Glatiramer acetate-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GLATIRAMER ACETATE-VISTA (GLATIRAMER ACETATE-VISTA)

Composition:

Active substance: glatiramer acetate;

1 ml of injection solution contains 20 mg of glatiramer acetate*;

Excipients: mannite (E 421), water for injections.

*The average molecular weight of the glatiramer acetate mixture ranges between 5000–9000 daltons. Variability in the composition of this substance does not allow identification of a specific polypeptide that could be fully characterized with respect to amino acid sequence, although the final composition of glatiramer acetate is not entirely random. 20 mg of glatiramer acetate contained in 1 pre-filled syringe corresponds to 18 mg of glatiramer base.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or slightly yellowish/brownish solution in a transparent colorless glass syringe with a needle with cap, and with a stopper and plunger.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Other immunostimulants. ATC code L03A X13.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

The mechanism by which glatiramer acetate exerts its therapeutic effect in patients with relapsing forms of multiple sclerosis (MS) is not fully understood; however, it is believed to involve modulation of immune processes. Studies in animals and in patients with MS suggest that glatiramer acetate affects innate immune cells, including monocytes, dendritic cells, and B-cells, which modulate adaptive functions of B- and T-cells and induce secretion of anti-inflammatory and regulatory cytokines. Whether the therapeutic effect is mediated by the cells described above is unknown, as the pathophysiology of MS is only partially understood. In clinical trials in patients with MS, treatment with glatiramer acetate resulted in a significant reduction in the number of relapses compared to patients receiving placebo. Glatiramer acetate has also demonstrated therapeutic effects compared to placebo on MRI parameters reflecting the course of relapsing-remitting MS.

One study showed that the cumulative percentage of patients with confirmed 3-month disability progression was lower in the group receiving glatiramer acetate compared to the placebo group. There is no evidence that glatiramer acetate therapy affects the duration or severity of relapses. To date, there is no information on the use of glatiramer acetate for the treatment of patients with primary or secondary progressive forms of the disease.

Pharmacokinetics.

Pharmacokinetic studies have not been conducted in patients. In vitro data and limited data from studies in healthy volunteers indicate that following subcutaneous administration of glatiramer acetate, the active substance is readily absorbed, and a significant portion of the dose is rapidly degraded into smaller fragments within the subcutaneous tissue.

Clinical Characteristics.

Indications.

The medicinal product Glatiramer Acetate-Vista is indicated for the treatment of patients with relapsing forms of multiple sclerosis.

Glatiramer Acetate-Vista is not indicated for primary or secondary progressive multiple sclerosis.

Contraindications.

Hypersensitivity to the active substance (glatiramer acetate) or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Interaction between glatiramer acetate and other medicinal products has not been formally evaluated.

Available clinical studies and post-marketing experience do not suggest any significant interaction of glatiramer acetate with commonly used treatments prescribed for patients with MS, including concomitant use of corticosteroids within a period of up to 28 days.

In vitro studies indicate that glatiramer acetate in blood is highly bound to plasma proteins, but it neither displaces nor is displaced by phenytoin or carbamazepine. However, since glatiramer acetate theoretically has the potential to affect the distribution of protein-bound substances, concomitant use of such medicinal products should be carefully monitored.

Special precautions for use.

The medicinal product Glatiramer Acetate-Vista is administered only by subcutaneous injection. The product must not be administered intravenously or intramuscularly. Treatment with Glatiramer Acetate-Vista should be initiated under the supervision of a neurologist or a physician experienced in the management of multiple sclerosis.

Glatiramer acetate may cause post-injection reactions as well as anaphylactic reactions.

Post-injection reactions

The prescribing physician must inform the patient that a reaction associated with at least one of the following symptoms—vasodilation (flushing), chest pain, dyspnea, palpitations, or tachycardia—may occur within minutes after injection (see section "Adverse reactions"). Most of these symptoms are transient and resolve spontaneously without consequences. In the event of a serious adverse effect, the patient must immediately discontinue treatment with Glatiramer Acetate-Vista and consult a physician. Symptomatic treatment may be administered if necessary.

There is no evidence of increased risk of such reactions in any specific patient group. Nevertheless, Glatiramer Acetate-Vista should be used with caution in patients with cardiac disorders. These patients should be monitored regularly throughout the treatment period.

Anaphylactic reactions

Anaphylactic reactions may occur shortly after administration of glatiramer acetate, or even several months or years after initiation of treatment.

Fatal cases have been reported. Some symptoms of anaphylactic reactions may overlap with post-injection reactions.

All patients receiving glatiramer acetate treatment and their caregivers should be informed about the signs and symptoms of anaphylactic reactions and instructed to seek immediate emergency medical assistance if such symptoms occur (see section "Adverse reactions").

If an anaphylactic reaction occurs, treatment with glatiramer acetate must be discontinued.

Glatiramer acetate-reactive antibodies have been detected in the serum of patients during continuous daily therapy with glatiramer acetate. Maximum levels were reached on average after 3–4 months of treatment, after which they declined and stabilized at a level slightly above baseline.

There are no data indicating that these glatiramer acetate-reactive antibodies are neutralizing or that their formation affects the clinical efficacy of glatiramer acetate.

Renal function should be monitored throughout the treatment period in patients with renal impairment. Although there is no evidence of glomerular deposition of immune complexes in patients, this possibility cannot be excluded.

During post-marketing use of glatiramer acetate, rare cases of severe hepatic injury have been reported, including hepatitis with jaundice, hepatic failure, and in isolated cases, liver transplantation (see section "Adverse reactions"). Hepatic injury occurred from several days to several years after initiation of glatiramer acetate treatment. In most cases, severe liver injury resolved upon discontinuation of treatment. In some cases, these reactions occurred in the presence of excessive alcohol consumption, pre-existing or past liver disease, or concomitant use of other potentially hepatotoxic medicinal products. Patients should undergo regular monitoring for signs of hepatic injury and should seek immediate medical attention if symptoms of liver injury occur. In cases of clinically significant liver injury, discontinuation of glatiramer acetate should be considered.

Use during pregnancy or breastfeeding.

Pregnancy. Available data from a limited number of pregnancies (300–1000 cases) indicate no fetotoxic/neonatal toxicity or developmental abnormalities. Animal studies have not shown reproductive toxicity. If necessary, Glatiramer Acetate-Vista may be considered for use during pregnancy.

Breastfeeding. Based on the physicochemical properties and low oral bioavailability of the medicinal product, the exposure of newborns/infants via breast milk is expected to be negligible. Data from a non-interventional retrospective study involving 60 infants breastfed by mothers receiving glatiramer acetate, compared to 60 infants whose mothers received no disease-modifying therapy, as well as post-marketing data, suggest no adverse effects of glatiramer acetate. Glatiramer Acetate-Vista may be used during breastfeeding.

Effect on ability to drive and use machines.

The effect on the ability to drive or operate machinery has not been studied.

Method of Administration and Dosage

Initiation of therapy with the medicinal product Glatiramer Acetate-Vista should be carried out under the supervision of a neurologist or a physician experienced in the treatment of multiple sclerosis. The recommended dose for adults and children aged 12 years and older is 20 mg of glatiramer acetate (one pre-filled syringe) administered subcutaneously once daily. The required duration of treatment with glatiramer acetate is currently unknown.

The decision regarding long-term treatment should be made by the physician for each individual patient.

Elderly patients. The use of glatiramer acetate in elderly patients has not been specifically studied.

Patients with renal impairment. Specific studies on the use of glatiramer acetate in patients with renal impairment have not been conducted (see section "Special Instructions for Use").

Patients should be instructed in the technique of self-injection and should be under medical supervision during the first self-injection and for 30 minutes thereafter.

The drug should be administered daily at a different injection site to reduce the likelihood of irritation or pain at the injection site. The drug may be injected into the abdomen, arms, thighs, and buttocks.

It is very important to administer Glatiramer Acetate-Vista correctly:

• Only into the subcutaneous tissue (see below "Instructions for Use").
• Only at the dose prescribed by the physician.
• Each pre-filled syringe containing the solution is intended for single use only. Any unused portion or leftover medication should be discarded.
• Do not mix Glatiramer Acetate-Vista with any other drug or administer it simultaneously with other medications.
• The solution should not be used if particles are present. Take another syringe instead.

At the first administration of the drug, the patient must receive complete instructions and be under the supervision of a physician or nurse. The patient must remain under the supervision of a healthcare professional during the first self-administration and for 30 minutes thereafter.

Instructions for Use:

1. Before administration, ensure that all necessary items for injection are available:
   • Pre-filled syringe with the drug solution;
   • Sharps container for disposal of used syringes and needles.
2. Remove one blister containing a pre-filled syringe from the outer packaging. Store all unused syringes in the refrigerator.
3. Wash hands thoroughly with soap and water before administering the injection.
4. Allow the blister with the pre-filled syringe to reach room temperature by leaving it at room temperature for at least 20 minutes. Ensure that the syringe has warmed to room temperature.
5. Do not use the solution if particulate matter is present. Return to step 1 and use another syringe.
6. Select an injection site on the body (Fig. 1). Seven possible injection sites on the body are indicated: arms, thighs, buttocks, and abdomen (periumbilical area). Within each injection area, multiple injection points are available.

Injection sites should be rotated regularly within each specific area.

Do not use injection sites that are painful, discolored, or have indurations or nodules. A plan for rotating injection sites should be developed and recorded in a patient diary.

V – upper; M – middle; L – lower.

Fig. 1

1. Remove the syringe from its protective blister packaging by peeling off the paper label.
2. Hold the syringe in the hand used for writing, gripping it like a pencil. Remove the needle cap.
3. Gently pinch the skin into a fold using the thumb and index finger (Fig. 2).
4. Insert the needle into the skin (Fig. 3). Administer the medication by steadily pressing down on the syringe plunger until the syringe is completely emptied.

Fig. 2

Adverse Reactions

Injection site reactions were the most commonly reported adverse reactions during all clinical trials and occurred in the majority of patients receiving glatiramer acetate. In controlled trials, the proportion of patients experiencing such reactions at least once was higher with glatiramer acetate (70%) than with placebo (37%). The most commonly reported injection site reactions during clinical trials and in the post-marketing period included erythema, pain, nodules, pruritus, swelling, inflammation, hypersensitivity, and rarely, lipoatrophy and skin necrosis.

Reactions associated with at least one or more of the following symptoms — vasodilatation (flushing), chest pain, dyspnea, palpitations, or tachycardia — have been described as an immediate post-injection reaction. This reaction may occur within minutes after administration of glatiramer acetate. At least one symptom of immediate post-injection reaction (individual symptoms of immediate post-injection reaction with frequency specified below) was reported in 31% of patients receiving glatiramer acetate compared to 13% of patients receiving placebo. All adverse reactions identified during clinical trials and in the post-marketing period are listed below.

Data from clinical trials were derived from four core double-blind, placebo-controlled clinical studies involving a total of 512 patients treated with glatiramer acetate and 509 patients treated with placebo for up to 36 months. Three studies in relapsing-remitting multiple sclerosis included 269 patients treated with glatiramer acetate and 271 patients treated with placebo over 35 months. The fourth study, involving patients with a first clinical episode and at high risk of developing clinically definite multiple sclerosis, included 243 patients treated with glatiramer acetate and 238 patients treated with placebo over 36 months.

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data).

Endocrine system.

Uncommon: goiter, hyperthyroidism.

Respiratory system.

Very common: dyspnoea*. Common: cough, seasonal rhinitis. Uncommon: apnoea, sensation of suffocation, hyperventilation, epistaxis, laryngospasm, lung disorder.

Immune system.

Common: hypersensitivity.

Uncommon: anaphylactic reaction.

Musculoskeletal and connective tissue system.

Very common: arthralgia, back pain*. Common: neck pain. Uncommon: arthritis, flank pain, bursitis, muscle atrophy, osteoarthritis.

Blood and lymphatic system.

Common: lymphadenopathy*. Uncommon: leukocytosis, leukopenia, splenomegaly, thrombocytopenia, abnormal lymphocyte morphology.

Metabolism and nutrition.

Common: anorexia, weight gain*. Uncommon: alcohol intolerance, gout, hyperlipidaemia, increased blood sodium, decreased plasma ferritin.

Nervous system.

Very common: headache. Common: dysgeusia, migraine, hypertonia, speech disorder, syncope, tremor*. Uncommon: carpal tunnel syndrome, cognitive disorder, convulsions, dysgraphia, dyslexia, dystonia, motor dysfunction, myoclonus, neuromuscular blockade, peroneal nerve paralysis, stupor, paralysis, visual field defect, neuritis, nystagmus.

Urinary system.

Common: urinary urgency, urinary retention, polyuria.

Uncommon: haematuria, nephrolithiasis, urinary tract disorder, abnormal urine analysis.

Eye disorders.

Common: diplopia, eye disorders*. Uncommon: cataract, corneal lesion, dry eyes, subconjunctival haemorrhage, ptosis of upper eyelid, mydriasis, optic nerve atrophy.

Ear and labyrinth disorders.

Common: hearing impairment.

Reproductive system and breast.

Uncommon: breast engorgement, erectile dysfunction, priapism, pelvic organ prolapse, abnormal cervical smear, vaginal haemorrhage, prostate disorder, testicular disorder, vulvovaginal disorder.

Cardiac disorders.

Common: feeling of chest discomfort*, palpitations, tachycardia*. Uncommon: extrasystoles, sinus bradycardia, paroxysmal tachycardia.

Vascular disorders.

Very common: vasodilatation*. Uncommon: varicose veins.

Skin and subcutaneous tissue.

Very common: rash*. Common: hyperhidrosis, pruritus, skin disorder*, urticaria, ecchymosis. Uncommon: angioedema, contact dermatitis, nodular erythema, skin nodules.

Gastrointestinal system.

Very common: nausea*. Common: dental caries, dysphagia, constipation, anorectal disorders, faecal incontinence, dyspepsia, vomiting*. Uncommon: colitis, enterocolitis, eructation, oesophageal ulcer, periodontitis, rectal haemorrhage, salivary gland enlargement, colon polyp.

Hepatobiliary system.

Common: abnormal liver function tests. Uncommon: cholelithiasis, liver injury, hepatomegaly. Rare: toxic hepatitis, liver injury. Frequency not known: hepatic failure****.

Infections and infestations.

Very common: infections, influenza. Common: bronchitis, gastroenteritis, herpes simplex, otitis media, rhinitis, dental abscess, vaginal candidiasis*. Uncommon: abscess, cellulitis, furunculosis, herpes zoster, pyelonephritis.

General disorders and administration site conditions.

Very common: asthenia, chest pain*, injection site reaction**, pain*. Common: chills*, facial swelling*, local reactions*, skin atrophy at injection site***, peripheral oedema, hyperthermia, oedema. Uncommon: immediate post-injection reaction, inflammation, skin necrosis at injection site, cyst, hangover syndrome, hypothermia, mucosal disorder.

Psychiatric disorders.

Very common: anxiety*, depression. Common: irritability. Uncommon: abnormal dreams, confusion, euphoria, hallucinations, hostility, mania, personality disorder, suicide attempt.

Benign, malignant and unspecified neoplasms (including cysts and polyps).

Common: benign skin tumour, neoplasm. Uncommon: skin cancer.

Injury, poisoning and procedural complications.

Uncommon: post-vaccination syndrome.

*The number of cases was more than 2% (> 2/100) higher in the glatiramer acetate group compared to the placebo group. Adverse reactions without the * symbol indicate a difference of less than 2% or equivalent to 2%.

**The term "injection site reaction" (various types) includes all adverse reactions occurring at the injection site, excluding injection site lipatrophy and skin necrosis at injection site, which are listed separately.

***Includes terms related to localized lipoatrophy at injection site.

****Cases of liver transplantation have been reported.

Description of selected adverse reactions

In the fourth study mentioned above, a placebo-controlled period was followed by an open-label phase. No new changes in the known risk profile of glatiramer acetate were observed during the open-label follow-up period of up to 5 years. Within uncontrolled clinical studies and in the post-marketing period, elevations in liver enzymes without clinically significant consequences have been reported in patients with multiple sclerosis treated with glatiramer acetate.

Anaphylactic reactions may occur shortly after administration of glatiramer acetate, or several months or even years after initiation of treatment (see section "Special warnings and precautions for use").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store in the original packaging to protect from light at 2–8 °C (in a refrigerator). Do not freeze. Keep out of reach of children.

If filled syringes cannot be stored in a refrigerator, they may be kept at 15–25 °C for no longer than 1 month.

If, after this one-month period, filled syringes containing Glatiramer Acetate-Vista 20 mg/ml solution have not been used and remain in the original packaging, they must be stored in a refrigerator at 2–8 °C. Repeated storage of these syringes at room temperature is not permitted.

Incompatibilities.

The product should not be mixed with other medicinal products, as compatibility studies have not been conducted.

Packaging. 1 ml of solution in a pre-filled syringe. One pre-filled syringe in a blister. 28, 30, and 90 (3x30) blisters in a cardboard box with the instruction for medical use.

Prescription status. Prescription only.

Manufacturers.

Synthon España, S.L. or Synthon BV.

Manufacturer addresses and locations of operations.

C/Castello, no 1, Sant Boi de Llobregat, Barcelona, 08830, Spain or Microvweg 22, Nijmegen, 6545 SM, the Netherlands.