Ajovi solution for subcutaneous injection 150mg/ml 1.5ml syringe, 1pc

Composition

>1 ml contains: Active ingredient: fremanezumab 150 mg; excipients: L-histidine 0,543 mg, L-histidine hydrochloride monohydrate 2,620 mg, sucrose 66 mg, disodium edetate dihydrate 0,136 mg, Polysorbate 80 0,02% m/V, water for injection up to 1 ml.

Pharmacological properties

Pharmacotherapeutic group: protivomigrenoznae Crestwood ATX: N02CD03 Pharmacological properties

Pharmacodynamics

Premantura a fully humanized monoclonal antibody class IgG2Δα/κ, which binds specifically to the ligand calcitonin gene-related peptide (Calcitonin gene-related peptide, CGRP) and blocks the binding of α – and β-isoforms of CGRP receptor CGRP.

The exact mechanism of action by which fremanezumab prevents migraine attacks is unknown, but it is assumed that the beneficial effect is achieved as a result of modulation of the trigeminal nerve system. The concentration of CGRP increases significantly during a migraine attack and returns to normal after the headache is relieved.

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

The efficacy of fremanezumab in preventing episodic or chronic migraine attacks was evaluated in two multicenter, randomized, double-blind, placebo-controlled trials lasting 12 weeks (Study 1 and study 2, respectively). All groups of study participants were balanced and comparable in terms of demographic indicators and baseline characteristics of the disease.

The elderly (over 70 years of age), patients who used opioids or barbiturates monthly for more than 4 days, and patients with a history of myocardial infarction, cerebrovascular events, and thromboembolic events were excluded from the study.

Episodic migraines

Study 1 included adult patients with a history of episodic migraines (patients with All patients were randomly assigned to receive subcutaneous injections of 675 mg fremanezumab once every 3 months (n=291),225 mg fremanezumab once a month (n=290), or placebo once a month (n=294) for a 12-week treatment period.

In study 1, a total of 875 patients (742 women and 133 men) aged 18 to 70 years were randomized. The median age of the patients,85% of whom were female and 80% were white, was 42 years. The average number of days with migraines at baseline was about 9 days per month and was similar in all treatment groups. A total of 791 patients completed the 12-week double-blind phase.

The primary endpoint was the mean change relative to baseline in the monthly number of days with migraines during the 12-week treatment period. Secondary endpoints were: the proportion of patients who achieved at least a 50% reduction in the average number of days with migraines per month (the frequency of 50% positive response to treatment); the average change, relative to the baseline MIDAS subjective score, in the number of days with migraines during the month; and the average change, relative to the baseline, in the average number of days of use of headache medications per month.

Treatment regimens with fremanezumab monthly (1 time per month) and quarterly (1 time in 3 months) showed statistically significant improvements in the endpoints of effectiveness compared to placebo starting from the first month and throughout the study period.

Chronic migraines

Study 2 included adult patients with a history of chronic migraines (patients with >15 days of headache per month). The initial level of headache frequency in patients averaged 21 days per month (at least 13 days of moderate severity). All patients were randomly assigned to receive subcutaneous injections of an initial dose of 675 mg fremanezumab, followed by 225 mg fremanezumab once a month (n=379),675 mg fremanezumab once every 3 months (n=376), or placebo once a month (n=375) for a 12-week treatment period.

In study 2, a total of 1,130 patients (991 women and 139 men) aged 18 to 70 years were randomized. The median age of the patients,88% of whom were female and 79% were white, was 41 years. A total of 1,034 patients completed the 12-week double-blind phase.

The primary endpoint was the mean change relative to baseline in the monthly number of days of at least moderate headache severity during the 12-week treatment period. Secondary endpoints were: achieving at least a 50% reduction in the average number of days with at least moderate headaches per month (frequency of 50% positive response to treatment); average change, relative to the baseline HIT-6 subjective score, in the number of days with migraines during the month; and average change, relative to the baseline, in the average number of days of medication use for headache attacks.

Both treatment regimens with fremanezumab on a monthly and quarterly basis showed statistically significant improvements in key performance parameters compared to placebo starting from the first month and throughout the study period.

Long-term research

In a long-term study (Study 3), the efficacy of fremanezumab was maintained for up to 12 months in patients with episodic and chronic migraines who received the drug at a dose of 225 mg once a month or 675 mg once every 3 months. A total of 79% of patients completed study 3.

After 15 months, the monthly frequency of migraine attacks with both dosage regimens combined decreased relative to the baseline level in studies 1 and 2 by 6.6 days. In the last month of the trial, a 50% response rate was achieved in 61% of patients who completed study 3.

During the 15-month combined treatment period, no safety signals were detected for the drug.

Internal and external factors

The efficacy and safety of fremanezumab did not depend on age, gender, race, the presence of concomitant prophylactic drug therapy with beta-blockers, calcium channel blockers/benzocyclopentene derivatives, antidepressants, anticonvulsants), migraine treatment with topiramate or onabotulotoxin A in the anamnesis, and drug abuse for the relief of acute headache. Data on the use of fremanezumab in people aged 65 years and older are limited (2% of patients).

Preclinical safety data sheet

No risk to humans was identified in preclinical trials, based on data from generally accepted studies of pharmacological safety, repeated use toxicity, and reproductive toxicity.

Since fremanezumab is a monoclonal antibody, no genotoxicity or carcinogenicity studies have been conducted.

Pharmacokinetics

Suction. After a single subcutaneous dose of 225 mg and 675 mg, the median time to reach the maximum concentration (Tmax) of fremanezumab is from 5 to 7 days, and the pharmacokinetic parameters are proportional. Absolute bioavailability in the dosage range from 225 mg to 900 mg is from 55% to 66%. When using the drug at a dose of 225 mg subcutaneously once a month and 675 mg subcutaneously once every 3 months, the equilibrium concentration was observed approximately 168 days (about 6 months) after the start of treatment. The median accumulation rate when prescribing a drug 1 time per month and 1 time in 3 months is about 2.4 and 1.2, respectively.

Distribution. The volume of distribution after subcutaneous use in doses of 225 mg,675 mg and 900 mg is 3.6 liters.

Metabolism. Similar to other monoclonal antibodies, fremanezumab is degraded by proteolytic enzymes to low-molecular-weight peptides and amino acids.

Output. The total clearance of fremanezumab is approximately 0.09 l / day, with a half-life (T 1/2) of 30 days. The low-molecular-weight peptides and amino acids formed during metabolism participate in de novo protein synthesis or are excreted through the kidneys.

Special populations

A population-based pharmacokinetic analysis based on data from 2,546 patients evaluated the effect of age, race, gender, and body weight on drug efficacy. According to the results obtained, dose adjustment of the drug is not required for body weight from 43.5 kg to 131.8 kg.

There are no data on the exposure-to-efficacy ratio of fremanezumab in patients weighing more than 132 kg.

Patients with impaired liver or kidney function

Impaired liver or kidney function is not expected to affect the pharmacokinetics of fremanezumab. A population-based pharmacokinetic analysis of summary data from clinical trials of fremanezumab revealed no differences in the pharmacokinetics of fremanezumab in patients with mild or moderate hepatic insufficiency compared to patients with normal liver function (see section “Dosage and use”). Patients with severe hepatic insufficiency did not participate in clinical trials of fremanezumab.

Indications

Preventative treatment of migraines in adults who have 4 or more days with migraines per month.

Use during pregnancy and lactation

Pregnancy

It is recommended to avoid using the drug during pregnancy.

Data on the use of Ajovi in pregnant women are limited.

The results of preclinical tests of pharmacological safety, toxicity with repeated use, as well as toxicity to reproductive function and offspring indicate that there is no direct or indirect adverse effect of the drug on human reproductive function.

Since fremanezumab is a monoclonal antibody, no genotoxicity or carcinogenicity studies have been conducted.

Breast-feeding period

There is no information about the penetration of fremanezumab into breast milk, the effect on the breastfed child or milk production. In the first days after delivery, human IgG antibodies are excreted in breast milk, but soon the concentration of the latter in it decreases. In this short period of time, the risk to the child cannot be excluded. Subsequently, the use of the drug Ajovi during breastfeeding can only be considered if clinically necessary.

Fertility

There are no data on the effect of fremanezumab on human fertility. Based on the results of preclinical studies, Ajovi therapy does not imply a negative effect on fertility.

Contraindications

• Hypersensitivity to the Active ingredient, as well as auxiliary substances that make up the drug.
• Under 18 years of age.

With caution:

Patients with serious cardiovascular diseases.

Side effects

The safety of Ajovi was evaluated in more than 2,500 patients with migraines who received at least one dose of the drug. Thus, the exposure was more than 1,900 patient-years. In more than 1,400 patients, the duration of therapy was at least 12 months.

Frequently reported adverse reactions (HP) included local injection site reactions [pain (24%), tightness (17%), erythema (16%), and pruritus (2%)].

HP described in clinical trials is listed in accordance with the system-organ class of the Medical Dictionary of Regulatory Activity (MedDRA). HP is classified according to the World Health Organization (WHO) Classification: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (

Description of individual adverse reactions

Injection site reactions

The most frequently observed local reactions at the injection site included pain, tightness, and erythema. All local reactions at the injection site were transient and mostly mild to moderate in severity. Pain, tightness, and erythema tended to occur immediately after the injection, while pruritus and rash appeared on average after 24 and 48 hours, respectively. All injection site reactions usually resolved within a few hours or days. In general, these adverse reactions did not require discontinuation of the drug.

Immunogenicity

In placebo-controlled trials, low-titer antibodies to the drug were observed in 0.4% (6 out of 1701) of patients after starting fremanezumab treatment. Neutralizing antibodies were detected in 1 of these 6 patients. After 12 months of treatment, antibodies to the drug were detected in 2.3% (43 out of 1888) of patients, and neutralizing antibodies were detected in 0.95% of patients. The presence of such antibodies did not affect the safety and efficacy of the drug.

Interaction

Formal clinical studies of drug interactions with fremanezumab have not been conducted. Based on the properties of fremanezumab, pharmacological drug interactions are unlikely. In addition, the concomitant use of medications taken to treat a migraine attack (especially analgesics, ergot alkaloids, and triptans) and medications for the preventive treatment of migraines did not affect the pharmacokinetics of fremanezumab.

How to take, course of use and dosage

Therapy should be initiated under the guidance of a doctor experienced in the diagnosis and treatment of migraines.

The drug is prescribed to patients who have 4 or more days with migraines per month.

Two dosage modes are available:

The decision on the duration of treatment is made by the attending physician.

When switching from one regimen to another, a new dose of the drug is prescribed on the next scheduled day, according to the previous therapy regimen. After starting fremanezumab therapy, concomitant preventive treatment of migraines can be continued if the doctor believes that this is necessary.

The effectiveness of therapy should be evaluated 3 months after its start. Any further decision to continue treatment should be made on a case-by-case basis. Subsequently, it is recommended to assess the need for continuing therapy regularly.

Missed dose

If the dose of the drug Ajovi, according to the schedule of admission, was missed, it is necessary to enter it as soon as possible. No refund of the missed dose by doubling it is required.

Special groups of patents

Elderly patients (over 65 years of age)

Data on the use of Ajovi in patients aged 65 years and older are limited. Based on the results of population pharmacokinetic analysis, no dose adjustment is required.

Impaired renal and/or hepatic function

In patients with mild or moderate hepatic insufficiency, no dose adjustment is required.

Children

The drug is not recommended for use in patients under 18 years of age, since the safety and efficacy of Ajovi in this group of patients have not been established.

Method of application

The drug is administered subcutaneously.

Intravenous or intramuscular injections are not allowed.

The drug Ajovi is applied subcutaneously in the abdomen, thigh or shoulder. It is necessary to change the injection sites with repeated use of the drug.

Ajovi injection can be performed by medical personnel, patients and / or their caregivers. Prior to use, patients and / or their caregivers should receive appropriate training on how to prepare for the use and use of Ajovi solution in a hypodermic syringe. Patients and/or their caregivers should be informed that they need to read the instructions for medical use and follow them every time they use Ajovi.

Overdose

The maximum dose of the drug in clinical trials was 2000 mg when administered intravenously. The development of adverse reactions and dose-limiting toxicity was not observed. In case of overdose, the patient is recommended to be under the supervision of a doctor in order to detect possible adverse reactions. If necessary, conduct symptomatic treatment.

Description

Clear or slightly opalescent solution of colorless to light yellow color.

Special instructions

Hypersensitivity

In clinical trials, hypersensitivity reactions to fremanezumab were reported in less than 1% of patients. If a hypersensitivity reaction develops, discontinuation of Ajovi should be considered and appropriate treatment should be prescribed.

Patients with cardiovascular (CV) diseases

Patients with significant cardiovascular diseases, vascular ischemia, or thrombotic events such as acute cerebrovascular accident, micro-strokes, deep vein thrombosis, or pulmonary embolism were excluded from clinical trials. The safety and efficacy of Ajovi in these patients have not been established.

Auxiliary substances

One dose (1.5 ml) of Ajovi contains less than 1 mmol of sodium (23 mg), which means that the drug is practically free of sodium.

Storage

Ajovi should be stored in the refrigerator between 2 °C and 8 °C in its original packaging to protect it from light. If necessary, the drug Ajovi can be stored at room temperature from 20 °C to 25 °C in the original packaging for no more than 24 hours. Once removed from the refrigerator, Ajovi must be used within 24 hours or disposed of.

DO NOT freeze or shake the product. In addition, it is FORBIDDEN to use the drug exposed to high temperatures or direct sunlight.

Influence on the ability to drive vehicles and mechanisms

The drug Ajovi does not affect the ability to drive vehicles and work with mechanisms. Caution should be exercised in case of side effects.

Storage conditions

Store at a temperature of 2 to 8 °C in the original packaging.

Do not freeze it.

Keep out of reach of children!

Shelf

life is 2 years.

Do not use after the expiration date.

Active ingredient

Fremanezumab

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection