AIMOVIG 140mg / ml injection for pre-filled pen medication leaflet

Aimovig 70 mg solution for injection in pre-filled syringe

Aimovig 140 mg solution for injection in pre-filled syringe

Aimovig 70 mg solution for injection in pre-filled pen

Aimovig 140 mg solution for injection in pre-filled pen

Aimovig 70 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 70 mg erenumab.

Aimovig 140 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 140 mg erenumab.

Aimovig 70 mg solution for injection in pre-filled pen

Each pre-filled pen contains 70 mg erenumab.

Aimovig 140 mg solution for injection in pre-filled pen

Each pre-filled pen contains 140 mg erenumab.

Erenumab is a fully human IgG2 monoclonal antibody produced using recombinant DNA technologyin Chinese hamster ovary (CHO) cells.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

The solution is clear to opalescent, colourless to light yellow.

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

Treatment should be initiated by physicians experienced in the diagnosis and treatment of migraine.

Treatment is intended for patients with at least 4 migraine days per month when initiating treatmentwith erenumab.

The recommended dose is 70 mg erenumab every 4 weeks. Some patients may benefit from a dose of140 mg every 4 weeks (see section 5.1).

Each 140 mg dose is given either as one subcutaneous injection of 140 mg or as two subcutaneousinjections of 70 mg.

Clinical studies have demonstrated that the majority of patients responding to therapy showed clinicalbenefit within 3 months. Consideration should be given to discontinuing treatment in patients whohave shown no response after 3 months of treatment. Evaluation of the need to continue treatment isrecommended regularly thereafter.

Elderly (aged 65 years and over)

Aimovig has not been studied in elderly patients. No dose adjustment is required as thepharmacokinetics of erenumab are not affected by age.

Renal impairment/hepatic impairment

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

The safety and efficacy of Aimovig in children below the age of 18 years have not yet beenestablished. No data are available.

Aimovig is for subcutaneous use.

Aimovig is intended for patient self-administration after proper training. The injections can also begiven by another individual who has been appropriately instructed. The injection can be administeredinto the abdomen, thigh or into the outer area of the upper arm (the arm should be used only if theinjection is being given by a person other than the patient; see section 5.2). Injection sites should berotated and injections should not be given into areas where the skin is tender, bruised, red or hard.

The entire contents of the Aimovig pre-filled syringe should be injected. Each pre-filled syringe is forsingle use only and designed to deliver the entire contents with no residual content remaining.

Comprehensive instructions for administration are given in the instructions for use in the packageleaflet.

Pre-filled pen

The entire contents of the Aimovig pre-filled pen should be injected. Each pre-filled pen is for singleuse only and designed to deliver the entire contents with no residual content remaining.

Comprehensive instructions for administration are given in the instructions for use in the packageleaflet.

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.

Cardiovascular effect

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

Serious hypersensitivity reactions, including rash, angioedema, and anaphylactic reactions, have beenreported with erenumab in post-marketing experience. These reactions may occur within minutes,although some may occur more than one week after treatment. In that context, patients should bewarned about the symptoms associated with hypersensitivity reactions. If a serious or severehypersensitivity reaction occurs, appropriate therapy should be initiated and treatment with erenumabshould be discontinued (see section 4.3).

Constipation is a common adverse reaction of erenumab and is usually mild or moderate in intensity.

In a majority of the cases, the onset was reported after the first dose of erenumab; however patientshave also experienced constipation later on in the treatment. In most cases constipation resolvedwithin three months. In the post-marketing setting, constipation with serious complications has beenreported with erenumab. In some of these cases hospitalisation was required, including cases wheresurgery was necessary. History of constipation or the concurrent use of medicinal products associatedwith decreased gastrointestinal motility may increase the risk for more severe constipation and thepotential for constipation-related complications. Patients should be warned about the risk ofconstipation and advised to seek medical attention in case constipation does not resolve or worsens.

Patients should seek medical attention immediately if they develop severe constipation. Constipationshould be managed promptly as clinically appropriate. For severe constipation, discontinuation oftreatment should be considered.

Latex-sensitive individuals

The removable cap of this medicinal product contains latex rubber. May cause severe allergicreactions.

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

No effect on exposure of co-administered medicinal products is expected based on the metabolicpathways of monoclonal antibodies. No interaction with oral contraceptives (ethinylestradiol/norgestimate) or sumatriptan was observed in studies with healthy volunteers.

There are a limited amount of data from the use of erenumab in pregnant women. Animal studies donot indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Asa precautionary measure, it is preferable to avoid the use of Aimovig during pregnancy.

It is unknown whether erenumab is excreted in human milk. Human IgGs are known to be excreted inbreast milk during the first few days after birth, which is decreasing to low concentrations soonafterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period.

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

Animal studies showed no impact on female and male fertility (see section 5.3).

Aimovig is expected to have no or negligible influence on the ability to drive and use machines.

A total of over 2 500 patients (more than 2 600 patient years) have been treated with Aimovig inregistration studies. Of these, more than 1 300 patients were exposed for at least 12 months and218 patients were exposed for 5 years. The overall safety profile of Aimovig remained consistent for5 years of long-term open-label treatment.

The reported adverse drug reactions for 70 mg and 140 mg were injection site reactions (5.6%/4.5%),constipation (1.3%/3.2%), muscle spasms (0.1%/2.0%) and pruritus (0.7%/1.8%). Most of thereactions were mild or moderate in severity. Less than 2% of patients in these studies discontinued dueto adverse reactions.

Table 1 lists all adverse drug reactions that occurred in Aimovig-treated patients during the 12-weekplacebo-controlled periods of the studies, as well as in the post-marketing setting. Within each systemorgan class, the ADRs are ranked by frequency, with the most frequent reactions first. Within eachfrequency grouping, adverse drug reactions are presented in order of decreasing seriousness. Inaddition, the corresponding frequency category for each adverse drug reaction is based on thefollowing 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); not known (cannot be estimated from theavailable data).

Table 1 List of adverse reactions

System Organ Class Adverse reaction Frequency category

Immune system disorders Hypersensitivity reactionsa Commonincluding anaphylaxis,angioedema, rash,swelling/oedema andurticaria

Gastrointestinal disorders Constipation Common

Oral soresb Not known

Skin and subcutaneous tissue disorders Pruritusc Common

Alopecia Not known

Rashd

Musculoskeletal and connective tissue Muscle spasms Commondisorders

General disorders and administration Injection site reactionsa Commonsite conditionsa See section “Description of selected adverse reactions”b Oral sores includes preferred terms of stomatitis, mouth ulceration, oral mucosal blistering.c Pruritus includes preferred terms of generalised pruritus, pruritus and pruritic rash.d Rash includes preferred terms of rash papular, exfoliative rash, rash erythematous, urticaria,blister.

In the integrated 12-week placebo-controlled phase of the studies, injection site reactions were mildand mostly transient. There was one case of discontinuation in a patient receiving the 70 mg dose dueto injection site rash. The most frequent injection site reactions were localised pain, erythema andpruritus. Injection site pain typically subsided within 1 hour after administration.

Cutaneous and hypersensitivity reactions

In the integrated 12-week placebo-controlled phase of the studies, non-serious cases of rash, pruritusand swelling/oedema were observed, which in the majority of cases were mild and did not lead totreatment discontinuation.

In the post-marketing setting, cases of anaphylaxis and angiodoema were observed.

During the double-blind treatment phase of the clinical studies, the incidence of anti-erenumabantibody development was 6.3% (56/884) among subjects receiving a 70 mg dose of erenumab (3 ofwhom had in vitro neutralising activity) and 2.6% (13/504) among subjects receiving the 140 mg doseof erenumab (none of whom had in vitro neutralising activity). In an open-label study with up to256 weeks of treatment, the incidence of anti-erenumab antibody development was 11.0% (25/225)among patients who only received 70 mg or 140 mg of Aimovig throughout the entire study (2 ofwhom had in vitro neutralising activity). There was no impact of anti-erenumab antibody developmenton the efficacy or safety of erenumab.

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.

No cases of overdose have been reported in clinical studies.

Doses up to 280 mg have been administered subcutaneously in clinical studies with no evidence ofdose-limiting toxicity.

In the event of an overdose, the patient should be treated symptomatically and supportive measuresinstituted as required.

Pharmacotherapeutic group: Analgesics, antimigraine preparations, ATC code: N02CD01

Erenumab is a human monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP)receptor. The CGRP receptor is located at sites that are relevant to migraine pathophysiology, such asthe trigeminal ganglion. Erenumab potently and specifically competes with the binding of CGRP andinhibits its function at the CGRP receptor, and has no significant activity against other calcitoninfamily of receptors.

CGRP is a neuropeptide that modulates nociceptive signalling and a vasodilator that has beenassociated with migraine pathophysiology. In contrast with other neuropeptides, CGRP levels havebeen shown to increase significantly during migraine and return to normal with headache relief.

Intravenous infusion of CGRP induces migraine-like headache in patients.

Inhibition of the effects of CGRP could theoretically attenuate compensatory vasodilation inischaemic-related conditions. A study evaluated the effect of a single intravenous dose of 140 mg

Aimovig in subjects with stable angina under controlled exercise conditions. Aimovig showed similarexercise duration compared to placebo and did not aggravate myocardial ischaemia in these patients.

Erenumab was evaluated for prophylaxis of migraine in two pivotal studies across the migrainespectrum in chronic and episodic migraine. In both studies, the patients enrolled had at least a12-month history of migraine (with or without aura) according to the International Classification of

Headache Disorders (ICHD-III) diagnostic criteria. Elderly patients (>65 years), patients with opioidoveruse in study in chronic migraine, patients with medication overuse in study in episodic migraine,and also patients with pre-existing myocardial infarction, stroke, transient ischaemic attacks, unstableangina, coronary artery bypass surgery or other re-vascularisation procedures within 12 months priorto screening were excluded. Patients with poorly controlled hypertension or BMI >40 were excludedfrom Study 1.

Chronic migraine

Study 1

Erenumab was evaluated as monotherapy for prophylaxis of chronic migraine in a randomised,multicentre, 12-week, placebo-controlled, double-blind study in patients suffering from migraine withor without aura (≥15 headache days per month with ≥8 migraine days per month).

667 patients were randomised in a 3:2:2 ratio to receive placebo (n = 286) or 70 mg (n = 191) or140 mg (n = 190) erenumab, stratified by the presence of acute medication overuse (present in 41% ofoverall patients). Patients were allowed to use acute headache treatments during the study.

Demographics and baseline disease characteristics were balanced and comparable between study arms.

Patients had a median age of 43 years, 83% were female and 94% were white. The mean migrainefrequency at baseline was approximately 18 migraine days per month. Overall, 68% had failed one ormore previous prophylactic pharmacotherapies due to lack of efficacy or poor tolerability, and 49%had failed two or more previous prophylactic pharmacotherapies due to lack of efficacy or poortolerability. A total of 366 (96%) patients in the erenumab arms and 265 (93%) patients in the placeboarm completed the study (i.e. completed Week 12 assessment).

Reduction in mean monthly migraine days from placebo was observed in a monthly analysis from

Month 1 and in a follow-up weekly analysis an onset of erenumab effect was seen from the first weekof administration.

Figure 1 Change from baseline in monthly migraine days over time in Study 1 (includingprimary endpoint at Month 3)

Table 2 Change from baseline in efficacy and patient-reported outcomes at Week 12 in

Study 1

Aimovig Aimovig Placebo Treatment p-value(erenumab) (erenumab) (n = 281) difference140 mg 70 mg (95% CI)(n = 187) (n = 188)

Efficacy outcomes

MMD

Mean change -6.6 -6.6 -4.2 Both -2.5 Both(95% CI) (-7.5, -5.8) (-7.5; -5.8) (-4.9, -3.5) (-3.5, -1.4) <0.001

Baseline (SD) 17.8 (4.7) 17.9 (4.4) 18.2 (4.7)≥50% MMD responders

Percentage [%] 41.2% 39.9% 23.5% n/a Both<0.001a,d≥75% MMD responders

Percentage [%] 20.9% 17.0% 7.8% n/a n/ab

Monthly acute migraine-specific medication days 70 mg:

Mean change (95% CI) -4.1 -3.5 -1.6 -1.9 (-2.6, -1.1) Both(-4.7, -3.6) (-4.0, -2.9) (-2.1, -1.1) 140 mg: <0.001a

- 2.6 (-3.3, -1.8)

Baseline (SD) 9.7 (7.0) 8.8 (7.2) 9.5 (7.6)

Patient-reported outcome measures

HIT-6 70 mg:

Mean changec (95% CI) -5.6 -5.6 -3.1 -2.5 (-3.7, -1.2) n/ab(-6.5, -4.6) (-6.5, -4.6) (-3.9, -2.3) 140 mg:

- 2.5 (-3.7, -1.2)

MIDAS total 70 mg:

Mean changec (95% CI) -19.8 -19.4 -7.5 -11.9 (-19.3, -4.4) n/ab(-25.6, -14.0) (-25.2, -13.6) (-12.4, -2.7) 140 mg:

- 12.2 (-19.7, -4.8)

CI = confidence interval; MMD = monthly migraine days; HIT-6 = Headache Impact Test; MIDAS = Migraine

Disability Assessment; n/a = not applicable.a For secondary endpoints, all p-values are reported as unadjusted p-values and are statistically significant afteradjustment for multiple comparisons.b For exploratory endpoints, no p-value is presented.c For HIT-6: Change and reduction from baseline were evaluated in the last 4 weeks of the 12-weekdouble-blind treatment phase. For MIDAS: Change and reduction from baseline were evaluated over12 weeks. For data collection a recall period of 3 months has been used.d p value was calculated based on the odds ratios.

In patients failing one or more prophylactic pharmacotherapies the treatment difference for thereduction of monthly migraine days (MMD) observed between erenumab 140 mg and placebowas -3.3 days (95% CI: -4.6, -2.1) and between erenumab 70 mg and placebo -2.5 days (95%

CI: -3.8, -1.2). In patients failing two or more prophylactic pharmacotherapies the treatment differencewas -4.3 days (95% CI: -5.8; -2.8) between 140 mg and placebo and -2.7 days (95% CI: -4.2, -1.2)between 70 mg and placebo. There was also a higher proportion of subjects treated with erenumabwho achieved at least 50% reduction of MMD compared to placebo in the patients failing one or moreprophylactic pharmacotherapies (40.8% for 140 mg, 34.7% for 70 mg versus 17.3% for placebo), withan odds ratio of 3.3 (95% CI: 2.0, 5.5) for 140 mg and 2.6 (95% CI: 1.6, 4.5) for 70 mg. In patientsfailing two or more prophylactic pharmacotherapies the proportion was 41.3% for 140 mg and 35.6%for 70 mg versus 14.2% for placebo with an odds ratio of 4.2 (95% CI: 2.2, 7.9) and 3.5 (95% CI: 1.8,6.6), respectively.

Approximately 41% of patients in the study had medication overuse. The treatment differenceobserved between erenumab 140 mg and placebo and between erenumab 70 mg and placebo for thereduction of MMD in these patients was -3.1 days (95% CI: -4.8, -1.4) in both cases, and for thereduction of acute migraine-specific medication days was -2.8 (95% CI: -4.2, -1.4) for 140 mgand -3.3 (95% CI: -4.7, -1.9) for 70 mg. There was a higher proportion of patients in the erenumabgroup who achieved at least a 50% reduction of MMD compared to placebo (34.6% for 140 mg,36.4% for 70 mg versus 17.7% for placebo), with an odds ratio of 2.5 (95% CI: 1.3, 4.9) and 2.7 (95%

CI: 1.4, pct. 5.2), respectively.

Efficacy was sustained for up to 1 year in the open-label extension of Study 1 in which patientsreceived 70 mg and/or 140 mg erenumab. 74.1% of patients completed the 52-week extension. Pooledacross the two doses, a reduction of -9.3 MMD was observed after 52 weeks relative to core studybaseline. 59% of patients completing the study achieved a 50% response in the last month of the study.

Episodic migraine

Study 2

Erenumab was evaluated for prophylaxis of episodic migraine in a randomised, multicentre, 24-week,placebo-controlled, double-blind study in patients suffering from migraine with or without aura(4-14 migraine days per month).

955 patients were randomised in a 1:1:1 ratio to receive 140 mg (n = 319) or 70 mg (n = 317)erenumab or placebo (n = 319). Patients were allowed to use acute headache treatments during thestudy.

Demographics and baseline disease characteristics were balanced and comparable between study arms.

Patients had a median age of 42 years, 85% were female and 89% were white. The mean migrainefrequency at baseline was approximately 8 migraine days per month. Overall, 39% had failed one ormore previous prophylactic pharmacotherapies due to lack of efficacy or poor tolerability. A total of294 patients (92%) for 140 mg, 287 (91%) patients for 70 mg and 284 patients (89%) in the placeboarm completed the double-blind phase.

Patients treated with erenumab had a clinically relevant and statistically significant reduction frombaseline in the frequency of migraine days from Months 4 to 6 (Figure 2) compared to patientsreceiving placebo. Differences from placebo were observed from Month 1 onwards.

Figure 2 Change from baseline in monthly migraine days over time in Study 2 (includingprimary endpoint over Months 4, 5 and 6)

Table 3 Change from baseline in efficacy and patient-reported outcomes at Weeks 13-24 in

Study 2

Aimovig Aimovig Placebo Treatment difference p-value(erenumab) (erenumab) (n = 316) (95% CI)140 mg 70 mg(n = 318) (n = 312)

Efficacy outcomes

MMD

Mean change -3.7 -3.2 -1.8 70 mg: -1.4 (-1.9, -0.9) Both(95% CI) (-4.0, -3.3) (-3.6, -2.9) (-2.2, -1.5) 140 mg: -1.9 (-2.3, -1.4) <0.001a

Baseline (SD) 8.3 (2.5) 8.3 (2.5) 8.2 (2.5)≥50% MMDresponders Both

Percentage [%] 50.0% 43.3% 26.6% n/a <0.001a,d≥75% MMDresponders

Percentage [%] 22.0% 20.8% 7.9% n/a n/ab

Monthly acutemigraine-specificmedication days 70 mg: -0.9(-1.2, -0.6) Both

Mean change -1.6 -1.1 -0.2 140 mg: -1.4 (-1.7, -1.1) <0.001a(95% CI) (-1.8, -1.4) (-1.3, -0.9) (-0.4, 0.0)

Baseline (SD) 3.4 (3.5) 3.2 (3.4) 3.4 (3.4)

Patient-reported outcome measures

HIT-6

Mean changec -6.9 -6.7 -4.6 70 mg: -2.1 (-3.0, -1.1) n/ab(95% CI) (-7.6, -6.3) (-7.4, -6.0) (-5.3, -4.0) 140 mg: -2.3 (-3.2, -1.3)

MIDAS(modified) total n/ab

Mean changec -7.5 -6.7 -4.6 70 mg: -2.1 (-3.3, -0.9)(95% CI) (-8.3, -6.6) (-7.6, -5.9) (-5.5, -3.8) 140 mg: -2.8 (-4.0, -1.7)

CI = confidence interval; MMD = monthly migraine days; HIT-6 = Headache Impact Test; MIDAS = Migraine

Disability Assessment; n/a = not applicable.a For the secondary endpoints, all p-values are reported as unadjusted p-values and are statisticallysignificant after adjustment for multiple comparisons.b For exploratory endpoints, no p-value was presented.c For HIT-6: Change and reduction from baseline were evaluated in the last 4 weeks of the 12-weekdouble-blind treatment phase. For MIDAS: Change and reduction from baseline were evaluated over24 weeks. For data collection a recall period of 1 month has been used.d p value is calculated based on the odds ratios.

In patients failing one or more prophylactic pharmacotherapies the treatment difference for thereduction of MMD observed between erenumab 140 mg and placebo was -2.5 (95% CI: -3.4, -1.7) andbetween erenumab 70 mg and placebo -2.0 (95% CI: -2.8, -1.2). There was also a higher proportion ofsubjects treated with erenumab who achieved at least 50% reduction of MMD compared to placebo(39.7% for 140 mg and 38.6% for 70 mg, with an odds ratio of 3.1 [95% CI: 1.7, 5.5] and 2.9 [95%

CI: 1.6, 5.3], respectively).

Efficacy was sustained up to 1 year in the active re-randomisation part of Study 2. Patients werere-randomised in the active treatment phase (ATP) to 70 mg or 140 mg erenumab. 79.8% completedthe entire study out to 52 weeks. The reduction in monthly migraine days from baseline to Week 52was -4.22 in the 70 mg ATP group and -4.64 days in the 140 mg ATP group. At Week 52, theproportion of subjects who achieved a ≥50% reduction in MMD from baseline was 61.0% in the70 mg ATP and 64.9% in the 140 mg ATP group.

Long-term follow-up study

Following a placebo-controlled study, 383 patients continued in an open-label treatment phase over5 years initially receiving erenumab 70 mg (median exposure: 2.0 years), of which 250 patientsincreased their dose to 140 mg (median exposure: 2.7 years). 214 completed the open-label treatmentphase of 5 years. Of the 383 patients, 168 (43.9%) discontinued with the most common reasons beingpatient request (84 patients; 21.9%), adverse events (19 patients; 5.0%), lost to follow-up (14 patients;3.7%) and lack of efficacy (12 patients; 3.1%). The results indicate that efficacy was sustained for upto 5 years in the open-label treatment phase of the study.

Study 3: Study in patients with previous failure or non-suitability of 2 to 4 migraine prophylacticpharmacotherapies246 adult patients with episodic migraine were randomised in a 1:1 ratio to receive either erenumab140 mg (n = 121) or placebo (n = 125) for 12 weeks. Three patients (erenumab: 2, placebo: 1) wereexcluded from the primary analysis due to not having received study treatment. During the last4 weeks of the double-blind treatment, 30.3% (36/119) of patients in the erenumab group achieved atleast a 50% reduction from baseline in MMD compared to 13.7% (17/124) in the placebo group(p = 0.002).

Study 4: Study to assess tolerability (primary endpoint) and efficacy versus topiramate777 adult patients with episodic or chronic migraine were randomised in a 1:1 ratio to receive eithererenumab (70 mg or 140 mg, n = 389) or topiramate 50 to 100 mg (n=388) for 24 weeks (double-blindtreatment phase). Safety and efficacy data were pooled for patients receiving the erenumab 70 mg and140 mg doses and compared with that for patients receiving topiramate.

Erenumab demonstrated superior tolerability versus topiramate based on the rate of discontinuation oftreatment due to adverse events (erenumab: 10.5%, topiramate: 38.9%; p <0.001; primary endpoint).

Additionally, 55.4% of patients in the erenumab group achieved at least a 50% reduction frombaseline in MMD during the last 3 months of the study, compared with 31.2% in the topiramate group(p <0.001).

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

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

Erenumab exhibits non-linear kinetics as a result of binding to the CGRP-R receptor. However, attherapeutically relevant doses, the pharmacokinetics of erenumab following subcutaneous dosingevery 4 weeks are predominantly linear due to saturation of binding to CGRP-R. Subcutaneousadministration of a 140 mg once monthly dose and a 70 mg once monthly dose in healthy volunteersresulted in a Cmax mean (standard deviation [SD]) of 15.8 (4.8) µg/ml and 6.1 (2.1) µg/ml,respectively, and AUClast mean (SD) of 505 (139) day*µg/ml and 159 (58) day*µg/ml, respectively.

Less than 2-fold accumulation was observed in trough serum concentrations following 140 mg dosesadministered subcutaneously every 4 weeks and serum trough concentrations approached steady stateby 12 weeks of dosing.

Following a single subcutaneous dose of 140 mg or 70 mg erenumab administered to healthy adults,median peak serum concentrations were attained in 4 to 6 days, and estimated absolute bioavailabilitywas 82%.

Following a single 140 mg intravenous dose, the mean (SD) volume of distribution during the terminalphase (Vz) was estimated to be 3.86 (0.77) l.

Biotransformation/Elimination

Two elimination phases were observed for erenumab. At low concentrations, the elimination ispredominately through saturable binding to target (CGRP-R), while at higher concentrations theelimination of erenumab is largely through a non-specific proteolytic pathway. Throughout the dosingperiod erenumab is predominantly eliminated via a non-specific proteolytic pathway with the effectivehalf-life of 28 days.

Patients with severe renal impairment (eGFR <30 ml/min/1.73 m2) have not been studied. Populationpharmacokinetic analysis of integrated data from the Aimovig clinical studies did not reveal adifference in the pharmacokinetics of erenumab in patients with mild or moderate renal impairmentrelative to those with normal renal function (see section 4.2).

No studies have been performed in patients with hepatic impairment. Erenumab, as a humanmonoclonal antibody, is not metabolised by cytochrome P450 enzymes and hepatic clearance is not amajor clearance pathway for erenumab (see section 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.

Carcinogenicity studies have not been conducted with erenumab. Erenumab is not pharmacologicallyactive in rodents. It has biological activity in cynomolgus monkeys, but this species is not anappropriate model for evaluation of tumorigenic risk. The mutagenic potential of erenumab has notbeen evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.

In repeated-dose toxicology studies there were no adverse effects in sexually mature monkeys dosedup to 150 mg/kg subcutaneously twice weekly for up to 6 months at systemic exposures up to 123-foldand 246-fold higher than the clinical dose of 140 mg and 70 mg, respectively, every 4 weeks, based onserum AUC. There were also no adverse effects on surrogate markers of fertility (anatomicalpathology or histopathology changes in reproductive organs) in these studies.

In a reproduction study in cynomolgus monkeys there were no effects on pregnancy, embryo-foetal orpost-natal development (up to 6 months of age) when erenumab was dosed throughout pregnancy atexposure levels approximately 17-fold and 34-fold higher than those achieved in patients receivingerenumab 140 mg and 70 mg, respectively, every 4 weeks dosing regimen based on AUC. Measurableerenumab serum concentrations were observed in the infant monkeys at birth, confirming thaterenumab, like other IgG antibodies, crosses the placental barrier.

Sucrose

Polysorbate 80

Sodium hydroxide (for pH adjustment)

Glacial acetic acid

Water for injections

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

3 years

Store in a refrigerator (2°C - 8°C). Do not freeze.

Keep the pre-filled syringe in the outer carton in order to protect from light.

After removal from the refrigerator, Aimovig must be used within 7 days when stored at roomtemperature (up to 25°C), or discarded. If it is stored at a higher temperature or for a longer period itmust be discarded.

Pre-filled pen

Store in a refrigerator (2°C - 8°C). Do not freeze.

Keep the pre-filled pen in the outer carton in order to protect from light.

After removal from the refrigerator, Aimovig must be used within 7 days when stored at roomtemperature (up to 25°C), or discarded. If it is stored at a higher temperature or for a longer period itmust be discarded.

Aimovig is supplied in a pre-filled syringe (1 ml, Type 1 glass) with a stainless steel needle and aneedle cover (rubber containing latex).

Aimovig is available in packs containing 1 pre-filled syringe.

Pre-filled pen

Aimovig is supplied in a pre-filled pen (1 ml, Type 1 glass) with a stainless steel needle and a needlecover (rubber containing latex).

Aimovig is available in packs containing 1 pre-filled pen and in multipacks containing3 (3x1) pre-filled pens.

Not all pack sizes may be marketed.

Before administration, the solution should be inspected visually. The solution should not be injected ifit is cloudy, distinctly yellow or contains flakes or particles.

To avoid discomfort at the site of injection, the pre-filled syringe(s) should be left to stand at roomtemperature (up to 25°C) for at least 30 minutes before injecting. It should also be protected fromdirect sunlight. The entire contents of the pre-filled syringe(s) must be injected. The syringe(s) mustnot be warmed by using a heat source such as hot water or microwave and must not be shaken.

Pre-filled pen

To avoid discomfort at the site of injection, the pre-filled pen(s) should be left to stand at roomtemperature (up to 25°C) for at least 30 minutes before injecting. It should also be protected fromdirect sunlight. The entire contents of the pre-filled pen(s) must be injected. The pen(s) must not bewarmed by using a heat source such as hot water or microwave and must not be shaken.

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

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/18/1293/001-006

Date of first authorisation: 26 July 2018

Date of latest renewal: 20 February 2023

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

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