (-3.41, -2.56)

CI) - -1.3 (-1.73, -0.78) -1.3 (-1.81, -0.86)

LS Mean (+/- SE) Change from Baseline

TD (95% CI)b 7.7 (3.60) 7.7 (3.70) 7.7 (3.37)

Baseline (SD)

P-value (vs. placebo)a - p<0.0001 p<0.0001

CI = confidence interval; MAHMD = monthly acute headache medicinal products days; MHD = monthlyheadache days of at least moderate severity; MIDAS = Migraine Disability Assessment; MMD = monthlymigraine days; SD = standard deviation; TD = treatment differencea For all endpoints mean change and CIs are based on the ANCOVA model that included treatment, gender,region, and baseline preventive medication use (yes/no) as fixed effects and corresponding baseline value andyears since onset of migraine as covariates.b Treatment difference is based on the MMRM analysis with treatment, gender, region, and baseline preventivemedication use (yes/no), month, and treatment month as fixed effects and corresponding baseline value and yearssince onset of migraine as covariates.

In patients on one other concomitant, migraine preventive medicinal product, the treatment differencefor the reduction of monthly migraine days (MMD) observed between fremanezumab 675 mgquarterly and placebo was -1.8 days (95% CI: -2.95, -0.55) and between fremanezumab 225 mgmonthly and placebo -2.0 days (95% CI: -3.21, -0.86).

In patients who had previously used topiramate the treatment difference for the reduction of monthlymigraine days (MMD) observed between fremanezumab 675 mg quarterly and placebo was -2.3 days(95% CI: -3.64, -1.00) and between fremanezumab 225 mg monthly and placebo -2.4 days(95% CI: -3.61, -1.13).

Chronic migraine study (Study 2)

Fremanezumab was evaluated in chronic migraine in a randomised, multicentre, 12-week, placebo-controlled, double-blind study (Study 2). The study population included adults with a history ofchronic migraine (15 headache days or higher per month). A total of 1,130 patients (991 females,139 males) were randomised into one of three arms: 675 mg fremanezumab starting dose followed by225 mg fremanezumab once a month (monthly, n=379), 675 mg fremanezumab every three months(quarterly, n=376), or monthly administration of placebo (n=375) administered via subcutaneousinjection. Demographics and baseline disease characteristics were balanced and comparable betweenthe study arms. Patients had a median age of 41 years (range: 18 to 70 years), 88% were female, and79% were white. The mean headache frequency at baseline was approximately 21 headache days permonth (of which 13 headache days were of at least moderate severity). Patients were allowed to useacute headache treatments during the study. A sub-set of patients (21%) was also allowed to use onecommonly used concomitant, preventive medicinal product (beta-blockers, calcium channelblocker/benzocycloheptene, antidepressants, anticonvulsants). Overall, 30% of the patients hadpreviously used topiramate and 15% onabotulinumtoxin A. A total of 1,034 patients completed the12-week double-blind treatment period.

The primary efficacy endpoint was the mean change from baseline in the monthly average number ofheadache days of at least moderate severity during the 12-week treatment period. Key secondaryendpoints were the achievement of at least 50% reduction from baseline in monthly headache days ofat least moderate severity (50% responder rate), mean change from baseline in the patient reported

HIT-6 score, and change from baseline in monthly average number of days of acute headachemedicinal product use. Both monthly and quarterly dosing regimens of fremanezumab demonstratedstatistically significant and clinically meaningful improvement from baseline compared to placebo forkey endpoints (see Table 3). The effect also occurred from as early as the first month and sustainedover the treatment period (see Figure 2).

Figure 2: Mean Change from Baseline in the Monthly Average Number of Headache Days of At

Least Moderate Severity for Study 2

Placebo AJOVY Quarterly AJOVY Monthly0.0

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- 2.0

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- 3.0

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- 4.0

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- 5.0

- 5.5

Visit: Baseline Week 1 Week 2 Week 3 Month 1 Month 2 Month 3

AJOVY Monthly <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001

AJOVY Quarterly <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.0007

Mean at baseline (monthly average number of headache days of at least moderate severity): Placebo: 13.3,

AJOVY Quarterly: 13.2, AJOVY Monthly: 12.8.

Table 3: Key Efficacy Outcomes in Study 2 in Chronic Migraine

Efficacy Endpoint Placebo Fremanezumab Fremanezumab(n=371) 675 mg quarterly 225 mg monthly with(n=375) 675 mg starting dose(n=375)

MHD

Mean changea (95% -2.5 (-3.06, -1.85) -4.3 (-4.87, -3.66) -4.6 (-5.16, -3.97)

CI) - -1.8 (-2.45, -1.13) -2.1 (-2.77, -1.46)

TD (95% CI)b 13.3 (5.80) 13.2 (5.45) 12.8 (5.79)

Baseline (SD)

P-value (vs. placebo)a - p<0.0001 p<0.0001

MMD

Mean changea (95% -3.2 (-3.86, -2.47) -4.9 (-5.59, -4.20) -5.0 (-5.70, -4.33)

CI) - -1.7 (-2.44, -0.92) -1.9 (-2.61, -1.09)

TD (95% CI)b 16.3 (5.13) 16.2 (4.87) 16.0 (5.20)

Baseline (SD)

P-value (vs. placebo)a - p<0.0001 p<0.000150% Responder Rate

MHD

Percentage [%] 18.1% 37.6% 40.8%

P-value (vs. placebo) - p<0.0001 p<0.000175% Responder Rate

MHD

Percentage [%] 7.0% 14.7% 15.2%

P-value (vs. placebo) - p=0.0008 p=0.0003

HIT-6 total

Mean changea (95% -4.5 (-5.38, -3.60) -6.4 (-7.31, -5.52) -6.7 (-7.71, -5.97)

CI) 64.1 (4.79) 64.3 (4.75) 64.6 (4.43)

Baseline (SD)

P-value (vs. placebo)a - p=0.0001 p<0.0001

MAHMD

Mean changea (95% -1.9 (-2.48, -1.28) -3.7 (-4.25, -3.06) -4.2 (-4.79, -3.61)

CI) - -1.7 (-2.40, -1.09) -2.3 (-2.95, -1.64)

LS Mean (+/- SE) Change from Baseline

TD (95% CI)b 13.0 (6.89) 13.1 (6.79) 13.1 (7.22)

Baseline (SD)

P-value (vs. placebo)a - p<0.0001 p<0.0001

CI = confidence interval; HIT-6 = Headache Impact Test; MAHMD = monthly acute headache medication days;

MHD = monthly headache days of at least moderate severity; MMD = monthly migraine days; SD = standarddeviation; TD = treatment differencea For all endpoints mean change and CIs are based on the ANCOVA model that included treatment, gender,region, and baseline preventive medication use (yes/no) as fixed effects and corresponding baseline value andyears since onset of migraine as covariates.b Treatment difference is based on the MMRM analysis with treatment, gender, region, and baseline preventivemedication use (yes/no), month, and treatment month as fixed effects and corresponding baseline value and yearssince onset of migraine as covariates.

In patients on one other concomitant, migraine preventive medicinal product, the treatment differencefor the reduction of monthly headache days (MHD) of at least moderate severity observed betweenfremanezumab 675 mg quarterly and placebo was -1.3 days (95% CI: -2.66, 0.03) and betweenfremanezumab 225 mg monthly with 675 mg starting dose and placebo -2.0 days(95% CI: -3.27, -0.67).

In patients who had previously used topiramate the treatment difference for the reduction of monthlyheadache days (MHD) of at least moderate severity observed between fremanezumab 675 mgquarterly and placebo was -2.7 days (95% CI: -3.88, -1.51) and between fremanezumab 225 mgmonthly with 675 mg starting dose and placebo -2.9 days (95% CI: -4.10, -1.78). In patients who hadpreviously used onabotulinumtoxin A the treatment difference for the reduction of monthly headachedays (MHD) of at least moderate severity observed between fremanezumab 675 mg quarterly andplacebo was -1.3 days (95% CI: -3.01, -0.37) and between fremanezumab 225 mg monthly with675 mg starting dose and placebo -2.0 days (95% CI: -3.84, -0.22).

Approximately 52% of the patients in the study had acute headache medication overuse. The observedtreatment difference for the reduction of monthly headache days (MHD) of at least moderate severitybetween fremanezumab 675 mg quarterly and placebo in these patients was -2.2 days (95% CI: -3.14,

- 1.22) and between fremanezumab 225 mg monthly with 675 mg starting dose and placebo -2.7 days(95% CI: -3.71, -1.78).

Long-term study (Study 3)

For all episodic and chronic migraine patients, efficacy was sustained for up to 12 additional months inthe long-term study (Study 3), in which patients received 225 mg fremanezumab monthly or 675 mgquarterly. 79% of patients completed the 12-month treatment period of Study 3. Pooled across the twodosing 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 lastmonth of the study. No safety signal was observed during the 15-month combined treatment period.

Intrinsic and extrinsic factors

The efficacy and safety of fremanezumab was demonstrated regardless of age, gender, race, use ofconcomitant preventive medicinal products (beta-blockers, calcium channelblocker/benzocycloheptene, antidepressants, anticonvulsants), use of topiramate oronabotulinumtoxin A for migraine in the past, and acute headache medication overuse.

There is limited data available on the use of fremanezumab in patients ≥65 years of age (2% of thepatients).

Difficult to treat migraine

The efficacy and safety of fremanezumab in a total of 838 episodic and chronic migraine patients withdocumented inadequate response to two to four classes of prior migraine preventive medicinalproducts 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 ofmigraine days during the 12-week double-blind treatment period. Key secondary endpoints were theachievement of at least 50% reduction from baseline in monthly migraine days, the mean change frombaseline in the monthly average number of headache days of at least moderate severity and changefrom baseline in monthly average number of days of acute headache medicinal product use. Bothmonthly and quarterly dosing regimens of fremanezumab demonstrated statistically significant andclinically 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 inaddition demonstrate efficacy in difficult to treat migraine, including mean reduction in monthlymigraine 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-treatedpatients. 34% of the patients treated with fremanezumab quarterly and 34% of the patients treated withfremanezumab monthly achieved at least 50% reduction in MMD, compared to 9% in placebo-treatedpatients (p<0.0001) during the 12-week treatment period. The effect also occurred from as early as thefirst month and was sustained over the treatment period (see Figure 3). No safety signal was observedduring the 6-month treatment period.

Figure 3: Mean Change from Baseline in Monthly Average Number of Migraine Days for

Study 4

Placebo AJOVY Quarterly AJOVY Monthly0.0

- 0.5

- 1.0

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- 3.0

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- 4.0

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- 5.5

Visit: Baseline Month 1 Month 2 Month 3

AJOVY Monthly <0.0001 <0.0001 <0.0001

AJOVY Quarterly <0.0001 <0.0001 <0.0001

Mean at baseline (monthly average number of migraine days): Placebo: 14.4, AJOVY Quarterly: 14.1, AJOVY

Monthly: 14.1.

The European Medicines Agency has deferred the obligation to submit the results of studies with

AJOVY in one or more subsets of the paediatric population in prevention of migraine headaches (seesection 4.2 for information on paediatric use).

After single subcutaneous administrations of 225 mg and 675 mg fremanezumab, median time tomaximum concentrations (tmax) in healthy subjects was 5 to 7 days. The absolute bioavailability offremanezumab after subcutaneous administration of 225 mg and 900 mg in healthy subjects was 55%(±SD of 23%) to 66% (±SD of 26%). Dose proportionality, based on population pharmacokinetics,was observed between 225 mg to 675 mg. Steady state was achieved by approximately 168 days(about 6 months) following 225 mg monthly and 675 mg quarterly dosing regimens. Median

LS Mean (+/- SE) Change from Baselineaccumulation ratio, based on once monthly and once quarterly dosing regimens, is approximately 2.4and 1.2, respectively.

Assuming the model-derived estimated bioavailability of 66% (±SD of 26%) holds for the patientpopulation, the volume of distribution for a typical patient was 3.6 L (35.1% CV) followingsubcutaneous administration of 225 mg, 675 mg and 900 mg of fremanezumab.

Similar to other monoclonal antibodies, fremanezumab is expected to be degraded by enzymaticproteolysis into small peptides and amino acids.

Assuming the model-derived estimated bioavailability of 66% (±SD of 26%) holds for the patientpopulation, central clearance for a typical patient was 0.09 L/day (23.4% CV) following subcutaneousadministration of 225 mg, 675 mg and 900 mg of fremanezumab. The formed small peptides andamino acids may be re-used in the body for de novo synthesis of proteins or are excreted by thekidney. Fremanezumab has an estimated half-life of 30 days.

A population pharmacokinetic analysis looking at age, race, gender, and weight was conducted on datafrom 2,546 subjects. Approximately twice as much exposure is expected in the lowest body weightquartile (43.5 to 60.5 kg) compared to the highest body weight quartile (84.4 to131.8 kg). However,body weight did not have an observed effect on the clinical efficacy based on the exposure-responseanalyses in episodic and chronic migraine patients. No dose adjustments are required forfremanezumab. No data on exposure-efficacy relationship in subjects with body weight >132 kg isavailable.

Since monoclonal antibodies are not known to be eliminated via renal pathways or metabolised in theliver, renal and hepatic impairment are not expected to impact the pharmacokinetics of fremanezumab.

Patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) have not been studied. Populationpharmacokinetic analysis of integrated data from the AJOVY clinical studies did not reveal adifference in the pharmacokinetics of fremanezumab in patients with mild to moderate renalimpairment or hepatic impairment relative to those with normal renal or hepatic function (seesection 4.2).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, toxicity to reproduction and development.

As fremanezumab is a monoclonal antibody, no genotoxicity or carcinogenicity studies have beenconducted.

L-histidine

L-histidine hydrochloride monohydrate

Sucrose

Disodium ethylenediaminetetraacetic acid (EDTA) dihydrate

Polysorbate 80 (E 433)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Pre-filled syringe3 years

Pre-filled pen3 years

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Keep the pre-filled syringe(s) or pre-filled pen(s) in the outer 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 bediscarded if it has been out of the refrigerator for longer than 7 days.

Once stored at room temperature, do not place back in the refrigerator.

Pre-filled syringe1.5 mL solution in a 2.25 mL Type I glass syringe with plunger stopper (bromobutyl rubber) andneedle.

Pack sizes of 1 or 3 pre-filled syringes. Not all pack sizes may be marketed.

Pre-filled pen

Pre-filled pen containing 1.5 mL solution in a 2.25 mL Type I glass syringe with plunger stopper(bromobutyl rubber) and needle.

Pack sizes of 1 or 3 pre-filled pens. Not all pack sizes may be marketed.

The detailed instructions for use provided at the end of the package leaflet must be followed step-by-step carefully.

The pre-filled syringe and the pre-filled pen are for single use only.

AJOVY should not be used if the solution is cloudy or discoloured or contains particles.

AJOVY should not be used if the solution has been frozen.

The pre-filled syringe and the pre-filled pen should not be shaken.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

TEVA GmbH

Graf-Arco-Str. 389079 Ulm

Germany

EU/1/19/1358/001 - 1 pre-filled syringe

EU/1/19/1358/002 - 3 pre-filled syringes

Pre-filled pen

EU/1/19/1358/003 - 1 pre-filled pen

EU/1/19/1358/004 - 3 pre-filled pens

Date of first authorisation: 28 March 2019

Date of latest renewal: 6 November 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.