Composition, form of production and packaging
Solution for the sc administration from colorless to light yellow, slightly opalescent.
glatiramer acetate 40 mg
Excipients: mannitol - 40 mg, water d / u - up to 1 ml.
1 ml - disposable syringes of colorless glass (3) - packings of cellular contour (4) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2017.
Immunomodulating agent. The mechanism of action of glatiramer acetate in patients with multiple sclerosis is not fully understood. It is believed that glatiramer acetate alters the immune processes presumably playing a major role in the pathogenesis of multiple sclerosis. This hypothesis is confirmed by the results of studies conducted to study the pathogenesis of experimental allergic encephalomyelitis (EAE). EAE is often used as an experimental model of multiple sclerosis. Studies conducted on animals and with the participation of patients with multiple sclerosis have shown that the administration of glatiramer acetate causes peripheral induction and activation of glatiramer acetate-specific suppressor T lymphocytes.
Recurrent-remitting multiple sclerosis
The results of a 12-month placebo-controlled study confirmed the efficacy of Copaxone В® 40 at a dose of 40 mg / ml with p / to administration 3 times a week to reduce the frequency of exacerbations.
When conducting the registration clinical study, the criteria for including patients with relapsing-remitting multiple sclerosis were at least one documented clinical exacerbation in the last 12 months, or two exacerbations in the last 24 months, or one exacerbation in the last 12-24 months, with at least one focus accumulating contrast (Gd +) and visualized on T1-weighted MRI images for the last 12 months.
The primary goal of the study was to determine the total number of confirmed exacerbations. The secondary goal is to determine the cumulative number of new / increased foci detected on T2-weighted MRI images and the cumulative number of foci accumulating contrast and visualized on T1-weighted images at the 6th and 12th month of the study.
The study randomized 1404 patients in a 2: 1 ratio to a group treated with Copaxone В® 40 at a dose of 40 mg / ml (n = 943) or placebo (n = 461), respectively. Both groups were comparable in terms of initial demographic characteristics, features of the course of multiple sclerosis and MRI parameters. Patients had an average of 2.0 exacerbations of the disease for 2 years prior to screening.
Compared to the placebo group, a statistically significant reduction in the frequency of exacerbations and the total number of foci in T2-weighted images and foci accumulating contrast on T1 -weighted images was observed in patients treated with Copaxone В® 40 at a dose of 40 mg / ml 3 times a week, which corresponds to the therapeutic effect of the drug Copaxone В® -Tev 20 mg / ml with its daily administration.
Direct comparative analysis of efficacy and safety of the drug at a dose of 20 mg / ml (with daily administration) and 40 mg / ml (with 3-fold weekly administration) was not carried out in this study.
During this 12-month study, there was no evidence of the effect of the drug on the progression of disability or the duration of exacerbations.
Currently, there is no data on the use of the drug in patients with primary or secondary-progressive multiple sclerosis.
Studies of pharmacokinetics in patients were not conducted.
The in vitro data, as well as the limited data obtained with the participation of healthy volunteers, show that with the s / w introduction, the active substance is rapidly absorbed, with most of it disintegrating into small fragments in the subcutaneous tissue.
Preclinical research data
Preclinical data based on pharmacological safety studies, repeated administration toxicity, reproductive toxicity, genotoxicity, or carcinogenicity do not indicate the presence of specific hazards to humans other than those already included in the following sections. In view of the lack of data on pharmacokinetics, it is impossible to determine the permissible concentration limits in humans in comparison with animals. In a small number of rats and monkeys injected with the drug for at least 6 months, there was a deposition of immune complexes in the renal glomeruli.
In a 2-year study, rats did not observe the deposition of immune complexes in the renal glomeruli.
Sensitized animals (guinea pigs and mice) had anaphylaxis after administration of the drug. The relevance of this data to a person is not known.
The toxic effect at the injection site after repeated administration of the drug to the animal is related to common reactions.
- relapsing-remitting multiple sclerosis.
Enter SC in the form of injections of 40 mg (1 filled with the drug syringe for injection) 3 times a week, the minimum interval between injections - 48 hours.
The drug is not intended for IV or IM.
Currently, there is no data on the duration of treatment. The decision on the appointment of a long-term course of treatment should be made by the attending physician in each specific case.
Patients are advised to undergo self-injection training. The first injection (and also 30 minutes after it) should be under the supervision of a qualified specialist. To reduce the risk of irritation or pain in the area of вЂ‹вЂ‹injection, it is necessary to change the injection zone every time.
The drug is not recommended for use in children and adolescents under the age of 18 , because clinical studies in patients of these age groups have not been conducted.
Efficacy and safety of the drug in elderly patients have not been studied.
The efficacy and safety of the drug in patients with renal insufficiency have not been studied.
Each syringe with Copaxone В® 40 is for single use only.
Recommendations for patients on the use of the drug
1. The patient should make sure that there is everything necessary for the injection: a disposable syringe,
filled with a solution of Copaxone В® 40, a container for used syringes, a cotton swab moistened with alcohol.
2. Before injection, remove the disposable syringe from the contour pack, removing the protective paper strip.
3. Withdraw the syringe with the solution at room temperature for at least 20 minutes.
4. Before you administer Copaxone В® 40, wash your hands thoroughly with soap and water.
5. Carefully inspect the solution in a syringe. In the presence of suspended particles or changes in the color of the solution, it should not be used.
6. Choose a site for injection. Possible areas for self-injection: arms, hips, buttocks, abdomen (about 5 cm around the navel). Do not inject into painful areas, discolored, reddened areas of skin or areas with seals and nodules. Within each injection zone, there is enough room for several injections. It is recommended to draw up a scheme of injection sites and have it with you. For injections into the gluteus muscle and on the hands, the help of another person may be required.
7. Remove the protective cap from the needle.
8. Pre-treating the injection site with a cotton wool moistened with alcohol solution, lightly fold the skin into the fold with the thumb and forefinger.
9. Having the syringe needle perpendicular to the injection site, pierce the skin and, evenly pressing the syringe onto the plunger, insert its contents into the injection site.
10. Remove the needle by moving the syringe perpendicular to the injection site.
11. Place the syringe in a container for used syringes.
If patients forgot to inject Copaxone В® 40, they should be injected immediately, as soon as they remembered this. Do not administer a double dose of the drug.
Most of the safety data for Copaxone В® 40 have been accumulated using Copaxone В® -Tev 20 mg / ml as daily injections. This section presents the data accumulated during the time of 4 placebo-controlled clinical trials on the use of Copaxone В® -Tev in the form of injections in a dose of 20 mg / ml once a day and 1 placebo-controlled study of Copakson В® 40 in the form of injections in a dose of 40 mg / ml 3 times a week.
Copaxone В® -Tev 20 mg / ml (with daily use)
Most often in the course of clinical trials of the Copaxone В® -Tev drug, reactions at the injection site were noted. Conducted placebo-controlled studies showed that the proportion of patients reporting these adverse events was at least 1 time 70% for Copaxone В® -Teva and 37% for placebo. Most often, redness, pain, denseness, itching, swelling, inflammation and hypersensitivity were observed.
A reaction associated with at least one or more symptoms (vasodilation, chest pain, dyspnoea, heart palpitations or tachycardia), which manifests itself a few minutes after the injection, is called an immediate post-injection reaction. At least 1 of the symptoms of this reaction was observed at least 1 time in 31% of patients treated with Copaxone В® -Teva, compared with 13% of patients with placebo.
All the undesirable reactions most frequently observed in patients receiving Copaxone В® -Tev compared to the placebo group are presented below. These data were obtained from 4 double-blind, placebo-controlled trials involving 512 patients who received Copaxone В® -Tev daily, and 509 patients who received a placebo for 36 months. Three studies involved 269 patients with a diagnosis of relapsing-remitting multiple sclerosis who received Copaxone В® -Teva every day for 35 months and 271 patients from the placebo group. The fourth study involved 243 patients (the Copaxone В® -Teva group) with the first clinical episode of the disease, who had a high risk of developing clinically confirmed multiple sclerosis, and 238 patients receiving a placebo. The duration of the study was 36 months.
Determination of the frequency of adverse reactions: very often (? 1/10); often (? 1/100, but <1/10); infrequently (? 1/1000, but <1/100); rarely (? 1 / 10,000, but <1/1000).
Infections and infestations: very often - infections, influenza; often - bronchitis, gastroenteritis, otitis media, infections caused by Herpes simplex, rhinitis, periodontal abscess, vaginal candidiasis *; infrequently - abscess, inflammation of subcutaneous fat, furunculosis, pyelonephritis, infections caused by Herpes zoster.
Neoplasms, including polyps and cysts: often - benign neoplasms of the skin, neoplasms; infrequently - skin cancer.
From the hematopoietic and lymphatic system: often - lymphadenopathy *, infrequently - leukocytosis, leukopenia, splenomegaly, thrombocytopenia, change in the morphology of lymphocytes.
From the immune system: often - hypersensitivity reactions.
From the endocrine system: infrequently - goitre, hyperthyroidism.
From the side of metabolism: often - anorexia, weight gain *; infrequent alcohol intolerance, gout, hyperlipidemia, hypernatremia, decreased ferritin concentration in serum.
Mental disturbance: very often - anxiety *, depression; often - nervousness; infrequent - unusual dreams, psychosis, euphoria, hallucinations, aggressiveness, mania, personality disorders, suicidal attempts.
From the nervous system: very often - headache; often - perversion of taste, hypertension of muscles, migraine, speech disorders, fainting, tremor *; infrequently, carpal tunnel syndrome, cognitive disorders, convulsions, dysgraphia, dyslexia, dystonia, motor function disorders, myoclonus, neuritis, neuromuscular blockade, nystagmus, paralysis, peroneal nerve palsy, stupor, visual field defect.
From the side of the organ of vision: often - diplopia, impaired vision *; infrequently - cataract, corneal damage, dryness of sclera and cornea, hemorrhage in the eye, ptosis of the eyelids, mydriasis, atrophy of the optic nerve.
From the organ of hearing and balance: often - hearing impairment.
From the cardiovascular system: very often - vasodilation *; often - a feeling of palpitations *, tachycardia *; infrequently - extrasystole, sinus bradycardia, paroxysmal tachycardia, varicose veins.
From the respiratory system: very often - shortness of breath *; often - cough, seasonal rhinitis; infrequently - apnea, sensation of suffocation, epistaxis, hyperventilation of the lungs, laryngospasm, pulmonary disorders.
From the side of the digestive system: very often - nausea *; often - anorectal disorders, constipation, caries, dyspepsia, dysphagia, incontinence, vomiting *;infrequently - colitis, enterocolitis, polyposis of the large intestine, belching, peptic ulcer of the esophagus, periodontitis, rectal bleeding, enlargement of the salivary glands.
From the side of the liver and biliary tract: often the deviation of indicators of liver tests; infrequently - cholelithiasis, hepatomegaly.
From the skin and subcutaneous fat: very often - skin rash *; often - ecchymosis, hyperhidrosis, skin itching, skin diseases *, urticaria; infrequently - angioedema, contact dermatitis, erythema nodosum, cutaneous nodules.
From the musculoskeletal system: very often - arthralgia, back pain *; often - pain in the neck; infrequently - arthritis, bursitis, pain in the side, muscle atrophy, osteoarthritis.
From the urinary system: often - mandatory urges, pollakiuria, urinary retention; infrequently - hematuria, nephrolithiasis, urinary tract diseases, deviations from laboratory norms of urinalysis.
On the part of the reproductive system: infrequent - spontaneous abortion, breast engorgement, erectile dysfunction, pelvic prolapse, priapism, prostate disease, deviation of laboratory parameters in smears from the cervical canal, testicular dysfunction, vaginal bleeding, vulvovaginal disorders.
Other: very often - asthenia, chest pain *, reactions at the injection site * and **, pain *; often - chills *, face swelling *, atrophy at the injection site ***, local reactions *, peripheral edema, edema, fever; infrequently - hypothermia, immediate postinjection reaction, inflammation, cyst, hangover syndrome, mucosal diseases, post-vaccination syndrome, necrosis at the injection site.
* The likelihood of such cases in patients taking Copaxone В® -Tev is more than 2% (> 2/100) compared with the placebo group. An undesired reaction without a "*" sign indicates a difference of less than or equal to 2%.
** Reactions at the injection site (various types) - include any adverse events occurring at the injection site, with the exception of atrophy and necrosis, which are listed separately.
*** Refers to localized lipoatrophy at the injection site.
In the fourth clinical study described above, after the placebo-controlled phase, an open phase of the study followed, lasting 5 years. During this study, no changes were detected in the previously established safety profile of Copaxone В® -Teva.
In patients with multiple sclerosis who received Copaxone В® -Tev in uncontrolled clinical trials, and also during post-marketing use, rare cases (? 1/10 000, but <1/1000) of anaphylactoid reactions were recorded.
Copaxone В® 40 in a dose of 40 mg / ml (with application 3 times a week)
In a double-blind, placebo-controlled study that lasted 12 months, the safety of CopaxoneВ® 40 was evaluated in 943 patients with a diagnosis of relapsing-remitting multiple sclerosis compared with a placebo group that included 461 patients.
In general, in patients who took Copaxone В® 40 3 times a week, adverse reactions at the injection site were the same as those observed with the daily administration of Copaxone В® -Tev 20 mg / ml.
In particular, reactions at the injection site (PMI) and immediate post-injection reactions (NPIR) with the administration of Copaxone В® 40 3 times a week were less frequent than with daily injections of Copaxone В® -Teva (35.5% compared to 70% for RMI and 7.8% compared to 31% for the IRPP, respectively).
In 36% of patients with COPAX В® 40, compared to 5% of patients, RMI was observed with placebo. In 8% of patients treated with Copaxone В® 40, compared with 2% of patients taking placebo, NPII was identified. In this case, several specific undesirable reactions were noted:
- anaphylactic reaction was observed in patients with multiple sclerosis who received Copaxone В® -Tev 20 mg / ml during uncontrolled clinical trials, and also in the postmarketing experience of using in rare cases (? 1/10 000, but <1/1000). In patients taking Copaxone В® 40, there were 0.3% of cases - infrequently (? 1/1000, but <1/100);
- no case of necrosis at the injection site was identified;
- in 2.1% of patients receiving drug Copaxone В® 40, often (1/100 but <1/10?) Observed cases of skin reddening, and pain in the extremities, which were not detected in the case of the drug Copaxone В® -Teva 20 mg / ml;
- 1 patient (0.1%) who received drug Copaxone В® 40, infrequently (> 1/1000 but <1/100) observed drug-induced liver damage and chronic hepatitis, which is also rare in patients with multiple sclerosis, taking drug Copaxone В® -Teva 20 mg / ml during the post-marketing surveillance.
- Hypersensitivity to glatiramer acetate or mannitol;
- child and adolescence to 18 years (effectiveness and safety have been studied).
Precautions: a predisposition to the development of allergic reactions, cardiovascular diseases, renal dysfunction.
PREGNANCY AND LACTATION
The drug Copaxone В® 40 is contraindicated during pregnancy. At the time of treatment must use reliable methods of contraception.
The use of the drug Copaxone data В® 40 during pregnancy is not present, the possible risk of pregnancy is not established.
Studies on animals are insufficient to determine the effect of the drug on pregnancy, embryo / fetus, childbirth and postnatal development.
It is not known whether glatiramer acetate in breast milk, so if you need the drug Copaxone stands В® 40 during lactation should evaluate the potential benefits of therapy for the mother and the potential risk to the child
APPLICATION FOR FUNCTIONS OF THE LIVER
The efficacy and safety of the drug in patients with renal impairment have not been studied.
APPLICATION FOR CHILDREN
The drug is not recommended for use in children and adolescents under the age of 18 years , as clinical studies have not been conducted in patients in these age groups.
APPLICATION IN ELDERLY PATIENTS
The efficacy and safety of the drug in elderly patients have not been studied.
Start treatment with Copaxone В® 40 must be carried out under the supervision of a neurologist and a doctor with experience in treating multiple sclerosis. The drug is not indicated for the treatment of primary or secondary progressive multiple sclerosis.
Patients should be informed of the possibility of adverse reactions, including occurring immediately after the injection Copaxone В® 40.
Most of the short duration of these symptoms spontaneously resolved without consequences. With the development of serious adverse reactions should immediately discontinue therapy and contact your doctor or call an ambulance. The decision on the application of symptomatic therapy takes a doctor.
There is no evidence that certain groups of patients at greater risk of such reactions. However, patients with cardiovascular disease should be under medical supervision throughout the treatment period.
It identified several cases of seizures and / or anaphylactoid or allergic reactions. It may also be rare severe hypersensitivity reactions (bronchospasm, anaphylaxis or urticaria). In case of severe reactions, you must assign the appropriate treatment and stop taking the drug.
In the blood serum of patients had antibodies to glatiramer acetate. After treatment, the average duration of 3-4 months of their maximum concentration was recorded, which was later dropped and stabilized at a level just above the base.
There is evidence that antibodies to glatiramer acetate possess neutralizing activity or influence the clinical efficacy of the drug.
In patients with renal insufficiency, renal function should be monitored, although there is no conclusive evidence that the deposition of immune complexes affects the glomerular filtration.
If the patient is not able to store the syringes with the drug Copaxone В®40 in the refrigerator, then be stored at 15-25 В° C, but not more than 1 month. If within a month with the drug syringes were not used, and thus blisters has been opened, these syringes should be further stored in a refrigerator (2 В° to 8 В° C).
Impact on the ability to drive vehicles and manage mechanisms
Studies on the effect on the ability to drive and use machinery has not been.
Symptoms received several reports of overdose (of up to 300 mg of glatiramer acetate). No adverse reactions other than those listed above is not observed.
Treatment: In case of overdose shown careful observation, symptomatic and supportive therapy.
The interaction between the drug Copaxone В® 40 and other drugs is not separately evaluated. There are no data on interaction with interferon beta.
Revealed increased incidence of injection site reactions while simultaneously introducing drug Copaxone В® 40 with corticosteroids.
In the in vitro study, it was assumed that the glatiramer acetate has a high degree of binding to plasma proteins and is not displaced from the connection with blood plasma protein alone, as well as phenytoin or carbamazepine. However, since the drug Copaxone В® 40 has a potential impact on the protein-binding agents, it is necessary to control the simultaneous application with other drugs.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be kept out of the reach of children, protected from light at a temperature of from 2 В° to 8 В° C. Do not freeze. Shelf life - 2 years.