Product Monograph - Aimovig
RECENT MAJOR LABEL CHANGES
| 7.0 WARNINGS AND PRECAUTIONS, Constipation with Serious Complications | 09/2022 |
TABLE OF CONTENTS
Sections or subsections that are not applicable at the time of authorization are not listed.
RECENT MAJOR LABEL CHANGES..............................................................................................2
TABLE OF CONTENTS ................................................................................................................2
PART I: HEALTH PROFESSIONAL INFORMATION .......................................................................4
1 INDICATIONS ................................................................................................................4
1.1 Pediatrics ............................................................................................................4
1.2 Geriatrics.............................................................................................................4
2 CONTRAINDICATIONS ...................................................................................................4
4 DOSAGE AND ADMINISTRATION...................................................................................4
4.1 Dosing Considerations .........................................................................................4
4.2 Recommended Dose and Dosage Adjustment.......................................................4
4.4 Administration.....................................................................................................5
4.5 Missed Dose ........................................................................................................5
5 OVERDOSAGE ...............................................................................................................5
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ...................................5
7 WARNINGS AND PRECAUTIONS ....................................................................................6
7.1 Special Populations ..............................................................................................7
7.1.1 Pregnant Women .......................................................................................... 7
7.1.2 Breast-feeding............................................................................................... 7
7.1.3 Pediatrics ...................................................................................................... 8
7.1.4 Geriatrics ...................................................................................................... 8
8 ADVERSE REACTIONS ....................................................................................................8
8.1 Adverse Reaction Overview..................................................................................8
8.2 Clinical Trial Adverse Reactions ............................................................................9
8.2.1 Clinical Trial Adverse Reactions – Pediatrics ..................................................14
8.3 Less Common Clinical Trial Adverse Reactions .................................................... 14
8.5 Post-Market Adverse Reactions.......................................................................... 15
9 DRUG INTERACTIONS.................................................................................................. 15
9.2 Drug Interactions Overview................................................................................ 15
9.4 Drug-Drug Interactions ...................................................................................... 15
9.5 Drug-Food Interactions ...................................................................................... 16
9.6 Drug-Herb Interactions ...................................................................................... 16
9.7 Drug-Laboratory Test Interactions ...................................................................... 16
10 CLINICAL PHARMACOLOGY ......................................................................................... 16
10.1 Mechanism of Action.................................................................................... 16
10.2 Pharmacodynamics ...................................................................................... 16
10.3 Pharmacokinetics ......................................................................................... 16
11 STORAGE, STABILITY AND DISPOSAL ........................................................................... 18
12 SPECIAL HANDLING INSTRUCTIONS............................................................................. 18
PART II: SCIENTIFIC INFORMATION ........................................................................................ 19
13 PHARMACEUTICAL INFORMATION.............................................................................. 19
14 CLINICAL TRIALS.......................................................................................................... 19
14.1 Trial Design and Study Demographics Clinical Trials by Indication .................. 19
Migraine Prevention....................................................................................................19
14.2 Comparative Bioavailability Studies .............................................................. 24
14.3 Immunogenicity ........................................................................................... 25
15 MICROBIOLOGY .......................................................................................................... 26
16 NON-CLINICAL TOXICOLOGY ....................................................................................... 26
PATIENT MEDICATION INFORMATION ................................................................................... 27
PATIENT MEDICATION INFORMATION ................................................................................... 39
PART I: HEALTH PROFESSIONAL INFORMATION
1 INDICATIONS
AIMOVIG® (erenumab injection) is indicated for:
- prevention of migraine in adults who have at least 4 migraine days per month
1.1 Pediatrics
Pediatrics (< 18 years of age): Safety and efficacy of Aimovig in patients below the age of 18 have not been studied. Aimovig is not authorized for pediatric use.
1.2 Geriatrics
Geriatrics (≥ 65 years of age): Safety and efficacy of Aimovig has not been studied in patients aged 65 or older. See 7.1.4 Geriatrics.
2 CONTRAINDICATIONS
- Aimovig 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 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
4 DOSAGE AND ADMINISTRATION
4.1 Dosing Considerations
- Aimovig is administered subcutaneously through single-dose pre-filled autoinjector or single-dose pre-filled syringe.
- Aimovig is intended for patient self-administration.
- Administration should be performed by an individual who has been trained to administer the product
- Aimovig should be initiated by health professionals experienced in the diagnosis and treatment of migraine.
4.2 Recommended Dose and Dosage Adjustment
The recommended dose of Aimovig is 70 mg administered once monthly. Some patients may benefit from a dose of 140 mg once monthly administered as one subcutaneous injection of 140 mg. See Part II- 14 CLINICAL TRIALS.
Aimovig is not approved for pediatric use.
4.4 Administration
To administer the recommended dose of 70 mg, give one subcutaneous injection. To administer the recommended dose of 140 mg, give one subcutaneous injection of 140 mg.
Prior to subcutaneous administration, allow Aimovig to sit at room temperature for at least 30 minutes and protect from direct sunlight. Do not warm by using a heat source such as hot water or microwave.
Do not shake the product.
Visually inspect the solution for particles and discolouration. Aimovig is a clear to opalescent, colourless to light yellow solution. Do not use if the solution is cloudy, discoloured or if flakes or particles are present.
Administer Aimovig subcutaneously in the abdomen, thigh, or upper arm. Injection sites should be rotated and injections should not be given into areas where the skin is tender, bruised, red, or hard.
Both the pre-filled syringe and the pre-filled SureClick® autoinjector are single-dose and designed to deliver the entire contents with no residual content.
The grey needle cover of the Aimovig pre-filled syringe and the needle shield within the white or orange cap of the Aimovig pre-filled autoinjector contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.
Comprehensive instructions for the administration of Aimovig are provided in the Patient Medication Information.
4.5 Missed Dose
If an Aimovig dose is missed, administer as soon as possible. Thereafter, Aimovig can be scheduled monthly from the date of the last dose.
5 OVERDOSAGE
There are no reported events of overdose in clinical trials with Aimovig and data regarding overdosage are unavailable. Doses up to 280 mg subcutaneously have been administered in clinical trials with no evidence of dose limiting toxicity.
In the event of an overdose, the patient should be treated symptomatically and supportive measures instituted as required.
| For management of a suspected drug overdose, contact your regional poison control centre. |
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING
| To help ensure the traceability of biologic products, including biosimilars, health professionals should recognise the importance of recording both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug |
| Identification Number (DIN) and the batch/lot number of the product supplied. |
Table 1 – Dosage Forms, Strengths, Composition and Packaging
Aimovig is a clear to opalescent, colourless to light yellow sterile, preservative-free solution, practically free from particles.
The grey needle cover of the glass pre-filled syringe and the needle shield within the white or orange cap of the pre-filled autoinjector is made from dry natural rubber (a derivative of latex).
Aimovig is available in a carton containing either:
- One 70 mg/mL pre-filled syringe*, delivering one dose totalling 70 mg.
- One 140 mg/mL pre-filled syringe*, delivering one dose totalling 140 mg.
- One 70 mg/mL pre-filled SureClick autoinjector, delivering one dose totalling 70 mg.
- One 140 mg/mL pre-filled SureClick autoinjector, delivering one dose totalling 140 mg.
*Pre-filled syringes are not available in Canada.
7 WARNINGS AND PRECAUTIONS
Constipation with Serious Complications
Constipation with serious complications has been reported following the use of Aimovig in the postmarketing setting. There were cases that required hospitalization, including cases where surgery was necessary. In a majority of these cases, the onset of constipation was reported after the first dose of Aimovig; however, patients have also presented with constipation later on in treatment. Aimovig was discontinued in most reported cases of constipation with serious complications. Constipation was one of the most common (up to 4.3%) adverse reactions reported in clinical studies. See section 8.2 Clinical Trial Adverse Reactions.
Monitor patients treated with Aimovig for severe constipation and manage as clinically appropriate. A history of constipation or the concurrent use of medications associated with decreased gastrointestinal motility may increase the risk for more severe constipation and the potential for constipation-related complications. Advise patients to seek medical attention if they develop severe constipation.
| Route of Administration | Dosage Form / Strength/Composition | Non-medicinal Ingredients |
| Subcutaneous injection | Solution for injection in Pre-filled syringe and Pre-filled autoinjector / 70 mg per mL and 140 mg per mL | Glacial acetic acid, Polysorbate 80, Sucrose, Water for injection. Sodium hydroxide may have been used to adjust the pH to 5.2. |
Driving and Operating Machinery
No data are available to evaluate the effect of Aimovig on driving and operating machinery. Aimovig is expected to have no influence on the ability to drive and use machines.
Sensitivity
Hypersensitivity Reactions
Serious hypersensitivity reactions, including rash, angioedema, and anaphylactoid reactions, have been reported with Aimovig in post-marketing experience. These reactions may occur within minutes, although some may occur more than one week after treatment. If a serious or severe hypersensitivity reaction occurs, discontinue administration of Aimovig and initiate appropriate therapy. See 2 CONTRAINDICATIONS.
Reproductive Health: Female and Male Potential
Fertility
No data are available on the effect of Aimovig on human fertility. No dedicated fertility studies have been conducted in animals; however, there were no histopathological changes in male or female reproductive organs in a study conducted in sexually mature monkeys at systemic exposures up to 123-fold higher than that predicted for the maximum recommended human dose of 140 mg once monthly. See 16 NON-CLINICAL TOXICOLOGY.
7.1 Special Populations
7.1.1 Pregnant Women
There are no adequate and well-controlled studies on the use of Aimovig in pregnant women.
In a cynomolgus monkey developmental study, there were no effects on pregnancy or on embryo-fetal and post-natal development (up to 6 months age) when erenumab was administered every two weeks from gestation day 20-22 to parturition at an exposure level 17-fold higher than that predicted for the maximum recommended clinical dose of 140 mg once monthly. Measurable erenumab serum concentrations were observed in the infant monkeys at birth, confirming that erenumab, like other IgG antibodies, crosses the placental barrier. See 16 NON-CLINICAL TOXICOLOGY.
Animal studies are not always predictive of human response and therefore, it is unknown whether Aimovig can cause fetal harm when administered to a pregnant woman. Because IgG antibodies cross the placenta, avoid the use of Aimovig during pregnancy as a precautionary measure.
7.1.2 Breast-feeding
It is unknown if Aimovig is excreted in human milk. Because antibodies are excreted in human milk, caution should be exercised. There are no data on the effects of Aimovig on the breastfed child or the effects of Aimovig on milk production. A decision should be made whether to discontinue nursing or discontinue Aimovig, taking into account the potential benefit of Aimovig to the mother and the potential benefit of breast feeding to the infant.
7.1.3 Pediatrics
Pediatrics (< 18 years of age): The safety and effectiveness of Aimovig has not been studied in pediatric patients. Aimovig is not authorized for pediatric use.
7.1.4 Geriatrics
No data are available for patients aged 65 years and older.
8 ADVERSE REACTIONS
8.1 Adverse Reaction Overview
A total of over 2,500 patients (more than 2,600 patient years) have been treated with AIMOVIG in registration studies. Of these, more than 1,300 patients were exposed for at least 12 months.
The adverse reactions reported in the placebo-controlled trials of Aimovig were injection site reactions, constipation, muscle spasm and pruritus.
Table 1 Adverse Reactions Reported with Aimovig-treated Patients (and More Frequently than in Patients Receiving Placebo) by System Organ Class and Preferred Term
System Organ Class Preferred Term | Aimovig 70 mg N = 893 n (%) | Aimovig 140 mg N = 507 n (%) | Placebo N = 1043 n (%) |
|---|---|---|---|
| General disorders and administration site conditions | |||
| Injection site reactions a | 50 (5.6%) | 23 (4.5%) | 33 (3.2%) |
| Gastrointestinal disorders | |||
| Constipation | 12 (1.3%) | 16 (3.2%) | 11 (1.1%) |
| Musculoskeletal and connective tissue disorders | |||
| Muscle spasm | 1 (0.1%) | 10 (2.0 %) | 4 (0.4%) |
| Skin and subcutaneous tissue disorders | |||
| Pruritus b | 6 (0.7%) | 9 (1.8%) | 5 (0.5%) |
System Organ Class Preferred Term | Aimovig 70 mg N = 893 n (%) | Aimovig 140 mg N = 507 n (%) | Placebo N = 1043 n (%) |
|---|---|---|---|
a Injection Site Reactions includes multiple preferred terms, such as injection site pain and injection site erythema. b Pruritus includes generalized pruritus, pruritus, and pruritic rash. | |||
8.2 Clinical Trial Adverse Reactions
Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.
In the 12 week placebo-controlled period, one grade 3 (0.2%) muscle spasm was reported in subjects treated with Aimovig 140 mg. This subject had a history of muscle spasms and experienced worsening of back spasms. All other adverse reactions were grade 1 (mild) or moderate (grade 2) in severity.
In the pivotal studies, the following adverse events were observed to occur at or above 1% during the double-blind treatment phase.
Table 3 Incidence of Treatment-emergent Adverse Events in ≥ 1% of Subjects in either Aimovig Group (70 mg or 140 mg) in Study 20120295
System Organ Class Preferred Term | Aimovig 70 mg (N=190) n (%) | Aimovig 140 mg (N=188) n (%) | Placebo (N=282) n (%) |
|---|---|---|---|
| Cardiac disorders | |||
| Palpitations | 1 (0.5) | 2 (1.1) | 2 (0.7) |
| Ear and labyrinth disorders | |||
| Tinnitus | 2 (1.1) | 1 (0.5) | 0 |
| Eye disorders | |||
| Eye irritation | 2 (1.1) | 0 | 0 |
System Organ Class Preferred Term | Aimovig 70 mg (N=190) n (%) | Aimovig 140 mg (N=188) n (%) | Placebo (N=282) n (%) |
|---|---|---|---|
| Gastrointestinal disorders | |||
| Nausea | 4 (2.1) | 6 (3.2) | 7 (2.5) |
| Constipation | 0 | 8 (4.3) | 1 (0.4) |
| Diarrhea | 2 (1.1) | 4 (2.1) | 4 (1.4) |
| Dyspepsia | 2 (1.1) | 2 (1.1) | 2 (0.7) |
| Abdominal pain upper | 2 (1.1) | 1 (0.5) | 2 (0.7) |
| Toothache | 2 (1.1) | 1 (0.5) | 2 (0.7) |
| General disorders and administration site conditions | |||
| Injection site pain | 7 (3.7) | 7 (3.7) | 3 (1.1) |
| Injection site erythema | 1 (0.5) | 6 (3.2) | 0 |
| Fatigue | 2 (1.1) | 4 (2.1) | 5 (1.8) |
| Administration site pain | 2 (1.1) | 1 (0.5) | 0 |
| Influenza like illness | 2 (1.1) | 1 (0.5) | 2 (0.7) |
| Injection site pruritus | 0 | 2 (1.1) | 0 |
| Infections and infestations | |||
Upper respiratory tract infection | 5 (2.6) | 6 (3.2) | 4 (1.4) |
| Nasopharyngitis | 6 (3.2) | 3 (1.6) | 16 (5.7) |
| Influenza | 4 (2.1) | 1 (0.5) | 0 |
| Sinusitis | 3 (1.6) | 2 (1.1) | 6 (2.1) |
| Urinary tract infection | 3 (1.6) | 2 (1.1) | 3 (1.1) |
| Bronchitis | 2 (1.1) | 2 (1.1) | 1 (0.4) |
| Pharyngitis | 3 (1.6) | 1 (0.5) | 2 (0.7) |
| Rhinitis | 0 | 4 (2.1) | 1 (0.4) |
| Viral infection | 1 (0.5) | 2 (1.1) | 2 (0.7) |
| Appendicitis | 2 (1.1) | 0 | 0 |
| Injury, poisoning and procedural complications |
System Organ Class Preferred Term | Aimovig 70 mg (N=190) n (%) | Aimovig 140 mg (N=188) n (%) | Placebo (N=282) n (%) |
|---|---|---|---|
| Contusion | 0 | 2 (1.1) | 2 (0.7) |
| Metabolism and nutrition disorders | |||
| Decreased appetite | 2 (1.1) | 0 | 0 |
| Hyperlipidemia | 0 | 2 (1.1) | 0 |
| Musculoskeletal and connective tissue disorders | |||
| Muscle spasms | 1 (0.5) | 7 (3.7) | 4 (1.4) |
| Arthralgia | 2 (1.1) | 1 (0.5) | 3 (1.1) |
| Back pain | 1 (0.5) | 2 (1.1) | 4 (1.4) |
| Myalgia | 2 (1.1) | 1 (0.5) | 2 (0.7) |
| Flank pain | 0 | 2 (1.1) | 0 |
| Pain in extremity | 0 | 2 (1.1) | 2 (0.7) |
| Nervous system disorders | |||
| Migraine | 3 (1.6) | 5 (2.7) | 3 (1.1) |
| Dizziness | 3 (1.6) | 2 (1.1) | 3 (1.1) |
| Hypoaesthesia | 3 (1.6) | 2 (1.1) | 0 |
| Cervicobrachial syndrome | 0 | 2 (1.1) | 0 |
| Disturbance in attention | 2 (1.1) | 0 | 0 |
| Paraesthesia | 0 | 2 (1.1) | 3 (1.1) |
| Psychiatric disorders | |||
| Insomnia | 2 (1.1) | 3 (1.6) | 0 |
| Respiratory, thoracic and mediastinal disorders | |||
| Oropharyngeal pain | 4 (2.1) | 3 (1.6) | 0 |
| Cough | 1 (0.5) | 5 (2.7) | 2 (0.7) |
| Epistaxis | 3 (1.6) | 0 | 0 |
System Organ Class Preferred Term | Aimovig 70 mg (N=190) n (%) | Aimovig 140 mg (N=188) n (%) | Placebo (N=282) n (%) |
|---|---|---|---|
| Nasal congestion | 1 (0.5) | 2 (1.1) | 3 (1.1) |
| Rhinorrhea | 1 (0.5) | 2 (1.1) | 0 |
| Dyspnea | 2 (1.1) | 0 | 1 (0.4) |
| Skin and subcutaneous tissue disorders | |||
| Alopecia | 1 (0.5) | 2 (1.1) | 0 |
| Rash | 0 | 3 (1.6) | 0 |
| Pruritus generalized | 0 | 2 (1.1) | 1 (0.4) |
| Vascular disorders | |||
| Hot flush | 1 (0.5) | 3 (1.6) | 1 (0.4) |
Table 4 Incidence of Treatment-emergent Adverse Events in ≥ 1% of Subjects in either Aimovig Group (70 mg or 140 mg) in Study 20120296
System Organ Class Preferred Term | Aimovig 70 mg (N=314) n (%) | Aimovig 140 mg (N=319) n (%) | Placebo (N=319) n (%) |
|---|---|---|---|
| Gastrointestinal disorders | |||
| Constipation | 6 (1.9) | 12 (3.8) | 4 (1.3) |
| Nausea | 7 (2.2) | 6 (1.9) | 6 (1.9) |
| Vomiting | 5 (1.6) | 5 (1.6) | 6 (1.9) |
| Abdominal Pain upper | 3 (1.0) | 5 (1.6) | 3 (0.9) |
| General disorders and administration site conditions | |||
| Fatigue | 6 (1.9) | 7 (2.2) | 8 (2.5) |
| Injection site pain | 10 (3.2) | 2 (0.6) | 1 (0.3) |
| Injection site erythema | 6 (1.9) | 5 (1.6) | 2 (0.6) |
| Injection site pruritus | 4 (1.3) | 2 (0.6) | 0 |
System Organ Class Preferred Term | Aimovig 70 mg (N=314) n (%) | Aimovig 140 mg (N=319) n (%) | Placebo (N=319) n (%) |
|---|---|---|---|
| Pyrexia | 4 (1.3) | 0 | 4 (1.3) |
| Infections and infestations | |||
| Viral upper respiratory tract infection | 32 (10.2) | 39 (12.2) | 34 (10.7) |
| Upper respiratory tract infection | 21 (6.7) | 15 (4.7) | 19 (6.0) |
| Sinusitis | 7 (2.2) | 11 (3.4) | 7 (2.2) |
| Influenza | 4 (1.3) | 10 (3.1) | 5 (1.6) |
| Urinary tract infection | 5 (1.6) | 7 (2.2) | 7 (2.2) |
| Bronchitis | 5 (1.6) | 6 (1.9) | 2 (0.6) |
| Gastroenteritis viral | 4 (1.3) | 5 (1.6) | 0 |
| Ear infection | 4 (1.3) | 1 (0.3) | 1 (0.3) |
| Musculoskeletal and connective tissue disorders | |||
| Arthralgia | 7 (2.2) | 7 (2.2) | 6 (1.9) |
| Back pain | 6 (1.9) | 7 (2.2) | 6 (1.9) |
| Osteoarthritis | 4 (1.3) | 3 (0.9) | 2 (0.6) |
| Neck pain | 1 (0.3) | 4 (1.3) | 1 (0.3) |
| Pain in extremity | 4 (1.3) | 1 (0.3) | 5 (1.6) |
| Nervous system disorders | |||
| Dizziness | 2 (0.6) | 6 (1.9) | 5 (1.6) |
| Headache | 4 (1.3) | 3 (0.9) | 3 (0.9) |
| Migraine | 4 (1.3) | 3 (0.9) | 10 (3.1) |
| Psychiatric disorders | |||
| Insomnia | 1 (0.3) | 4 (1.3) | 5 (1.6) |
| Skin and subcutaneous tissue disorders |
System Organ Class Preferred Term | Aimovig 70 mg (N=314) n (%) | Aimovig 140 mg (N=319) n (%) | Placebo (N=319) n (%) |
|---|---|---|---|
| Pruritus | 5 (1.6) | 3 (0.9) | 4 (1.3) |
| Pruritus generalized | 0 | 4 (1.3) | 0 |
| Vascular disorders | |||
| Hypertension | 6 (1.9) | 0 | 7 (2.2) |
Injection site reactions
In the integrated 12-week placebo controlled period of studies, in subjects treated with Aimovig the most frequent injection site reactions were injection site pain, injection site erythema, and injection site pruritus. A majority of injection site reactions were mild in severity.
Constipation
In the integrated 12-week placebo-controlled period of studies, 28 cases of constipation were reported out of 1,400 Aimovig-treated patients. All constipation events were mild or moderate in severity. There were no serious events. A majority of the cases (23) had onset within one month after the first dose; however, some patients also presented with constipation later on in treatment. In most cases (18), constipation resolved within three months. All but one case continued treatment.
Muscle spasms
In the integrated 12-week placebo controlled period of studies, majority of muscle spasms were mild or moderate in severity. There were no serious events.
Pruritus
In the integrated 12-week placebo controlled period of studies, the most frequent pruritus was generalized pruritus. All pruritus events were mild or moderate in severity. There were no serious events.
8.2.1 Clinical Trial Adverse Reactions – Pediatrics
The safety and efficacy of Aimovig has not been studied in pediatric patients.
8.3 Less Common Clinical Trial Adverse Reactions
None.
8.5 Post-Market Adverse Reactions
Immune system disorders
- Hypersensitivity reactions including rash, angioedema and anaphylactoid reactions. See 7 WARNINGS AND PRECAUTIONS. Most hypersensitivity reactions were not serious and occurred within hours of administration, although some occurred more than one week after administration. If a serious or severe hypersensitivity reaction occurs, discontinue administration of Aimovig and initiate appropriate therapy.
Gastrointestinal disorders
- Constipation with serious complications has been reported. See 7 WARNINGS AND PRECAUTIONS. In a majority of these cases, the onset was reported after the first dose of Aimovig; however patients have also experienced these events later on in the treatment. Many of the cases of constipation with serious complications were reported for patients who have a history of constipation or concurrently use medications associated with decreased gastrointestinal motility. In some severe cases hospitalization was required.
- Oral sores (e.g., stomatitis, mouth ulceration, oral mucosal blistering)
Skin and subcutaneous tissue disorders
- Alopecia
- Rash (e.g., rash papular, exfoliative rash, rash erythematous, urticaria, blister)
9 DRUG INTERACTIONS
9.2 Drug Interactions Overview
Erenumab is not metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.
9.4 Drug-Drug Interactions
Oral Contraceptive
In an open-label study, in healthy female subjects, a single subcutaneous 140 mg dose of erenumab did not affect the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate.
Sumatriptan
In a randomized, double-blind, placebo-controlled study in healthy subjects, concomitant administration of a single intravenous 140 mg dose of erenumab with two subcutaneous 6 mg doses of sumatriptan (separated by one hour) had no effect on the pharmacokinetics of sumatriptan and resting blood pressure compared with administration of sumatriptan alone. Aimovig is for subcutaneous use only.
9.5 Drug-Food Interactions
Interactions with food have not been studied.
9.6 Drug-Herb Interactions
Interactions with herbal products have not been studied.
9.7 Drug-Laboratory Test Interactions
Interference of Aimovig with laboratory and/or diagnostic tests has not been studied.
10 CLINICAL PHARMACOLOGY
10.1 Mechanism of Action
Erenumab is a recombinant human monoclonal antibody that competes with CGRP for binding to the CGRP receptor and antagonizes CGRP receptor function. It has no significant activity at adrenomedullin, calcitonin, and amylin receptors.
CGRP is a neuropeptide that modulates nociceptive signaling and a vasodilator that has been associated with migraine pathophysiology.
10.2 Pharmacodynamics
In a study in healthy subjects, concomitant administration of erenumab with sumatriptan had no effect on resting blood pressure compared with administration of sumatriptan alone. See 9.4 Drug-Drug Interactions.
10.3 Pharmacokinetics
Erenumab exhibits non-linear kinetics as a result of binding to the CGRP receptor.
Erenumab exposure demonstrated approximate dose proportionality from 70 mg to 140 mg following a single subcutaneous administration of erenumab. The Cmax and AUClast values following a single subcutaneous administration of 70 mg or 140 mg erenumab in healthy subjects are included in Table 5.
Following multiple subcutaneous administrations of erenumab once monthly to healthy and migraine subjects, the accumulation ratio was estimated to be less than 2-fold. The trough serum concentrations (Cmin) for episodic and chronic migraine patients following subcutaneous administration of 70 mg once monthly and 140 mg once monthly doses are included in Table 5.
Based on population pharmacokinetics modeling, the effective half-life of Aimovig is 28 days.
Table 5 Pharmacokinetic Parameters of Aimovig
| Aimovig 70 mg | Aimovig 140 mg | ||
Healthy subjects Single dose | Cmax mean (SD) | 6.1 (2.1) mcg/mL | 15.8 (4.8) mcg/mL |
| AUClast mean (SD) | 159 (58) | 505 (139) |
| day*mcg/mL | day*mcg/mL |
| Migraine patients Multiple doses | Cmin mean (SD) |
| Episodic migraine | 5.7 (3.1) mcg/mL |
| 12.8 (6.5) mcg/mL | |
| Chronic migraine | 6.2 (2.9) mcg/mL |
| 14.9 (6.5) mcg/mL | |
Absorption
Following a single subcutaneous dose of 70 mg or 140 mg Aimovig administered to healthy subjects, median peak serum concentrations were attained in 4 to 6 days. Absolute bioavailability was estimated to be 82% based on population pharmacokinetic analysis.
Distribution
Following a single 140 mg intravenous dose in healthy subjects, the mean (SD) volume of distribution during the terminal phase (Vz) was estimated to be 3.86 (0.77) L.
Metabolism and Elimination
Two elimination phases were observed for Aimovig. At low concentrations, the elimination is predominantly through saturable binding to target (CGRP receptor), while at higher concentrations the elimination of Aimovig is largely through a non-specific, non-saturable proteolytic pathway.
Special Populations and Conditions
The pharmacokinetics of erenumab were not affected by age, gender, race, migraine subtype (episodic or chronic migraine) based on population pharmacokinetic analysis.
- Hepatic Insufficiency: No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of Aimovig. The liver is not thought to be a major contributor toward the metabolism of Aimovig, an IgG2 antibody, to an appreciable degree.
- Renal Insufficiency: No clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of Aimovig. Population pharmacokinetic analysis of integrated data from the Aimovig clinical trials did not reveal a difference in the pharmacokinetics of erenumab in patients with mild or moderate renal impairment relative to those with normal renal function. Based on the population pharmacokinetic analysis, no dose adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) have not been studied.
11 STORAGE, STABILITY AND DISPOSAL
Store refrigerated at 2°C to 8°C in the original carton to protect from light until time of use.
If removed from the refrigerator, Aimovig should be kept at controlled room temperature (up to 25°C) in the original carton and must be used within 7 days. Throw away Aimovig that has been left at room temperature for more than 7 days.
Do not freeze. Do not shake.
12 SPECIAL HANDLING INSTRUCTIONS
Any unused product or waste material should be disposed of in accordance with local requirements.
PART II: SCIENTIFIC INFORMATION
13 PHARMACEUTICAL INFORMATION
Drug Substance
| Proper name: | erenumab |
| Chemical name: | anti-Calcitonin gene-related peptide receptor (anti-CGRPR) recombinant Human IgG2 monoclonal antibody |
| Molecular formula and molecular mass: | Erenumab has an approximate molecular weight of 150 kDa. Molecular formula: C6472H9964N1728O2018S50 (peptide) |
| Structural formula: | Erenumab is composed of 2 heavy chains, each containing 456 amino acids and with 4 intrachain disulfide bonds, as well as, 2 light chains of the lambda subclass, each containing 216 amino acids and with 2 intrachain disulfide bonds. |
| Physicochemical properties: | Aimovig is supplied as a sterile, preservative free solution of erenumab for subcutaneous administration. The solution of Aimovig is clear to opalescent and colourless to light yellow, with a pH of 5.2. |
| Pharmaceutical standard: | Professed Standard |
Product Characteristics:
Aimovig (erenumab) is an anti-calcitonin gene-related peptide receptor fully human IgG2 monoclonal antibody expressed in a Chinese hamster ovary (CHO) cell line. Erenumab is produced by recombinant DNA technology in a mammalian cell expression system and is purified by a process that includes specific viral inactivation and removal steps.
14 CLINICAL TRIALS
14.1 Trial Design and Study Demographics Clinical Trials by Indication
Migraine Prevention
Aimovig was evaluated for prevention of migraine in two pivotal studies across the spectrum of episodic and chronic migraine (Error! Reference source not found.). Both studies enrolled patients with a history of migraine, with or without aura according to the International Classification of Headache Disorders (ICHD-III) diagnostic criteria. Patients with preexisting myocardial infarction, stroke, transient ischemic attacks, unstable angina, coronary artery bypass surgery or other revascularization procedures within 12 months prior to screening were excluded. Patients with poorly controlled hypertension or BMI >40 were excluded from Study 20120295.
Table 6 Summary of Trial Design and Patient Demographics for Clinical Trials in Migraine Prevention
| Study # | Trial Design | Dosage, Route of Administration and Duration | Study Subjects (n) | Mean Age (Range) | Sex (Female) |
| 20120295 | Randomized, double-blind, placebo-controlled Efficacy and Safety in Chronic Migraine Prevention | Aimovig 140 mg SC QM Aimovig 70 mg SC QM Placebo SC QM Duration: 12 weeks | 190 191 286 | 42.9 (18-64) 41.4 (18-64) 42.1 (18-66) | 84.2% 86.9% 79.0% |
| 20120296 (STRIVE) | Randomized, double-blind, placebo-controlled Efficacy and Safety in Episodic Migraine Prevention | Aimovig 140 mg SC QM Aimovig 70 mg SC QM Placebo SC QM Duration: 24 weeks | 319 317 319 | 40.4 (19-65) 41.1 (18-63) 41.3 (18-65) | 85.3% 84.5% 85.9% |
| QM = once monthly; SC = subcutaneously | |||||
Chronic Migraine
Aimovig was evaluated for prevention of chronic migraine in a pivotal phase 2 randomized, multi-centre, 12-week, placebo-controlled, double-blind study (Study 20120295). A total of 667 patients with a history of migraine with or without aura (≥ 15 headache days per month with ≥ 8 migraine days per month) were randomized to receive subcutaneous injection monthly for 3 months either placebo (n = 286), Aimovig 70 mg (n=191), or Aimovig 140 mg (n = 190). Randomization was stratified by region (North America vs. other) and the presence of acute medication overuse.
Patients had a median age of 43 years (range; 18 – 66 years), 83% (552/667) were female and 94% (628/667) were white. The mean migraine frequency at baseline was approximately 18 days per month. Patients were allowed to use acute headache treatments including triptans, ergotamine derivatives and nonsteroidal anti-inflammatory drugs (NSAIDS) during the study. Medication overuse was present in 41% (274/667) of patients. Overall in this study population, 68% (453/667) had failed one or more previous prophylactic treatments due to lack of efficacy or poor tolerability, and 49% (327/667) had failed two or more previous prophylactic treatments due to lack of efficacy or poor tolerability. The study excluded patients with opioid overuse and concurrent use of migraine prophylactic treatments or other headache disorders. A total of 182 (96%) patients in the Aimovig 140 mg arm, 184 (96%) patients in the Aimovig 70 mg arm and 265 (93%) patients in the placebo arm completed the study (completed week 12 assessment). Of the 23 (3.4%) patients who discontinued treatment, two patients in the Aimovig 140 mg-treated group, no patients in the Aimovig 70 mg-treated group and two patients in the placebo group discontinued due to adverse events.
The primary outcome measure was the change in monthly migraine days from baseline to the last 4 weeks of the 12-week double-blind treatment phase. Secondary outcome measures included amongst others the achievement of 50% or more reduction in monthly migraine days from baseline (≥ 50% responders) and change from baseline in monthly acute migraine-specific medication days. Results are presented in Table 7.
Table 7 Efficacy Outcomes at Month 3 (Study 20120295)
| Aimovig 70 mg N = 188 | Aimovig 140 mg N = 187 | Placebo N = 281 | Treatment Difference | |||||||||
| Monthly migraine days (MMD) | ||||||||||||
| Baseline | 17.94 | 17.78 | 18.24 | |||||||||
| Week 12 | 11.34 | 11.28 | 14.03 | |||||||||
| Mean changea (95% CI) | -6.64 (-7.47; -5.81) | -6.63 (-7.45, -5.80) | -4.18 (-4.86, -3.50) | 70 mg-placebo: -2.46 (-3.52, -1.39) 140 mg-placebo: -2.45 (-3.51, -1.38) | ||||||||
| (p-value)b | Both < 0.001b | |||||||||||
| ≥ 50% MMD responders | ||||||||||||
| % | 39.9% | 41.2% | 23.5% | |||||||||
| Odds ratioc (95% CI) | 70 mg-placebo: 2.18 (1.46, 3.27) 140 mg-placebo: 2.34 (1.56, 3.51) | |||||||||||
| (p-value)b | Both < 0.001b | |||||||||||
| Monthly acute migraine-specific medication days e | ||||||||||||
| Mean changea (95% CI) | -3.45 (-4.02, -2.87) | -4.13 (-4.70, -3.56) | -1.58 (-2.05, -1.11) | 70 mg-placebo: -1.86 (-2.60, -1.13) 140 mg-placebo: -2.55 (-3.28, -1.82) | ||||||||
| (p-value)b | Both < 0.001b | |||
CI = confidence interval; MMD = monthly migraine days a LS mean change from baseline at month 3, treatment difference, and p-value are based on a linear mixed effects model including treatment group, baseline monthly value, stratification factors (region [North America vs. Europe] and medication overuse [presence vs absence]), scheduled visit, and the interaction of treatment group with scheduled visit, without any imputation for missing data. b Hierarchical gate-keeping procedures and the Hochberg method were used to maintain the 2-sided study-wise type I error at 0.05 between the 2 erenumab doses and the primary and secondary endpoints. c Odds ratio and p-value for ≥ 50% responders at month 3 are based on a stratified Cochran-Mantel-Haenszel test after missing data were imputed as non-response. d Migraine-specific medications include triptans and ergotamine derivatives. | ||||
A treatment effect was observed in a prespecified monthly analysis as early as month one.
In patients failing one or more prophylactic pharmacotherapies (68%) the treatment difference for the reduction of monthly migraine days (MMD) observed between erenumab 140 mg and placebo was -3.3 days and between erenumab 70 mg and placebo -2.5 days. In patients failing two or more prophylactic pharmacotherapies (49%) the treatment difference was -4.3 days between 140 mg and placebo and -2.7 days between 70 mg and placebo.
Approximately 41% of patients in the study had medication overuse. The treatment difference observed between erenumab 140 mg and placebo and between erenumab 70 mg and placebo for the reduction of MMD in these patients was -3.1 days in both cases.
Episodic Migraine
Aimovig was evaluated for prevention of episodic migraine in a phase 3 randomized, multi-centre, 24-week, placebo-controlled, double-blind study (Study 20120296). A total of 955 patients with history of migraine with or without aura for a duration of ≥ 12 months and 4 – 14 migraine days per month were randomized to receive subcutaneous injection monthly for 6 months either Aimovig 70 mg (n=317), Aimovig 140 mg (n = 319), or placebo (n = 319). Randomization was stratified by prior, concomitant, or no prior use of prophylactic medications and region (North America vs. other).
Patients had a median age of 42 years (range; 18 – 65 years), 85% (814/955) were female and 89% (851/955) were white. The mean migraine frequency at baseline was approximately 8 migraine days per month. Patients were allowed to use acute headache treatments including triptans, ergotamine derivatives and NSAIDS. Overall in this study population, 39% (370/955) had failed one or more previous prophylactic treatments due to lack of efficacy or poor tolerability, and 17% (161/955) had failed two or more previous prophylactic treatments due to lack of efficacy or poor tolerability. The study excluded patients with opioid overuse and other headache disorders. Only a few patients with a concomitant prophylactic medication were enrolled. A total of 292 (92%) patients in the Aimovig 140 mg arm, 284 (90%) patients in the Aimovig 70 mg arm and 282 (88%) patients in the placebo arm completed the double-blind phase. Of the 87 (9.14%) patients who discontinued treatment, 7 (2.2%) patients in the 70 mg
Aimovig group, 6 (1.9%) patients in the 140 mg Aimovig group and 7 (2.2%) patients in the placebo group discontinued due to adverse events.
The primary outcome measure was the change from baseline in mean monthly migraine days. The mean monthly migraine days were calculated using the monthly migraine days from each of the last 3 months of the double-blind treatment phase. Secondary outcome measures included amongst others the achievement of a 50% or more reduction in mean monthly migraine days from baseline (≥ 50% responders) and change from baseline in mean monthly acute migraine-specific medication days.
Results are presented in Table 8.
Table 8 Efficacy Outcomes at Months 4 – 6 (Study 20120296)
| Aimovig 70 mg N = 312 | Aimovig 140 mg N = 318 | Placebo N = 316 | Treatment Difference | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Monthly migraine days (MMD) | |||||||||||||
| Baseline | 8.31 | 8.33 | 8.25 | ||||||||||
| Mean of months 4-6 | 4.95 | 4.48 | 6.33 | ||||||||||
| Mean changea (95% CI) | -3.23 (-3.58, -2.88) | -3.67 (-4.02, -3.33) | -1.83 (-2.18, -1.48) | 70 mg-placebo: -1.40 (-1.88, -0.92) 140 mg-placebo: -1.85 (-2.33, -1.37) | |||||||||
| (p-value)b | Both < 0.001b | ||||||||||||
| ≥ 50% MMD responders | |||||||||||||
| % | 43.3 | 50.0 | 26.6 | ||||||||||
| Odds ratioc (95% CI) | 70 mg-placebo: 2.13 (1.52, 2.98) 140 mg-placebo: 2.81 (2.01, 3.94) | ||||||||||||
| (p-value)b | Both < 0.001b | ||||||||||||
| Monthly acute migraine-specific medication dayse | |||||||||||||
| Mean changea (95% CI) | -1.13 (-1.34, -0.92) | -1.61 (-1.83, -1.40) | -0.20 (-0.41, 0.02) | 70 mg-placebo: -0.94 (-1.23, -0.64) 140 mg-placebo: -1.42 (-1.71, -1.12) | |||||||||
| (p-value)b | Both < 0.001b | ||||||||||||
| Aimovig 70 mg N = 312 | Aimovig 140 mg N = 318 | Placebo N = 316 | Treatment Difference | |
|---|---|---|---|---|
CI = confidence interval; MMD = Monthly Migraine Days a LS mean change from baseline at month 4 – 6, treatment difference, and p-value are based on a linear mixed effects model including treatment group, baseline value, stratification factors (region [North America vs. rest of world] and prior prophylactic medication use [naïve, prior use only, concurrent use]), scheduled visit, and the interaction of treatment group with scheduled visit, without any imputation for missing data. b Hierarchical gate-keeping procedures and the Hochberg method were used to maintain the 2-sided study-wise type I error at 0.05 between the 2 erenumab doses and the primary and secondary endpoints. c Odds ratio and p-value for ≥ 50% responders at month 4-6 are based on a stratified Cochran-Mantel-Haenszel test after missing data were imputed as non-response. d Migraine-specific medications include triptans and ergotamine derivatives. | ||||
A treatment effect was observed in a prespecified monthly analysis as early as month one.
In patients failing one or more prophylactic pharmacotherapies (39%) the treatment difference for the reduction of MMD observed between erenumab 140 mg and placebo was -2.5 and between erenumab 70 mg and placebo -2.0.
14.2 Comparative Bioavailability Studies
The results from a comparative bioavailability study (Study 20160349) investigating the bioavailability of a single subcutaneous dose of 140 mg Aimovig delivered by pre-filled syringe as one injection of erenumab 140 mg (test; 1 x 140 mg/mL; Novartis Pharmaceuticals Canada Inc.) compared to two injections of erenumab 70 mg (reference; 2 x 70 mg/mL; Novartis Pharmaceuticals Canada Inc.) in healthy volunteers are presented below. This was a Phase I, multicenter, open-label, randomized, single-dose, parallel-group study with 211 healthy adult subjects, 18 to 55 years old.
Table 9 Summary Table of the Comparative Bioavailability Data (Study 20160349)
erenumab (1 x 140 mg) From measured data Least Squares Geometric Means Arithmetic Mean (CV%) | ||||
|---|---|---|---|---|
| Parameter | Aimovig 1 x 140 mg/mL | Aimovig 2 x 70 mg/mL | % Ratio of Geometric Means | 90% Confidence Interval |
AUCinf (day*μg/mL) | 333.25 358 (35.2) | 364.39 381 (28.4) | 0.91 NA | (0.84, 0.99) NA |
AUCIast (day*μg/mL) | 339.43 361 (33.5) | 365.43 382 (27.8) | 0.93 NA | (0.86, 1.01) NA |
CMAX (μg/mL) | 12.43 13.2 (32.5) | 13.04 13.6 (26.3) | 0.95 NA | (0.88, 1.03) NA |
14.3 Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Aimovig has been evaluated using an immunoassay for the detection of binding anti-erenumab antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.
In the pivotal studies, the incidence of anti-erenumab antibody development among subjects was 6.3% (56/884) among subjects receiving a 70 mg dose of erenumab (3 of whom had in vitro neutralizing activity) and 2.6% (13/504) in patients receiving Aimovig 140 mg once monthly (none of whom had in vitro neutralizing activity). The mean trough levels of erenumab at week 12 were 40% lower among anti-erenumab antibody-positive subjects than among antibody-negative subjects. There was no impact of anti-erenumab antibody development on efficacy or safety of erenumab.
The incidence of anti-drug antibodies (ADAs) is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to erenumab with the incidence of antibodies to other products may be misleading.
15 MICROBIOLOGY
No microbiological information is required for this drug product.
16 NON-CLINICAL TOXICOLOGY
General Toxicology: In a repeat-dose toxicity study conducted in sexually mature cynomolgus monkeys, there were no erenumab-related adverse effects at doses up to 150 mg/kg administered subcutaneously twice weekly for up to 6 months. At the no-observed-adverse-effect level (NOAEL) of 150 mg/kg, systemic exposure was 123-fold higher than that predicted for the maximum recommended clinical dose of 140 mg once monthly based on serum AUC.
Carcinogenicity: Animal studies have not been performed to evaluate the carcinogenic potential of erenumab.
Genotoxicity: No studies have been performed to evaluate the genotoxic potential of erenumab.
Reproductive and Developmental Toxicology: No dedicated fertility studies have been conducted in animals. However, in the 6-month toxicity study conducted in sexually mature cynomolgus monkeys, there were no erenumab-related adverse histopathological changes in male and female reproductive organs at systemic exposures up to 123-fold than that predicted for the maximum recommended clinical dose of 140 mg once monthly based on serum AUC.
In an enhanced pre- and post-natal developmental study conducted in cynomolgus monkeys, there were no erenumab-related adverse effects on pregnancy or on embryo-fetal and post-natal development (up to 6 months age) when erenumab was administered at a dose of 50 mg/kg subcutaneously every two weeks from gestation day 20-22 to parturition. At the NOAEL of 50 mg/kg, maternal systemic exposure was17-fold higher than that predicted for the maximum recommended clinical dose of 140 mg once monthly. Measurable erenumab serum concentrations, greater than those observed in maternal animals, were observed in the infant monkeys at birth, demonstrating that erenumab crosses the placental barrier.
Safety Pharmacology: In a study conducted in conscious telemetered cynomolgus monkeys administered a single subcutaneous dose of 225 mg/kg of erenumab, there were no erenumab-related adverse neurobehavioral effects or adverse effects on respiration rate and cardiovascular endpoints (e.g. arrythmias, ECG waveform, QRS duration, and QTc interval).