Erinex^® (Solution) Instructions for Use

Marketing Authorization Holder

Novartis Overseas Investments AG (Switzerland)

Manufactured By

Amgen Manufacturing, Limited (Puerto Rico)

Packaging and Quality Control Release

NOVARTIS MANUFACTURING, NV (Belgium)

Or

ALCON-COUVREUR N.V., S.A. (Belgium)

Or

NOVARTIS PHARMACEUTICAL MANUFACTURING, GmbH (Austria)

Or

SANDOZ, GmbH (Austria)

Contact Information

NOVARTIS PHARMA LLC (Russia)

ATC Code

N02CD01 (Erenumab)

Active Substance

Erenumab (Rec.INN registered by WHO)

Dosage Forms

	Erinex®	Solution for subcutaneous injection 70 mg/1 ml: syringe or pen-injector 1 ml
		Solution for subcutaneous injection 140 mg/ml: syringe or pen-injector 1 ml 1 pc.

Dosage Form, Packaging, and Composition

Solution for s.c. injection from colorless to light yellow.

Excipients: sucrose, polysorbate-80, glacial acetic acid, sodium hydroxide, water for injections.

1 ml – single-use prefilled syringes (1) – cardboard packs with primary opening control^×.
1 ml – single-use prefilled pen-injectors* with white cap (1) – cardboard packs with primary opening control^××.

Solution for s.c. injection from colorless to light yellow.

Excipients: sucrose, polysorbate-80, glacial acetic acid, sodium hydroxide, water for injections.

1 ml – single-use prefilled syringes (1) – cardboard packs with primary opening control^#.
1 ml – single-use prefilled pen-injectors* with gray cap (1) – cardboard packs with primary opening control^##.

* prefilled glass syringe with needle in an autoinjector (pen-injector).
^× packaging and quality control release by NOVARTIS MANUFACTURING NV (Belgium).
^×× packaging and quality control release by NOVARTIS PHARMACEUTICAL MANUFACTURING GmbH (Austria).
^#packaging and quality control release by s.a. ALCON-COUVREUR n.v. (Belgium).
^## packaging and quality control release by SANDOZ GmbH (Austria).

Clinical-Pharmacological Group

Drug with antimigraine activity

Pharmacotherapeutic Group

Antimigraine agent

Pharmacological Action

Mechanism of action

Erenumab is a human monoclonal antibody that is a CGRP receptor antagonist and does not have significant pharmacological activity against adrenomedullin, calcitonin, and amylin receptors, nor does it have agonistic activity against the CGRP receptor.

CGRP is a neuropeptide that modulates nociceptive signal transmission and is a vasodilator associated with the pathophysiology of migraine. It has been shown that, unlike other neuropeptides, the concentration of CGRP increases significantly during a migraine attack and returns to normal after its resolution. Intravenous administration of CGRP induces migraine-like headache in patients, suggesting that CGRP may be a cause of migraine.

The CGRP receptor is localized in areas related to the pathophysiology of migraine. Erenumab is a potent and specific competitor of CGRP for binding to the receptor and thereby suppresses its action on the receptor.

Pharmacodynamics

In a randomized, double-blind, placebo-controlled study evaluating the efficacy of a single intravenous dose of 140 mg of erenumab in patients with stable angina, there was no reduction in exercise tolerance during a stress ECG test (treadmill test) compared to placebo and no worsening of myocardial ischemia.

Clinical data

Erenumab was evaluated in 3 pivotal studies investigating the preventive treatment of episodic and chronic migraine. The studies included patients with a history of migraine with or without aura according to the diagnostic criteria of the International Classification of Headache Disorders (ICHD-III).

Erenumab demonstrated statistically and clinically significant improvement in key efficacy endpoints compared to placebo.

Chronic migraine

Erenumab was evaluated as monotherapy for the prevention of chronic migraine in a randomized, multicenter, 12-week, placebo-controlled, double-blind study in patients suffering from migraine with or without aura (≥15 headache days per month and ≥8 migraine days per month).

In the clinical study of patients with chronic migraine, the efficacy of the drug was assessed based on the change in the number of monthly migraine days (MMD) at month 3 compared to before treatment with erenumab (baseline). Secondary efficacy endpoints were a reduction of ≥50% from baseline in MMD (≥50% response rate), change from baseline in the number of monthly days patients used specific acute migraine medications. Figure 1 and Table 1 show the key study results.

Analysis of monthly changes showed that the mean monthly number of migraine days decreased compared to placebo as early as the first month, and subsequent analysis of weekly changes showed that the effect of erenumab developed as early as the first week after injection.

Figure 1. Change from baseline in MMD in patients with chronic migraine^a

* Least squares means and 95% confidence intervals are presented.
All p-values for the difference in least squares means between the erenumab and placebo groups, assessed at 3 months (primary efficacy endpoint), were < 0.001.

Table 1. Efficacy endpoints at week 12 in patients with chronic migraine

CI – confidence interval; HIT (headache impact test) – headache impact test; MIDAS (migraine disability assessment) – migraine disability assessment; MMD – monthly migraine days.

^a All p-values are presented as unadjusted values and are statistically significant after correction for multiple comparisons.

^b Least squares mean change at month 3 from baseline, intergroup difference and p-value are based on a linear mixed-effects model including treatment group, baseline monthly value, stratification factors (region [North America or Europe] and medication overuse [present or absent]), scheduled visit and “treatment group-scheduled visit” interaction; no imputation for missing data was performed.

^c Odds ratio and p-value for patients with ≥50% response at month 3 are based on the stratified Cochran-Mantel-Haenszel test after imputation for missing data, which were considered non-response.

^d Post-hoc analysis; no hypothesis testing was performed.

^e Specific migraine medications include triptans and ergot derivatives.

In patients who had not achieved a clinical response to one or more preventive therapies, the difference in MMD reduction observed between the 140 mg dose and placebo was -3.3 days (95% CI: -4.6; -2.1), and between the 70 mg dose and placebo – -2.5 days (95% CI: -3.8; -1.2). In patients who had not achieved a clinical response to two or more preventive therapies, the MMD difference was -4.3 days (95% CI: -5.8; -2.8) between the 140 mg dose and placebo and -2.7 days (95% CI: -4.2; -1.2) between the 70 mg dose and placebo, respectively. The proportion of patients receiving Erenumab who achieved at least a 50% reduction in MMD was higher compared to the placebo group among patients who had not achieved a clinical response to one or more preventive therapies (40.8% for the 140 mg dose and 34.7% for the 70 mg dose versus 17.3% for placebo), with an odds ratio of 3.3 (95% CI: 2.0; 5.5) for the 140 mg dose and 2.6 (95% CI: 1.6; 4.5) for the 70 mg dose. In patients who had not achieved a clinical response after using two or more preventive therapies, the proportion was 41.3% for the 140 mg dose and 35.6% for the 70 mg dose versus 14.2% for placebo, with odds ratios of 4.2 (95% CI: 2.2; 7.9) and 3.5 (95% CI: 1.8; 6.6), respectively.

Episodic migraine

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

In the clinical study of patients with episodic migraine, the efficacy of the drug was assessed based on the change in the mean monthly number of migraine days during months 4-6 from baseline.

Secondary efficacy endpoints were a ≥50% reduction from baseline in the mean MMD (≥50% response rate), change from baseline in the mean number of monthly days patients used specific acute migraine medications, and change from baseline in scores on the two domains of the MPFID questionnaire (Migraine Physical Function Impact Diary), related to physical impairment (PI) and everyday activities (EA). The MPFID is a patient-reported outcome instrument that measures the impact of migraine on physical functioning. It contains 13 items to assess the impact of migraine over the past 24 hours on two aspects of physical functioning of interest – impact on everyday activities (EA: 7 items, e.g., difficulty doing activities that require concentration) and physical impairment (PI: 5 items, e.g., difficulty doing activities that require physical effort), as well as one overall item to assess the overall impact on daily activities. Patients rate daily the amount of time they felt the impact of migraine or the level of difficulty related to migraine. MPFID scale scores for the month are averaged over days with and without migraine; the higher the score, the greater the impact of migraine on the EA and PI domains.

Figure 2 and Table 2 show the key study results.

Figure 2. Change from baseline in monthly migraine days in the study of patients with episodic migraine

Table 2. Efficacy endpoints at weeks 13-24 in patients with episodic migraine

CI – confidence interval; HIT (headache impact test) – headache impact test; MIDAS (migraine disability assessment) – migraine disability assessment; MMD – monthly migraine days; MPFID — Migraine Physical Function Impact Diary.

^a All p-values are presented as unadjusted values and are statistically significant after correction for multiple comparisons.

^b Least squares mean change at months 4-6 from baseline, intergroup difference and p-value are based on a linear mixed-effects model including treatment group, baseline value, stratification factors (region [North America or other] and prior use of migraine preventive medications [never used, used in the past, currently used as concomitant medications]), scheduled visit and “treatment group-scheduled visit” interaction; no imputation for missing data was performed.

^c Odds ratio and p-value for patients with ≥ 50% response at months 4-6 are based on the stratified Cochran-Mantel-Haenszel test after imputation for missing data, which were considered non-response.

^d Post-hoc analysis; no hypothesis testing was performed.

^e Specific migraine medications include triptans and ergot derivatives.

^f Reduction of ≥ 5 in the mean monthly PI and EA score from baseline.

In patients who had not achieved a clinical response to one or more preventive treatments, the difference in MMD reduction observed between the 140 mg dose and placebo was -2.5 (95% CI: -3.4; -1.7) and between the 70 mg dose and placebo -2.0 (95% CI: -2.8; -1.2). Also, the proportion of patients who achieved a 50% reduction in MMD was greater compared to the placebo group (39.7% for 140 mg and 38.6% for 70 mg, with odds ratios of 3.1 [95% CI: 1.7; 5.5] and 2.9 [95% CI: 1.6; 5.3], respectively).

Pharmacokinetics

Erenumab is characterized by nonlinear kinetics due to its binding to the CGRP receptor. However, at therapeutically relevant doses, the pharmacokinetics of erenumab after s.c. administration every 4 weeks is predominantly linear due to saturation of CGRP receptors as a result of binding. In healthy volunteers who received the drug subcutaneously (s.c.) at a dose of 70 mg once a month or 140 mg once a month, the mean C_max was 6.1 µg/ml and 15.8 µg/ml (standard deviation [SD] 2.1 µg/ml and 4.8 µg/ml), respectively, and the mean AUC_last was 159 day×µg/ml and 505 day×µg/ml (SD 58 day×µg/ml and 139 day×µg/ml), respectively.

In patients who received the drug at a dose of 140 mg subcutaneously every 4 weeks, the minimum serum concentration increased over time by less than 2 times and reached a steady state 12 weeks after the start of treatment.

Absorption

In healthy adult volunteers who received a single subcutaneous injection of erenumab at a dose of 70 mg or 140 mg, the median C_max in plasma was reached in 4-6 days, and the estimated absolute bioavailability was 82%.

Distribution

After a single intravenous administration at a dose of 140 mg, the mean volume of distribution (SD) in the terminal elimination phase (Vz) was about 3.86 L (0.77).

Metabolism and Elimination

The elimination of erenumab is described by a biphasic curve. At low concentrations, elimination occurs primarily through saturable target binding (CGRP receptor), while at higher concentrations, erenumab elimination occurs primarily through non-specific non-saturable proteolysis. During the dosing period, Erenumab is eliminated primarily through non-specific proteolysis with an effective T_1/2 of 28 days.

Pharmacokinetics in Special Patient Groups

Patients with Renal Impairment

No studies have been conducted in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²). No differences in the pharmacokinetics of erenumab were identified in patients with mild or moderate renal impairment compared to patients with normal renal function based on population pharmacokinetic analysis (see section “Dosage Regimen”).

Patients with Hepatic Impairment

No clinical studies have been conducted in patients with hepatic impairment. Erenumab, as a human monoclonal antibody, is not metabolized by cytochrome P450 isoenzymes. Hepatic elimination is not a major route of elimination for erenumab (see section “Dosage Regimen”).

Indications

• Prevention of migraine in adults who have at least 4 migraine days per month.

ICD codes

Dosage Regimen

The drug Erinex^® should be administered subcutaneously.

The drug Erinex^® is intended for self-administration by a patient who has received appropriate training.

The administration should be performed by a person trained in the injection technique.

The drug can be injected into the abdomen, thigh, or the outer area of the upper arm (the arm injection should only be used if the injection is administered by someone other than the patient). Injection sites should be rotated and injections should not be given into areas of sensitive, reddened, hardened skin, or bruises.

To administer a 140 mg dose, two consecutive subcutaneous injections of Erinex^® 70 mg each should be performed.

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

The drug is indicated for patients who have at least 4 migraine days per month at the start of erenumab use.

The recommended dose is 70 mg once every 4 weeks. In some patients, a clinical effect may be achieved with a dose of 140 mg once every 4 weeks.

Clinical studies have shown that in most responding patients, the effect occurs within 3 months. Discontinuation of treatment should be considered in patients who have not responded after 3 months of therapy.

The need for continued treatment should be regularly assessed.

If a scheduled dose is missed, it is recommended to resume treatment as soon as possible. Thereafter, the drug is administered once every 4 weeks, starting from the last dose received.

Use in patients aged 65 years and older

The drug Erinex^® has not been studied in elderly patients. No dose adjustment is required.

Renal impairment/Hepatic impairment

No dose adjustment is required in patients with mild to moderate renal impairment or hepatic impairment.

Instructions for use of the drug Erinex^®

Solution for subcutaneous injection 70 mg/ml, in a pre-filled syringe

Single-use pre-filled syringe

Important! The needle is inside the gray cap.

• Important

Before using Erinex^® (pre-filled syringe), read the important information.

Storage

Keep the drug out of reach and sight of children.

Store the drug in the original package to protect it from light or physical damage. Store the drug in a refrigerator at a temperature between 2°C (35.6°F) and 8°C (46.4°F).

Outside the refrigerator, the storage time of the drug at room temperature (up to 25°C (77°F)) should not exceed 7 days.

Do not return the drug to the refrigerator after it has been removed.

Do not use the drug if it has been stored at room temperature (up to 25°C (77°F)) for more than 7 days.

The drug should be disposed of if stored at a higher temperature, or for more than 7 days.

Do not expose the drug to extremely low or high temperatures.

For example, avoid storing the drug in a car.

Do not freeze.

Use

Do not attempt to inject Erinex^® until your doctor or nurse has trained you in the injection technique.

Do not use the drug after the expiration date printed on the packaging.

Do not shake the syringe.

Do not remove the gray cap from the syringe until you are ready to administer the injection.

Do not freeze the drug and do not use the drug if it has been frozen.

Do not use the syringe if it has been dropped on a hard surface, as part of the syringe may be damaged, even if you do not see any damage. In this case, take a new syringe and inform your doctor.

The gray needle cap contains natural latex, which may cause allergic reactions in individuals with a latex allergy. Inform your doctor if you have an allergic reaction to latex.

For more information or assistance, contact your doctor.

• Step 1. Preparation before injection

Read this information before administering the injection. Check your doctor’s prescription.

Your doctor has prescribed you a dose of 70 mg or 140 mg.

To administer a 70 mg dose, you will need to fully inject the contents of one pre-filled syringe.

To administer a 140 mg dose, 2 consecutive injections (2 pre-filled syringes) of 70 mg each will be required.

To avoid discomfort at the injection site, leave the syringes at room temperature for at least 30 minutes before the injection.

Do not attempt to warm the syringe using an external heat source, such as hot water or a microwave oven.

Do not leave the syringe in direct sunlight.

A) Remove the pre-filled syringe with Erinex^® from the carton.

Grasp the syringe barrel to remove it from the packaging.

Hold the holder with your index finger and thumb. Hold the syringe by the barrel.

B) Carefully inspect the pre-filled syringe with Erinex^®.

Always hold the syringe by the barrel. Make sure the drug in the syringe is a clear, colorless or pale yellow solution.

Leave the syringe at room temperature for at least 30 minutes before injection.

Do not use the syringe if the drug in it is cloudy or has changed color, or contains flakes or particles.

Do not use the syringe if any part of it is cracked or broken.

Do not use the syringe if it has been dropped.

Do not use the syringe if the gray needle cap is missing or not securely attached.

Do not use the syringe if the expiration date on the label has passed.

In all these cases, use a new syringe, and if in doubt, contact your doctor.

C) Prepare all materials needed for the injection. Wash your hands thoroughly with soap.

On a clean, well-lit work surface, place

• 1 or 2 new syringes (depending on the prescribed dose)
• Alcohol wipes
• Cotton balls or gauze pads
• Adhesive bandage
• Sharps disposal container

D) Prepare and clean the injection site(s).

The injection can only be given into the

• Thigh
• Abdomen, except for a 5 cm area around the navel
• Outer surface of the upper arm (only if the injection is administered with assistance)

Clean the intended injection site with an alcohol wipe and wait for the skin surface to dry.

Do not touch this area before the injection.

If you want to inject into the same area, make sure it is not the same spot as the previous injection.

Do not inject into areas of damaged skin (thinning, redness, irritation, hardening, scaling, rash, bruising). Avoid injecting into areas with scars and stretch marks.

• Step 2. Immediately before administration

E) Pull the gray cap straight off the needle away from you when you are ready to inject. Do not leave the gray cap off for more than 5 minutes. This may cause the drug to dry out. The presence of a drop of drug at the tip of the needle is normal.

Do not twist or bend the gray cap.

Do not put the gray cap back on the syringe.

Do not remove the gray cap from the needle until you are ready to inject.

F) Pinch the skin at the injection site to create a firm surface for the injection.

Hold the skin between your thumb and index finger, creating an area about 5 cm wide.

Important. During the injection itself, continue to hold the skin in this position.

• Step 3. Injection

G) While holding the skin pinched, insert the syringe needle with the gray cap removed into the skin at a 45-90 degree angle.

Do not place your finger on the plunger while inserting the needle.

H) Slowly and steadily push the plunger all the way down until it stops moving.

I) Then, release your finger and smoothly remove the syringe from the skin.

Important. If upon removing the syringe you find that solution remains in the barrel, you have administered an incomplete dose. Inform your doctor immediately.

• Step 4. After injection

J) Dispose of the used syringe and gray cap.

Place the used syringe in a sharps disposal container immediately after use. Do not throw it in household trash.

Discuss with your doctor how to properly dispose of the syringe.

Do not reuse the syringe.

Do not reuse the syringe or the sharps disposal container or throw them in household trash.

Important. Always keep the sharps disposal container out of the reach of children.

K) Inspect the injection site.

If bleeding occurs, press a cotton ball or gauze pad onto the injection site.

Do not rub the injection site. Apply an adhesive bandage if necessary.

If you were prescribed a 140 mg dose, repeat all steps with the second syringe containing 70 mg of the drug to receive the full dose.

Instructions for use of the drug Erinex^®, solution for subcutaneous injection 70 mg/ml in a pre-filled syringe in an autoinjector (pen)

Single-use pre-filled syringe in an autoinjector (pen)

Important! The needle is inside the green safety guard.

• Important

Before using Erinex^® (pre-filled syringe in an autoinjector (pen)), read the following important information.

Storage

Keep the drug out of reach and sight of children.

Store the drug in the original package to protect it from light or physical damage.

Store the drug in a refrigerator at a temperature between 2°C (35.6°F) and 8°C (46.4°F).

Outside the refrigerator, the storage time of the drug at room temperature (up to 25°C (77°F)) should not exceed 7 days.

Do not return the drug to the refrigerator after it has been removed.

Do not use the drug if it has been stored at room temperature (up to 25°C (77°F)) for more than 7 days.

The drug should be disposed of if stored at a higher temperature, or for more than 7 days.

Do not expose the drug to extremely low or high temperatures. For example, avoid storing the drug in a car.

Do not freeze.

Use

Do not attempt to inject Erinex^® until your doctor or nurse has trained you in the injection technique.

Do not use the drug after the expiration date printed on the packaging.

Do not shake the autoinjector.

Do not remove the white cap from the autoinjector until you are ready to administer the injection.

Do not freeze the drug and do not use the drug if it has been frozen.

Do not use the autoinjector if it has been dropped on a hard surface, as part of the autoinjector may be damaged, even if you do not see any damage. In this case, take a new autoinjector and inform your doctor.

The white needle cap contains natural latex, which may cause allergic reactions in individuals with a latex allergy. Inform your doctor if you have an allergic reaction to latex.

For more information or assistance, contact your doctor.

• Step 1. Preparation before injection

Read this information before administering the injection. Check your doctor’s prescription.

Your doctor has prescribed you a dose of 70 mg or 140 mg.

To administer a 70 mg dose, you need to fully inject the contents of one pre-filled pen. To administer a 140 mg dose, 2 consecutive injections (2 pre-filled pens) of 70 mg each will be required.

To avoid discomfort at the injection site, leave the pens at room temperature for at least 30 minutes before the injection.

A) Remove the pen (autoinjector) with Erinex^® from the carton.

Gently pull the autoinjector straight up and out of the carton.

Leave the autoinjector at room temperature for at least 30 minutes before injection.

Do not return the autoinjector to the refrigerator after the drug has reached room temperature.

Do not attempt to warm the autoinjector using an external heat source, such as hot water or a microwave oven.

Do not leave the autoinjector in direct sunlight.

Do not shake the autoinjector.

At this stage, do not remove the white cap from the autoinjector.

B) Carefully inspect the pre-filled syringe with Erinex^®.

Make sure the drug in the window is a clear, colorless or pale yellow solution.

Do not use the autoinjector if the drug in it is cloudy or has changed color, or contains flakes or particles.

Do not use the autoinjector if any part of it is cracked or broken.

Do not use the autoinjector if it has been dropped.

Do not use the autoinjector if the white needle cap is missing or not securely attached.

Do not use the autoinjector if the expiration date on the label has passed.

In all these cases, use a new autoinjector, and if in doubt, contact your doctor.

C) Prepare all materials needed for the injection. Wash your hands thoroughly with soap.

On a clean, well-lit work surface, place

• 1 or 2 new autoinjectors (depending on the prescribed dose)
• Alcohol wipes
• Cotton balls or gauze pads
• Adhesive bandage,
• Sharps disposal container

D) Prepare and clean the injection site(s).

The injection can only be given into the

• Thigh
• Abdomen, except for a 5 cm area around the navel
• Outer surface of the upper arm (only if the injection is administered with assistance)

Clean the intended injection site with an alcohol wipe and wait for the skin surface to dry.

Do not touch this area before the injection.

If you want to inject into the same area, make sure it is not the same spot as the previous injection.

Do not inject into areas of damaged skin (thinning, redness, irritation, hardening, scaling, rash, bruising). Avoid injecting into areas with scars and stretch marks.

• Step 2. Immediately before administration

E) Pull the white cap straight off the needle away from you when you are ready to inject. Do not leave the white cap off for more than 5 minutes. This may cause the drug to dry out.

The presence of a drop of drug at the tip of the needle is normal.

Do not twist or bend the white cap.

Do not put the white cap back on the autoinjector.

Do not touch the green safety guard.

Do not remove the white cap from the needle until you are ready to inject.

F) Create a skin fold at the chosen injection site (thigh, abdomen, upper arm) using the skin stretching method or the skin pinching method.

Skin Stretching Method

Firmly stretch the skin by pressing down and pulling your thumb and index finger apart, creating an area about 5 cm wide.

OR

Skin Pinching Method

Pinch the skin by grasping it with your thumb and index finger and creating an area about 5 cm wide.

Important! During the injection, keep the skin stretched or pinched.

• Step 3. Injection

G) Hold the skin stretched or pinched. Place the pen with the white cap removed against the skin at a 90-degree angle. The needle is inside the green safety guard.

Do not touch the purple start button yet.

H) Push the pen down firmly until it stops moving.

Pushing Down

Important! You must push the autoinjector all the way down, without touching the purple start button until you are ready to inject.

I) When you are ready to inject, press the purple start button. You will hear a click.

J) Continue to hold against the skin. The injection may take about 15 seconds.

Important! After the injection is completed, the window turns yellow, and you may hear a second click.

Note after you remove the autoinjector from the skin, the needle will be automatically covered.

Important! If after removing the autoinjector the window has not turned yellow or it seems to you that the drug injection is continuing, it means you have administered an incomplete dose. Contact your doctor immediately.

• Step 4. After injection

L) Dispose of the used autoinjector and the white cap.

Place the used autoinjector in a sharps disposal container immediately after use.

Discuss with your doctor how to properly dispose of the autoinjector.

Do not reuse the autoinjector.

Do not place the autoinjector or the sharps disposal container in recycling bins or dispose of them with household waste.

Important. Always keep the sharps disposal container out of the reach and sight of children.

M) Inspect the injection site.

If bleeding occurs, apply a cotton ball or gauze pad to the injection site.

Do not rub the injection site. Use a bandage if necessary.

If you have been prescribed a 140 mg dose, repeat all steps with the second 70 mg autoinjector to receive the full dose.

Adverse Reactions

In total, in registration studies, Erenumab was used in more than 2500 patients (more than 2600 patient-years). Of these, more than 1300 patients used the drug for at least 12 months.

Adverse reactions for 70 mg and 140 mg were reported: 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 reactions were mild or moderate in severity. Less than 2% of patients discontinued these studies due to adverse reactions.

All adverse reactions (ARs) reported in patients receiving Erenumab during the 12-week placebo-controlled period of clinical studies, as well as during the post-marketing period, are presented in Table 3. Within each system organ class, ARs are presented by frequency categories, with the most frequent reactions listed first. Within each frequency category, ARs are listed in order of decreasing severity. In addition, for each AR, the corresponding frequency category is provided according to the following designations: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥1/10,000, < 1/1000); very rare (< 1/10000).

Table 3. Adverse reactions occurring during the use of erenumab

^a See subsection “Description of selected adverse reactions”.

^b The term “Oral ulcerations” includes such preferred terms as stomatitis, mouth ulcers, oral mucosal blistering.

^c The term “pruritus” includes such preferred terms as generalized pruritus, itching, and pruritic rash.

^d The term “rash” includes such preferred terms as papular rash, exfoliative rash, erythematous rash, urticaria, blister.

Description of selected adverse reactions

Injection site reactions

In a pooled analysis of the 12-week placebo-controlled period of clinical studies, injection site reactions were mild and transient. In one patient who received Erenumab 70 mg, the drug was discontinued due to the development of a rash at the injection site. The most common injection site reactions were injection site pain, injection site erythema, and injection site pruritus. Typically, injection site pain resolves within 1 hour after injection.

Skin reactions and hypersensitivity reactions

In a pooled analysis of the 12-week placebo-controlled period of studies, non-serious cases of rash, pruritus, and swelling/edema were observed, which were mostly mild and did not lead to treatment discontinuation.

Constipation

In a pooled analysis of the 12-week placebo-controlled period of studies, 28 reports of constipation were recorded among 1400 patients receiving Erinex^®. All adverse events were mild or moderate in severity. In most of these cases (23), symptoms appeared within one month after the first administration of the drug, however, in some patients, constipation was observed later during continued therapy. In most cases (18), constipation resolved within three months. All patients, except one, continued treatment.

Immunogenicity

In clinical studies of migraine prevention during the double-blind phase of the study, the incidence of anti-erenumab antibody formation in patients receiving Erenumab 70 mg was 6.3% (56/884) (in 3 patients neutralizing activity was determined in vitro) and 2.6% (13/504) in patients receiving Erenumab 140 mg (no neutralizing activity was detected in vitro in any patient). The formation of antibodies to erenumab did not affect its efficacy or safety.

Post-marketing data

Immune system disorders

In the post-marketing period, hypersensitivity reactions have been observed, including rash, angioedema, and anaphylactoid reactions (see section “Special Precautions”).

Gastrointestinal disorders

Cases of constipation with serious complications have been reported in post-marketing use. In most of these cases, adverse reactions were observed after the first dose of Erinex^®, but they could also occur later during continued therapy. Many cases of constipation with serious complications were reported in patients with a history of constipation, or those receiving concomitant therapy with drugs that reduce gastrointestinal motility. In some severe cases, hospitalization was required.

Oral ulcers (e.g., stomatitis, oral mucosal ulceration, oral mucosal blistering) have been observed.

Skin and subcutaneous tissue disorders

Alopecia, skin rash (e.g., papular rash, exfoliative rash, erythematous rash, urticaria, blistering).

Vascular disorders

Hypertension.

Contraindications

• Hypersensitivity to erenumab or to any of the components of the drug;
• Children and adolescents under 18 years of age (no experience of use in children).

Use with caution

Patients with certain underlying cardiovascular diseases were excluded from clinical studies, therefore safety data in these patients are not available.

Use in Pregnancy and Lactation

Pregnancy

Data on the use of erenumab in pregnant women are limited. Animal studies have not revealed direct or indirect reproductive toxicity of erenumab. As a precaution, it is preferable to avoid the use of Erinex^® during pregnancy.

Breastfeeding period

It is unknown whether Erenumab passes into human breast milk. There is evidence that IgG passes into breast milk during the first few days after the birth of the child, then the concentration of IgG decreases to low levels. Therefore, during the first few days after birth, a risk to the breastfed infant cannot be excluded. During the subsequent period of breastfeeding, the use of the drug should be considered solely from the point of view of clinical necessity.

Use in Hepatic Impairment

No dose adjustment is required in patients with hepatic impairment.

Use in Renal Impairment

No dose adjustment is required in patients with mild to moderate renal impairment.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Erinex^® has not been studied in elderly patients. No dose adjustment is required.

Special Precautions

Hypersensitivity reaction

In the post-marketing period, cases of serious hypersensitivity reactions have been reported with the use of Erinex^®, including rash, angioedema, and anaphylactoid reactions. These reactions may occur within minutes, although some may occur more than a week after treatment. If a serious or severe hypersensitivity reaction occurs, it is necessary to discontinue Erinex^® and initiate appropriate therapy (see section “Contraindications”).

Patients with hypersensitivity to latex

The removable cap of the pre-filled syringe and autoinjector (pen) contains dry natural rubber latex, which may cause allergic reactions in individuals sensitive to latex.

Constipation

Constipation is a common side effect of Erinex^® and is usually characterized as mild or moderate in intensity. In most cases, constipation was reported immediately after the first dose of the drug, but patients experienced constipation later during the course of treatment. In most cases, constipation resolved within three months. In post-marketing use, constipation with serious complications has been observed with erenumab. In some cases, hospitalization was required, including due to the need for surgical intervention.

A history of constipation or concomitant use of drugs associated with reduced gastrointestinal motility may lead to an increased risk of developing more severe constipation and complications associated with constipation. Patients should be warned about the risk of developing severe constipation and advised to consult a doctor if constipation persists or worsens. If severe constipation develops, patients should seek immediate medical attention.

Treatment of constipation should be initiated immediately, taking into account medical indications. If severe constipation develops, the drug should be discontinued.

Cardiovascular diseases

Patients with certain underlying cardiovascular diseases were excluded from clinical studies, therefore safety data in these patients are not available.

Hypertension

Development of hypertension and worsening of pre-existing hypertension have been reported following the use of Erinex^®. Many patients already had hypertension or risk factors for this disease. In some cases, drug therapy and even hospitalization were required. When using Erinex^®, patients should be monitored for the development of hypertension or worsening of pre-existing hypertension. In appropriate cases, if an alternative etiology for complications cannot be established, discontinuation of Erinex^® should be considered.

Fertility

There are no data on the effect of erenumab on human fertility. At systemic exposure values of erenumab in sexually mature monkeys, up to 283 or 123 times the exposure (assessed by serum AUC) in humans achieved with the clinical dose of 70 mg or 140 mg once a month, no adverse effects on surrogate markers of fertility (pathological or histopathological changes in reproductive organs) were observed.

Effect on ability to drive and use machines

Erinex^® has no significant effect on the ability to drive and/or use machines.

Overdose

No cases of overdose of erenumab in humans have been identified in clinical studies. In clinical studies, Erenumab was administered subcutaneously at doses up to 280 mg without any signs of dose-limiting toxicity.

Treatment in case of overdose should include supportive and symptomatic therapy as needed.

Drug Interactions

In an open-label study of the pharmacokinetic drug interaction between erenumab and combined oral contraceptives in healthy women, Erenumab (a single subcutaneous injection of 140 mg) did not affect the pharmacokinetics of combined oral contraceptives containing ethinyl estradiol and norgestimate.

In a randomized, double-blind, placebo-controlled study in healthy volunteers, Erenumab (a single intravenous dose of 140 mg), administered concomitantly with sumatriptan, did not affect resting blood pressure parameters compared to sumatriptan monotherapy.

Erenumab did not affect the pharmacokinetics of sumatriptan.

Erenumab is not metabolized by cytochrome P450 isoenzymes; it is also unlikely to cause noticeable changes in the concentration of pro-inflammatory cytokines that can affect the expression or activity of cytochrome P450 isoenzymes. For this reason, drug interactions with concomitant use of drugs that are substrates, inducers, or inhibitors of cytochrome P450 isoenzymes seem unlikely.

Effect on laboratory and diagnostic test results

The effect of erenumab on laboratory and/or diagnostic test results has not been studied.

Storage Conditions

Pre-filled syringes/pens should be stored in the original carton to protect from light, out of the reach of children, at a temperature between 2°C (35.6°F) and 8°C (46.4°F). Do not freeze.

Shelf Life

The shelf life is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.