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Indications/Uses
Erenumab (Aerinex) is indicated for prophylaxis of migraine in adults.
Dosage/Direction for Use
Dosage: The recommended dose of erenumab (Aerinex) is 70 mg administered once monthly.
Some patients may benefit from a dosage of 140 mg administered once monthly (see Pharmacology: Clinical Studies under Actions).
If a dose is missed, administer as soon as possible. Thereafter, injection can be scheduled monthly from the date of the last dose.
Special populations: Pediatrics: The safety and effectiveness of erenumab (Aerinex) has not been studied in pediatric patients.
Geriatrics: Clinical studies of erenumab (Aerinex) did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. No dose adjustment is required as the pharmacokinetics of erenumab are not affected by age.
Renal impairment: No dose adjustment is necessary in patients with mild to moderate renal impairment. Population pharmacokinetic analysis of integrated data from 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. Patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) have not been studied.
Hepatic impairment: No clinical studies have been performed in patients with hepatic impairment. Erenumab, as a human monoclonal antibody, is not metabolized by cytochrome P450 enzymes and hepatic clearance is not a major clearance pathway for erenumab.
Method of administration: Erenumab (Aerinex) is administered subcutaneously.
Erenumab (Aerinex) is intended for patient self-administration.
Administration should be performed by an individual who has been trained to administer the product. To administer the 140 mg dose, give two consecutive subcutaneous injections of the 70 mg/mL pre-filled syringe.
For detailed instructions on storage, handling and administration, follow the directions provided in the Instructions for Use and Handling under Patient Counselling Information.
Important administration instructions: Visually inspect for particles and discoloration. The product is a clear to opalescent, colorless to light yellow solution. Do not use if the solution is cloudy or discolored or contains flakes or particles.
Administer subcutaneously in the abdomen, thigh, or upper arm. If the patient wants to use the same injection site, make sure it is not the same spot the patient used for a previous injection. Do not inject into areas where the skin is tender, bruised, red, or hard.
The pre-filled syringe is for single use only and designed to deliver the entire contents with no residual content.
The gray needle cap of the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.
Some patients may benefit from a dosage of 140 mg administered once monthly (see Pharmacology: Clinical Studies under Actions).
If a dose is missed, administer as soon as possible. Thereafter, injection can be scheduled monthly from the date of the last dose.
Special populations: Pediatrics: The safety and effectiveness of erenumab (Aerinex) has not been studied in pediatric patients.
Geriatrics: Clinical studies of erenumab (Aerinex) did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. No dose adjustment is required as the pharmacokinetics of erenumab are not affected by age.
Renal impairment: No dose adjustment is necessary in patients with mild to moderate renal impairment. Population pharmacokinetic analysis of integrated data from 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. Patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) have not been studied.
Hepatic impairment: No clinical studies have been performed in patients with hepatic impairment. Erenumab, as a human monoclonal antibody, is not metabolized by cytochrome P450 enzymes and hepatic clearance is not a major clearance pathway for erenumab.
Method of administration: Erenumab (Aerinex) is administered subcutaneously.
Erenumab (Aerinex) is intended for patient self-administration.
Administration should be performed by an individual who has been trained to administer the product. To administer the 140 mg dose, give two consecutive subcutaneous injections of the 70 mg/mL pre-filled syringe.
For detailed instructions on storage, handling and administration, follow the directions provided in the Instructions for Use and Handling under Patient Counselling Information.
Important administration instructions: Visually inspect for particles and discoloration. The product is a clear to opalescent, colorless to light yellow solution. Do not use if the solution is cloudy or discolored or contains flakes or particles.
Administer subcutaneously in the abdomen, thigh, or upper arm. If the patient wants to use the same injection site, make sure it is not the same spot the patient used for a previous injection. Do not inject into areas where the skin is tender, bruised, red, or hard.
The pre-filled syringe is for single use only and designed to deliver the entire contents with no residual content.
The gray needle cap of the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.
Overdosage
There is no experience with overdose in clinical trials with erenumab (Aerinex). Doses up to 280 mg SC 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.
In the event of an overdose, the patient should be treated symptomatically and supportive measures instituted as required.
Contraindications
Erenumab (Aerinex) is contraindicated in patients with serious hypersensitivity to erenumab or to any of the excipients [see PRECAUTIONS and ADVERSE REACTIONS].
Special Precautions
Hypersensitivity Reactions: Serious hypersensitivity reactions, including rash, angioedema, and anaphylactoid reactions, have been reported with erenumab (Aerinex) 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 erenumab (Aerinex) and initiate appropriate therapy [see CONTRAINDICATIONS].
Effects on ability to drive and use machines: It is expected to have no influence on the ability to drive and use machines.
Effects on ability to drive and use machines: It is expected to have no influence on the ability to drive and use machines.
Use In Pregnancy & Lactation
Pregnancy: There are no adequate and well controlled studies on the use of erenumab (Aerinex) in pregnant women. In a cynomolgus monkey reproduction study, there were no effects on pregnancy, embryo-fetal or post-natal development (up to six months age) when erenumab was dosed throughout pregnancy at exposure levels 40 or 17-fold higher than those achieved in patients receiving erenumab at the 70 or 140 mg once monthly dosing regimen, respectively based on area under the concentration curve (AUC). Measurable erenumab serum concentrations were observed in the infant monkeys at birth, confirming that erenumab, like other IgG antibodies, crosses the placental barrier.
Animal studies are not always predictive of human response and therefore, it is not known whether erenumab can cause fetal harm when administered to a pregnant woman. Consider the use during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: It is not known whether erenumab is present in human milk. There are no data on the effects of erenumab on the breastfed child or its effect on milk production. Because drugs are excreted in human milk and because of the potential for adverse effects in nursing infants from erenumab, a decision should be made whether to discontinue nursing or discontinue erenumab (Aerinex), taking into account the potential benefit of the treatment to the mother and the potential benefit of breast feeding to the infant.
Fertility: No data are available on the effect of erenumab on human fertility. There were no adverse effects on surrogate markers of fertility (anatomic pathology or histopathology changes in reproductive organs) in sexually mature monkeys at systemic exposures up to 283 or 123-fold higher than the clinical dose of 70 or 140 mg once monthly, respectively based on serum AUC (see Pharmacology: Toxicology: Non-Clinical Safety Data under Actions).
Animal studies are not always predictive of human response and therefore, it is not known whether erenumab can cause fetal harm when administered to a pregnant woman. Consider the use during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: It is not known whether erenumab is present in human milk. There are no data on the effects of erenumab on the breastfed child or its effect on milk production. Because drugs are excreted in human milk and because of the potential for adverse effects in nursing infants from erenumab, a decision should be made whether to discontinue nursing or discontinue erenumab (Aerinex), taking into account the potential benefit of the treatment to the mother and the potential benefit of breast feeding to the infant.
Fertility: No data are available on the effect of erenumab on human fertility. There were no adverse effects on surrogate markers of fertility (anatomic pathology or histopathology changes in reproductive organs) in sexually mature monkeys at systemic exposures up to 283 or 123-fold higher than the clinical dose of 70 or 140 mg once monthly, respectively based on serum AUC (see Pharmacology: Toxicology: Non-Clinical Safety Data under Actions).
Adverse Reactions
Summary of the safety profile: Data from two phase 3 and two phase 2 clinical studies in migraine were pooled to evaluate the safety of erenumab (Aerinex) in comparison to placebo up to 12 weeks after treatment initiation.
There were a total of 2656 patients (1613 erenumab and 1043 placebo) in these studies. Of these, 893 subjects received 70 mg dose and 507 subjects received 140 mg of erenumab.
The overall safety population including ongoing open-label extension phases with erenumab (Aerinex) includes 2537 patients (2310.3 patient years) who received at least one dose of the drug: 2066 patients were exposed for at least 6 months and 1213 were exposed for at least 12 months.
Tabulated summary of adverse drug reactions: Table 5 summarizes all adverse reactions that occurred in erenumab-treated patients during the 12-week placebo-controlled period of the pooled trials. Most of the adverse drug reactions (ADR's) were mild or moderate in severity.
Frequency is provided by CIOMS category (e.g., Very Common (≥ 10%), Common (≥ 1% and < 10%), uncommon (≥ 0.1% and < 1%), rare (≥ 0.01% and < 0.1%), very rare (< 0.01%)). (See Table 5.)
There were a total of 2656 patients (1613 erenumab and 1043 placebo) in these studies. Of these, 893 subjects received 70 mg dose and 507 subjects received 140 mg of erenumab.
The overall safety population including ongoing open-label extension phases with erenumab (Aerinex) includes 2537 patients (2310.3 patient years) who received at least one dose of the drug: 2066 patients were exposed for at least 6 months and 1213 were exposed for at least 12 months.
Tabulated summary of adverse drug reactions: Table 5 summarizes all adverse reactions that occurred in erenumab-treated patients during the 12-week placebo-controlled period of the pooled trials. Most of the adverse drug reactions (ADR's) were mild or moderate in severity.
Frequency is provided by CIOMS category (e.g., Very Common (≥ 10%), Common (≥ 1% and < 10%), uncommon (≥ 0.1% and < 1%), rare (≥ 0.01% and < 0.1%), very rare (< 0.01%)). (See Table 5.)
Description of selected adverse reactions: Injection site reactions: In the integrated 12-week placebo-controlled period of studies, in subjects treated with erenumab (Aerinex) the most frequent injection site reactions were injection site pain, injection site erythema, and injection site pruritus. A majority of injection site reactions were Grade 1 in severity (mild) and transient. Injection site pain typically subsided within 1 hour after administration. One subject treated with 70 mg SC discontinued due to injection site rash and no subject treated with 140 mg SC discontinued due to injection site reactions in the 12-week placebo-controlled period of studies.
Constipation: In the integrated 12-week placebo-controlled period of studies, 28 cases of constipation were reported out of 1400 erenumab-treated patients. All were mild or moderate severity. 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.
Post-Marketing Experience: Hypersensitivity reactions including rash,
angioedema, and anaphylactoid reactions [see PRECAUTIONS].
Constipation with serious complications has been reported. In a majority of these cases, the onset was reported after the first dose of erenumab (Aerinex); 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.
Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of erenumab (Aerinex) 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 four migraine prophylaxis efficacy studies [20120178, 20120295, 20120296 and 20120297], the incidence of anti-erenumab antibody development during the double-blind treatment phase was 6.3% (56/884) among subjects receiving 70 mg dose of erenumab (three of whom had in-vitro neutralizing activity) and 2.6% (13/504) among subjects receiving the 140 mg dose (none of whom had in-vitro neutralizing activity). 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.
Constipation: In the integrated 12-week placebo-controlled period of studies, 28 cases of constipation were reported out of 1400 erenumab-treated patients. All were mild or moderate severity. 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.
Post-Marketing Experience: Hypersensitivity reactions including rash,
angioedema, and anaphylactoid reactions [see PRECAUTIONS].
Constipation with serious complications has been reported. In a majority of these cases, the onset was reported after the first dose of erenumab (Aerinex); 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.
Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of erenumab (Aerinex) 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 four migraine prophylaxis efficacy studies [20120178, 20120295, 20120296 and 20120297], the incidence of anti-erenumab antibody development during the double-blind treatment phase was 6.3% (56/884) among subjects receiving 70 mg dose of erenumab (three of whom had in-vitro neutralizing activity) and 2.6% (13/504) among subjects receiving the 140 mg dose (none of whom had in-vitro neutralizing activity). 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.
Caution For Usage
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Important administration instructions: Visually inspect for particles and discoloration. The product is a clear to opalescent, colorless to light yellow solution. Do not use if the solution is cloudy or discolored or contains flakes or particles.
Administer subcutaneously in the abdomen, thigh, or upper arm. If you want to use the same injection site, make sure it is not the same spot you used for a previous injection. Do not inject into areas where the skin is tender, bruised, red, or hard.
The pre-filled syringe is for single use only and designed to deliver the entire contents with no residual content.
The gray needle cap of the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.
Important administration instructions: Visually inspect for particles and discoloration. The product is a clear to opalescent, colorless to light yellow solution. Do not use if the solution is cloudy or discolored or contains flakes or particles.
Administer subcutaneously in the abdomen, thigh, or upper arm. If you want to use the same injection site, make sure it is not the same spot you used for a previous injection. Do not inject into areas where the skin is tender, bruised, red, or hard.
The pre-filled syringe is for single use only and designed to deliver the entire contents with no residual content.
The gray needle cap of the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.
Storage
Store at temperatures between 2-8°C.
Keep in the original carton to protect from light until time of use.
If removed from the refrigerator, product should be kept at controlled room temperature (up to 25°C) in the original carton and must be used within 14 days. Throw away any product that has been left at room temperature for more than 14 days.
Do not freeze.
Do not shake.
Keep in the original carton to protect from light until time of use.
If removed from the refrigerator, product should be kept at controlled room temperature (up to 25°C) in the original carton and must be used within 14 days. Throw away any product that has been left at room temperature for more than 14 days.
Do not freeze.
Do not shake.
Action
Pharmacology: Mechanism of action: Erenumab is a human monoclonal antagonist antibody against the CGRP receptor with no significant pharmacological activity at adrenomedulin, calcitonin, and amylin receptors and lacks agonist activity at the CGRP receptor.
CGRP is a neuropeptide that modulates nociceptive signaling and a vasodilator that has been associated with migraine pathophysiology. In contrast with other neuropeptides, CGRP levels have been shown to increase significantly during migraine and return to normal with headache relief. Intravenous infusion of CGRP induces migraine-like headache in patients suggesting that CGRP may play a causal role in migraine.
The CGRP receptor is located at sites that are relevant to migraine pathophysiology. Erenumab potently and specifically competes with the binding of CGRP and inhibits its function at the CGRP receptor.
Pharmacodynamic effect: In a randomized, double-blind, placebo-controlled study (20140254) to evaluate the effect of erenumab (Aerinex) (140 mg IV, single dose) in patients with stable angina, the drug did not decrease exercise duration during a treadmill test compared to placebo and did not aggravate myocardial ischemia in these patients.
Clinical Studies: Erenumab (Aerinex) was evaluated for prophylaxis of migraine in two pivotal studies across the spectrum of episodic and chronic migraine. Studies enrolled patients with a history of migraine, with or without aura according to the International Classification of Headache Disorders (ICHD-III) diagnostic criteria.
Treatment with erenumab (Aerinex) demonstrated statistically significant and clinically meaningful improvements from baseline compared to placebo for key efficacy outcomes.
Chronic Migraine: Study 1 (Study 20120295): Erenumab (Aerinex) was evaluated for prophylaxis of chronic migraine in a randomized, multi-center, 12 week, placebo-controlled, double-blind study. 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 placebo (n = 286), erenumab 70 mg (n = 191) or erenumab 140 mg (n = 190) subcutaneous injections monthly for 12 weeks.
Randomization was stratified by region (North America versus other) and the presence of acute medication overuse (present in 41% of overall patients) excluding patients with opioid overuse. The mean migraine frequency at baseline was approximately 18 migraine days per month and was similar across treatment groups. Patients were allowed to use acute headache treatments including triptans, ergotamine derivatives and NSAIDs during the study.
Patients had a median age of 43 years (range: 18 to 66 years); 83% were female and 94% were white. Patients could have failed (i.e., no therapeutic response) up to three previous prophylactic treatment categories due to lack of efficacy, while there was no limit to the number of previous failures for poor tolerability. Overall in this study population, 68% had failed one or more previous prophylactic treatments due to lack of efficacy or poor tolerability, and 49% had failed two or more previous prophylactic treatments due to lack of efficacy or poor tolerability. In addition to excluding patients with opioid overuse, the study excluded patients with concurrent use of migraine prophylactic treatments. A total of 182 (96%) patients in the 140 mg arm, 184 (96%) patients in the 70 mg arm, and 265 (93%) patients in the placebo arm completed the study (i.e. completed Week 12 assessment). Of the 23 (3.4%) patients who discontinued treatment, 2 patients in the 140 mg-treated group, no patients in the 70 mg-treated group, and 2 patients in the placebo group discontinued due to adverse events.
The primary outcome measure was the change from baseline at Month 3 in monthly migraine days. Secondary outcome measures included the achievement of 50 to 100% reduction in monthly migraine days from baseline (≥50% responders), change from baseline in monthly acute migraine specific medication days, and change from baseline in cumulative monthly headache hours. Other than for cumulative monthly headache hours, erenumab (Aerinex) demonstrated statistically significant and clinically meaningful improvements from baseline at Month 3 compared to placebo for efficacy outcomes as summarized in Figure 1 and Table 1.
Reduction in mean monthly migraine days from placebo were observed in a monthly analysis from Month 1 and in a follow up weekly analysis an onset of treatment effect was seen from the first week of administration. (See Figure 1 and Table 1.)
CGRP is a neuropeptide that modulates nociceptive signaling and a vasodilator that has been associated with migraine pathophysiology. In contrast with other neuropeptides, CGRP levels have been shown to increase significantly during migraine and return to normal with headache relief. Intravenous infusion of CGRP induces migraine-like headache in patients suggesting that CGRP may play a causal role in migraine.
The CGRP receptor is located at sites that are relevant to migraine pathophysiology. Erenumab potently and specifically competes with the binding of CGRP and inhibits its function at the CGRP receptor.
Pharmacodynamic effect: In a randomized, double-blind, placebo-controlled study (20140254) to evaluate the effect of erenumab (Aerinex) (140 mg IV, single dose) in patients with stable angina, the drug did not decrease exercise duration during a treadmill test compared to placebo and did not aggravate myocardial ischemia in these patients.
Clinical Studies: Erenumab (Aerinex) was evaluated for prophylaxis of migraine in two pivotal studies across the spectrum of episodic and chronic migraine. Studies enrolled patients with a history of migraine, with or without aura according to the International Classification of Headache Disorders (ICHD-III) diagnostic criteria.
Treatment with erenumab (Aerinex) demonstrated statistically significant and clinically meaningful improvements from baseline compared to placebo for key efficacy outcomes.
Chronic Migraine: Study 1 (Study 20120295): Erenumab (Aerinex) was evaluated for prophylaxis of chronic migraine in a randomized, multi-center, 12 week, placebo-controlled, double-blind study. 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 placebo (n = 286), erenumab 70 mg (n = 191) or erenumab 140 mg (n = 190) subcutaneous injections monthly for 12 weeks.
Randomization was stratified by region (North America versus other) and the presence of acute medication overuse (present in 41% of overall patients) excluding patients with opioid overuse. The mean migraine frequency at baseline was approximately 18 migraine days per month and was similar across treatment groups. Patients were allowed to use acute headache treatments including triptans, ergotamine derivatives and NSAIDs during the study.
Patients had a median age of 43 years (range: 18 to 66 years); 83% were female and 94% were white. Patients could have failed (i.e., no therapeutic response) up to three previous prophylactic treatment categories due to lack of efficacy, while there was no limit to the number of previous failures for poor tolerability. Overall in this study population, 68% had failed one or more previous prophylactic treatments due to lack of efficacy or poor tolerability, and 49% had failed two or more previous prophylactic treatments due to lack of efficacy or poor tolerability. In addition to excluding patients with opioid overuse, the study excluded patients with concurrent use of migraine prophylactic treatments. A total of 182 (96%) patients in the 140 mg arm, 184 (96%) patients in the 70 mg arm, and 265 (93%) patients in the placebo arm completed the study (i.e. completed Week 12 assessment). Of the 23 (3.4%) patients who discontinued treatment, 2 patients in the 140 mg-treated group, no patients in the 70 mg-treated group, and 2 patients in the placebo group discontinued due to adverse events.
The primary outcome measure was the change from baseline at Month 3 in monthly migraine days. Secondary outcome measures included the achievement of 50 to 100% reduction in monthly migraine days from baseline (≥50% responders), change from baseline in monthly acute migraine specific medication days, and change from baseline in cumulative monthly headache hours. Other than for cumulative monthly headache hours, erenumab (Aerinex) demonstrated statistically significant and clinically meaningful improvements from baseline at Month 3 compared to placebo for efficacy outcomes as summarized in Figure 1 and Table 1.
Reduction in mean monthly migraine days from placebo were observed in a monthly analysis from Month 1 and in a follow up weekly analysis an onset of treatment effect was seen from the first week of administration. (See Figure 1 and Table 1.)
Based on a pre-specified analysis, the 70 mg and 140 mg dose of erenumab (Aerinex) were efficacious in patients who had previously been treated with migraine prophylactics. Table 2 provides subgroup results of Study 1 based on prior prophylactic failure(s) due to lack of efficacy or intolerance, in a pre-specified analysis. (See Table 2.)
In patients with medication overuse (41% of the total population in Study 1), efficacy was observed with 70 mg and 140 mg erenumab (Aerinex) compared to placebo for monthly migraine days [LSM (95% CI) 70 mg: -3.10 days (-4.83, -1.37); 140 mg: -3.10 days (-4.81, -1.39)], 50% responders [(34.6% for 140 mg, 36.4% for 70 mg versus 17.7% for placebo) with odds ratio (95% CI) 70 mg: 2.67 (1.36, 5.22);140 mg: 2.51 (1.28, 4.94)], and in acute migraine-specific medication days [(LSM (95% CI) 70 mg: -3.33 (-4.72, -1.94); 140 mg: -2.79 (-4.16, -1.42)].
Improvement in functional ability was assessed by the Headache Impact Test (HIT-6) and the Migraine Disability Assessment (MIDAS) questionnaires. Mean change from baseline to Month 3 compared to placebo for the patient reported outcome measures are summarized in Table 1. The established between-group Minimally Important Difference (MID) for the reduction in HIT-6 total score is 2.3.
Episodic Migraine: Study 2 (Study 20120296, STRIVE): Study 2 was a randomized, multi-center, 24-week, placebo-controlled, double-blind study evaluating erenumab (Aerinex) for prophylaxis of episodic migraine. 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 either erenumab 70 mg (n=317), erenumab 140 mg (n = 319), or placebo (n = 319) by subcutaneous injection monthly for 6 months. Randomization was stratified by use of prophylactic medications (concomitant, prior use or no prior use) and region (North America vs. other). The mean migraine frequency at baseline was approximately 8 migraine days per month and was similar across treatment groups. Patients were allowed to use acute headache treatments including triptans, ergotamine derivatives and NSAIDs during the study.
Patients had a median age of 42 years (range: 18 to 65 years), 85% were female and 89% were white. Patients could have failed to respond up to two previous prophylactic treatments. The study excluded patients with medication overuse. Overall, 865 (90.6%) patients completed the double-blind phase, including 287 (90.5%) in the 70 mg group, 294 (92.2%) in the 140 mg group, and 284 (89.0%) in the placebo group. Of the 87 (9.1%) patients who discontinued treatment, 7 patients in the 70 mg group, 6 patients in the 140 mg group, and 7 patients in the placebo group discontinued due to adverse events.
The primary outcome measure was the change from baseline during months 4-6 in monthly migraine days. Secondary outcome measures included the achievement of a 50 to 100% reduction in mean monthly migraine days from baseline (≥ 50% responders), change from baseline in mean monthly acute migraine specific medication days and change from baseline in the two Migraine Physical Function Impact Diary (MPFID) domain scores: physical impairment (PI) and impact on everyday activities (EA).
The MPFID is a patient reported outcomes instrument that measures the impact of migraine on physical functioning. It contains 13 items evaluating the impact of migraine during the previous 24 hours on two physical functioning concepts of interest: "impact on everyday activities (EA)" (7 items, e.g. difficulty doing activities requiring concentration), "physical impairment (PI)" (5 items, e.g. difficulty doing activities requiring physical effort) and one global item assessing the overall impact on everyday activities. Patients rate the duration of impact or level of difficulty associated with migraine on a daily basis. Monthly MPFID scores are averaged over days with and without migraine; higher scores indicate worse impact on the EA and PI domains.
Erenumab (Aerinex) treatment demonstrated statistically significant and clinically meaningful improvements from baseline during Months 4 to 6 compared to placebo for efficacy outcomes as summarized in Figure 2 and Table 3. Differences from placebo were observed as early as Month 1.
Based on a pre-specified analysis, the 70 mg and 140 mg dose of erenumab (Aerinex) were efficacious in patients who had previously been treated with migraine prophylactics. Table 4 provides subgroup results of Study 2 based on prior prophylactic failure due to lack of efficacy or intolerance, in a pre-specified analysis. (See Figure 2 and Tables 3 and 4.)
Improvement in functional ability was assessed by the Headache Impact Test (HIT-6) and the Migraine Disability Assessment (MIDAS) questionnaires. Mean change from baseline to Month 3 compared to placebo for the patient reported outcome measures are summarized in Table 1. The established between-group Minimally Important Difference (MID) for the reduction in HIT-6 total score is 2.3.
Episodic Migraine: Study 2 (Study 20120296, STRIVE): Study 2 was a randomized, multi-center, 24-week, placebo-controlled, double-blind study evaluating erenumab (Aerinex) for prophylaxis of episodic migraine. 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 either erenumab 70 mg (n=317), erenumab 140 mg (n = 319), or placebo (n = 319) by subcutaneous injection monthly for 6 months. Randomization was stratified by use of prophylactic medications (concomitant, prior use or no prior use) and region (North America vs. other). The mean migraine frequency at baseline was approximately 8 migraine days per month and was similar across treatment groups. Patients were allowed to use acute headache treatments including triptans, ergotamine derivatives and NSAIDs during the study.
Patients had a median age of 42 years (range: 18 to 65 years), 85% were female and 89% were white. Patients could have failed to respond up to two previous prophylactic treatments. The study excluded patients with medication overuse. Overall, 865 (90.6%) patients completed the double-blind phase, including 287 (90.5%) in the 70 mg group, 294 (92.2%) in the 140 mg group, and 284 (89.0%) in the placebo group. Of the 87 (9.1%) patients who discontinued treatment, 7 patients in the 70 mg group, 6 patients in the 140 mg group, and 7 patients in the placebo group discontinued due to adverse events.
The primary outcome measure was the change from baseline during months 4-6 in monthly migraine days. Secondary outcome measures included the achievement of a 50 to 100% reduction in mean monthly migraine days from baseline (≥ 50% responders), change from baseline in mean monthly acute migraine specific medication days and change from baseline in the two Migraine Physical Function Impact Diary (MPFID) domain scores: physical impairment (PI) and impact on everyday activities (EA).
The MPFID is a patient reported outcomes instrument that measures the impact of migraine on physical functioning. It contains 13 items evaluating the impact of migraine during the previous 24 hours on two physical functioning concepts of interest: "impact on everyday activities (EA)" (7 items, e.g. difficulty doing activities requiring concentration), "physical impairment (PI)" (5 items, e.g. difficulty doing activities requiring physical effort) and one global item assessing the overall impact on everyday activities. Patients rate the duration of impact or level of difficulty associated with migraine on a daily basis. Monthly MPFID scores are averaged over days with and without migraine; higher scores indicate worse impact on the EA and PI domains.
Erenumab (Aerinex) treatment demonstrated statistically significant and clinically meaningful improvements from baseline during Months 4 to 6 compared to placebo for efficacy outcomes as summarized in Figure 2 and Table 3. Differences from placebo were observed as early as Month 1.
Based on a pre-specified analysis, the 70 mg and 140 mg dose of erenumab (Aerinex) were efficacious in patients who had previously been treated with migraine prophylactics. Table 4 provides subgroup results of Study 2 based on prior prophylactic failure due to lack of efficacy or intolerance, in a pre-specified analysis. (See Figure 2 and Tables 3 and 4.)
Pharmacokinetics: Erenumab exhibits non-linear kinetics as a result of binding to CGRP receptor. Subcutaneous administration of a 70 mg and 140 mg dose in healthy volunteers resulted in a Cmax mean (standard deviation [SD]) of 6.1 (2.1) mcg/mL and 15.8 (4.8) mcg/mL respectively, and AUClast mean (SD) of 159 (58) day*mcg/mL and 505 (139) day*mcg/mL respectively.
Less than 2 fold accumulation was observed in trough serum concentrations (Cmin [SD] 5.7 [3.1] and 6.2 [2.9] mcg/mL for episodic and chronic migraine subjects, respectively following 70 mg doses; Cmin [SD] 12.8 [6.53] and 14.9 [6.45] mcg/mL for episodic and chronic migraine subjects, respectively following 140 mg doses) administered subcutaneously every 4 weeks and serum trough concentrations approached steady state by 12 weeks of dosing. The effective half-life of erenumab is 28 days.
Absorption: Following a single subcutaneous dose of 70 mg or 140 mg administered to healthy adults, median peak serum concentrations were attained in approximately 6 days, and estimated absolute bioavailability was 82%.
Distribution: Following a single 140 mg intravenous dose, the mean (SD) volume of distribution during the terminal phase (Vz) was estimated to be 3.86 (0.77) L.
Metabolism and excretion: Two elimination phases were observed for erenumab. At low concentrations, the elimination is predominately through saturable binding to target (CGRP-R), while at higher concentrations, elimination is largely through a non-specific, non-saturable proteolytic pathway.
Specific populations: The pharmacokinetics of erenumab were not affected by age, gender, race, migraine subtype (episodic or chronic migraine), or creatinine clearance, across all approved populations based on population pharmacokinetics (PK) analysis.
Toxicology: Non-Clinical Safety Data: Carcinogenesis, mutagenesis, impairment of fertility: Carcinogenicity studies have not been conducted with erenumab. Erenumab is not pharmacologically active in rodents and has biologic activity in the cynomolgus monkeys, but this species is not an appropriate model for evaluation of tumorigenic risk. The mutagenic potential of erenumab has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.
There were no adverse effects on surrogate markers of fertility (anatomic pathology or histopathology changes in reproductive organs) in the chronic toxicology study in sexually mature monkeys subcutaneously administered erenumab at dose levels up to 150 mg/kg twice weekly for 6 months, at systemic exposures up to 283 or 123-fold higher than the clinical dose of 70 mg or 140 mg once monthly, respectively based on serum AUC.
Animal toxicology: There were no adverse effects in monkeys dosed up to 150 mg/kg SC twice weekly for up to 6 months at systemic exposures up to 283 or 123-fold higher than the clinical dose of 70 or 140 mg once monthly, respectively, based on serum AUC.
Less than 2 fold accumulation was observed in trough serum concentrations (Cmin [SD] 5.7 [3.1] and 6.2 [2.9] mcg/mL for episodic and chronic migraine subjects, respectively following 70 mg doses; Cmin [SD] 12.8 [6.53] and 14.9 [6.45] mcg/mL for episodic and chronic migraine subjects, respectively following 140 mg doses) administered subcutaneously every 4 weeks and serum trough concentrations approached steady state by 12 weeks of dosing. The effective half-life of erenumab is 28 days.
Absorption: Following a single subcutaneous dose of 70 mg or 140 mg administered to healthy adults, median peak serum concentrations were attained in approximately 6 days, and estimated absolute bioavailability was 82%.
Distribution: Following a single 140 mg intravenous dose, the mean (SD) volume of distribution during the terminal phase (Vz) was estimated to be 3.86 (0.77) L.
Metabolism and excretion: Two elimination phases were observed for erenumab. At low concentrations, the elimination is predominately through saturable binding to target (CGRP-R), while at higher concentrations, elimination is largely through a non-specific, non-saturable proteolytic pathway.
Specific populations: The pharmacokinetics of erenumab were not affected by age, gender, race, migraine subtype (episodic or chronic migraine), or creatinine clearance, across all approved populations based on population pharmacokinetics (PK) analysis.
Toxicology: Non-Clinical Safety Data: Carcinogenesis, mutagenesis, impairment of fertility: Carcinogenicity studies have not been conducted with erenumab. Erenumab is not pharmacologically active in rodents and has biologic activity in the cynomolgus monkeys, but this species is not an appropriate model for evaluation of tumorigenic risk. The mutagenic potential of erenumab has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.
There were no adverse effects on surrogate markers of fertility (anatomic pathology or histopathology changes in reproductive organs) in the chronic toxicology study in sexually mature monkeys subcutaneously administered erenumab at dose levels up to 150 mg/kg twice weekly for 6 months, at systemic exposures up to 283 or 123-fold higher than the clinical dose of 70 mg or 140 mg once monthly, respectively based on serum AUC.
Animal toxicology: There were no adverse effects in monkeys dosed up to 150 mg/kg SC twice weekly for up to 6 months at systemic exposures up to 283 or 123-fold higher than the clinical dose of 70 or 140 mg once monthly, respectively, based on serum AUC.
MedsGo Class
Antimigraine Preparations
Features
Brand
Aerinex
Full Details
Dosage Strength
70 mg / ml
Drug Ingredients
- Erenumab
Drug Packaging
Solution for Injection (S.C.) 1ml x 1's
Generic Name
Erenumab
Dosage Form
Solution For Injection (S.C.)
Registration Number
BR-1313
Drug Classification
Prescription Drug (RX)
Product Questions
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