Eporatio (Solution) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Merckle, GmbH (Germany)

ATC Code

B03XA01 (Erythropoietin)

Active Substance

Epoetin theta (Rec.INN registered by WHO)

Dosage Forms

	Eporatio	Solution for intravenous and subcutaneous administration 1000 IU/0.5 ml: syringes 6 pcs. in a set with sterile needles
		Solution for intravenous and subcutaneous administration 2000 IU/0.5 ml: syringes 6 pcs. in a set with sterile needles
		Solution for intravenous and subcutaneous administration 3000 IU/0.5 ml: syringes 6 pcs. in a set with sterile needles
		Solution for intravenous and subcutaneous administration 4000 IU/0.5 ml: syringes 6 pcs. in a set with sterile needles
		Solution for intravenous and subcutaneous administration 5000 IU/0.5 ml: syringes 6 pcs. in a set with sterile needles
		Solution for intravenous and subcutaneous administration 10000 IU/1 ml: syringes 1, 4 or 6 pcs. in a set with sterile needles
		Solution for intravenous and subcutaneous administration 20000 IU/1 ml: syringes 1, 4 or 6 pcs. in a set with sterile needles
		Solution for intravenous and subcutaneous administration 30000 IU/1 ml: syringes 1, 4 or 6 pcs. in a set with sterile needles

Dosage Form, Packaging, and Composition

Solution for IV and SC administration clear, colorless.

Excipients : sodium dihydrogen phosphate dihydrate – 1.56 mg, sodium chloride – 1.96 mg, polysorbate 20 – 0.15 mg, trometamol (Tris) – 4.24 mg, hydrochloric acid (6M) – 4.85 µl, water for injections – up to 0.5 ml.

0.5 ml – disposable glass syringes of Luer type (1) in a set with a sterile needle with Luer adapter (needle in a plastic container) – blisters (6) – cardboard boxes.
0.5 ml – disposable glass syringes of Luer type (1) in a set with a sterile SurGuard2 needle with a needle safety device (needle in a blister) – blisters (6) – cardboard boxes.

Solution for IV and SC administration clear, colorless.

Excipients : sodium dihydrogen phosphate dihydrate – 3.12 mg, sodium chloride – 3.92 mg, polysorbate 20 – 0.3 mg, trometamol (Tris) – 8.48 mg, hydrochloric acid (6M) – 9.7 µl, water for injections – up to 1 ml.

1 ml – disposable glass syringes of Luer type (1) in a set with a sterile needle with Luer adapter (needle in a plastic container) – blisters (1) – cardboard boxes.
1 ml – disposable glass syringes of Luer type (1) in a set with a sterile needle with Luer adapter (needle in a plastic container) – blisters (4) – cardboard boxes.
1 ml – disposable glass syringes of Luer type (1) in a set with a sterile needle with Luer adapter (needle in a plastic container) – blisters (6) – cardboard boxes.
1 ml – disposable glass syringes of Luer type (1) in a set with a sterile SurGuard2 needle with a needle safety device (needle in a blister) – blisters (1) – cardboard boxes.
1 ml – disposable glass syringes of Luer type (1) in a set with a sterile SurGuard2 needle with a needle safety device (needle in a blister) – blisters (4) – cardboard boxes.
1 ml – disposable glass syringes of Luer type (1) in a set with a sterile SurGuard2 needle with a needle safety device (needle in a blister) – blisters (6) – cardboard boxes.

Clinical-Pharmacological Group

Erythropoiesis stimulant

Pharmacotherapeutic Group

Hematopoiesis stimulant

Pharmacological Action

Human erythropoietin is an endogenous glycoprotein hormone that is the main regulator of erythropoiesis through specific interactions with erythropoietin receptors on erythroid progenitor cells in the bone marrow. It acts as a mitosis-stimulating factor and a differentiating hormone. The production of erythropoietin primarily occurs and is regulated by the kidneys in response to changes in tissue oxygen concentration. In patients with chronic renal failure (CRF), the production of endogenous erythropoietin is impaired, and the main cause of anemia is erythropoietin deficiency. In patients with malignant neoplasms receiving chemotherapy, the etiology of anemia is multifactorial. In such patients, the cause of anemia is both erythropoietin deficiency and a reduced response of erythroid progenitor cells to endogenous erythropoietin.

Epoetin theta is identical in its amino acid sequence and similar in its carbohydrate composition (glycosylation) to endogenous human erythropoietin.

Pharmacokinetics

The pharmacokinetics of epoetin theta have been studied in healthy volunteers, in patients with CRF, and in patients with cancer receiving chemotherapy. The pharmacokinetics of epoetin theta are independent of age or gender.

The bioavailability of epoetin theta after SC administration is 31% of the bioavailability after IV administration. T_max of epoetin theta in plasma – 10-14 h.

In patients with chronic renal failure (CRF) after SC administration of 40 IU/kg, the terminal T_1/2 is higher than after IV administration, averaging 25 h after a single dose and 34 h at steady state after repeated doses 3 times a week. No accumulation effect of epoetin theta was found.

In patients with cancer receiving chemotherapy, after repeated SC administration of 20,000 IU epoetin theta once a week, T_1/2 – 29 h after the first dose and 28 h with multiple applications. No accumulation effect of epoetin theta was found.

V_d is approximately equal to the volume of circulating blood.

In patients with CRF undergoing hemodialysis, T_1/2 of epoetin theta is 6 h after a single dose and 4 h after repeated IV administration of epoetin theta 40 IU/kg 3 times a week. No accumulation effect of epoetin theta was found.

Pharmacokinetics in special clinical cases

The pharmacokinetics of epoetin theta in patients with hepatic impairment have not been studied.

Indications

• Treatment of anemia associated with CRF, including in patients on hemodialysis;
• Treatment of anemia in patients with non-myeloid tumors receiving chemotherapy (only SC administration).

ICD codes

Dosage Regimen

Treatment is carried out under medical supervision.

IV slow injection over 2 minutes and SC slow injection into the abdomen, shoulder, or thigh. The injection site for SC administration should be regularly changed to avoid the development of local reactions.

Before use, it is necessary to ensure that the syringe is suitable for use, filled with a clear solution, and does not contain suspended visible particles. The solution for injection should not be shaken. Before use, the solution for injection should reach room temperature. If the drug Eporatio is replaced with another epoetin drug, the same route of administration must be maintained. The goal of treatment is to increase the Hb concentration. The effectiveness of therapy depends on an adequately selected individual treatment regimen. Since the individual response to treatment with Eporatio cannot be predicted, the Hb concentration can be adjusted by changing the dose of Eporatio, maintaining it within the range of not less than 10 g/dl (6.21 mmol/l), but not more than 12 g/dl (7.45 mmol/l).

Treatment of anemia associated with CRF, including in patients on hemodialysis

SC and IV administration. For patients not receiving hemodialysis, SC administration is preferable to avoid repeated punctures of peripheral veins.

For patients on hemodialysis – through the arteriovenous shunt at the end of the dialysis session.

If the Hb concentration increases by more than 2 g/dl (1.24 mmol/l) within 4 weeks or the Hb concentration increases above 12 g/dl (7.45 mmol/l), the dose of Eporatio is reduced by 25-50%.

It is recommended to monitor the Hb concentration every 2 weeks before and after achieving stabilization of parameters. If the Hb concentration continues to increase, therapy is interrupted until the Hb concentration begins to decrease, after which therapy is resumed at a dose of approximately 25% of the initial dose.

In the presence of concomitant cardiovascular diseases, including arterial hypertension, cerebrovascular disease, and peripheral vascular disease, the increase in Hb concentration and the target Hb concentration should be determined individually for each patient, taking into account the clinical picture.

Hb concentration correction stage

SC administration initial dose – 20 IU/kg 3 times a week. In case of insufficient increase in Hb concentration (less than 1 g/dl (0.62 mmol/l) within 4 weeks), the dose is increased to 40 IU/kg 3 times a week every 4 weeks. If necessary, the dose of Eporatio is additionally increased by 25% of the previous dose at 1-month intervals until the individual target Hb concentration is reached.

IV administration initial dose – 40 IU/kg 3 times a week. Additionally, the dose is increased after 4 weeks to 80 IU/kg 3 times a week. If necessary, the dose is increased by 25% of the previous dose at 1-month intervals.

The maximum dose for SC and IV administration should not exceed 700 IU/kg per week.

Hb concentration stabilization stage

The maintenance dose is adjusted to maintain the individual target Hb concentration within the range of not less than 10 g/dl (6.21 mmol/l), but not more than 12 g/dl (7.45 mmol/l). If dose adjustment is necessary, the dose is changed by approximately 25%.

SC administration the total weekly dose is administered as a single dose or the dose is divided into 3 administrations per week.

IV administration with stable Hb concentration, the total weekly dose is divided into 3 administrations per week or into 2 administrations per week.

When changing the administration regimen, the Hb concentration should be monitored and, if necessary, the dose and administration regimen should be adjusted.

The maximum dose for SC and IV administration should not exceed 700 IU/kg per week.

Treatment of anemia in patients with non-myeloid tumors receiving chemotherapy

Only SC administration.

Initial dose – 20,000 IU once a week. If the Hb concentration increases by 1 g/dl (0.62 mmol/l) within 4 weeks, therapy is continued at the initial dose. In case of insufficient increase in Hb concentration (less than 1 g/dl (0.62 mmol/l) within 4 weeks), the dose is increased to 40,000 IU. If after 4 weeks the increase in Hb concentration is still insufficient, the possibility of increasing the total weekly dose to 60,000 IU is considered.

The maximum dose should not exceed 60,000 IU per week.

If after 12 weeks of therapy there is no increase in Hb concentration by at least 1 g/dl (0.62 mmol/l), the effectiveness of treatment with Eporatio is assessed and, if necessary, treatment is discontinued.

If the increase in Hb concentration exceeds 2 g/dl (1.24 mmol/l) within 4 weeks or the Hb concentration exceeds 12 g/dl (7.45 mmol/l), then the dose is reduced by 25-50%. If the Hb concentration is above 13 g/dl (8.07 mmol/l), then therapy is interrupted until the Hb concentration decreases to 12 g/dl (7.45 mmol/l) or below, after which therapy is resumed at a dose of approximately 25% of the initial dose.

Treatment with Eporatio should continue for up to 4 weeks after the end of chemotherapy.

Recommendations for drug use

Ensure that everything necessary for the injection is available: a filled syringe with Eporatio, an alcohol swab, a piece of gauze bandage or a sterile gauze pad, a puncture-resistant container for used syringes.

What to do before injecting the drug

1. Take one blister with Eporatio from the refrigerator.

2. Open the blister and remove the filled syringe and the container with the needle from it. Do not pull the filled syringe by the plunger or protective cap.

3. Check the expiration date on the label of the filled syringe (Expiry date:). Do not use the drug if the date of the last day of the month indicated on the label has passed.

4. Assess the appearance of Eporatio. It should be a clear and colorless liquid. Do not use the drug if it contains particles or if the solution is cloudy.

5. There is a cap on the end of the needle container; open the marked seal/label and remove the cap.

6. Remove the protective cap from the filled syringe.

7. Connect the needle to the syringe. Do not remove the needle protective cap yet.

8. For a more comfortable injection procedure, leave the filled syringe for 30 minutes to warm to room temperature (not above 25°C (77°F)) or, carefully, hold the syringe in your hand for a few minutes. Do not warm Eporatio in any other way (for example, do not heat it in a microwave or in hot water).

9. Do not remove the protective cap from the needle until you are ready to perform the injection.

10. Choose a comfortable, well-lit place. The materials necessary for the injection (filled syringe with Eporatio, alcohol swab, a piece of gauze bandage or a sterile gauze pad, and a puncture-resistant container) should be laid out so that they are within reach.

11. Wash hands thoroughly.

How to prepare for drug administration

Before performing the injection of Eporatio, the following must be done

1. Take the syringe and carefully remove the protective cap from the needle, avoiding rotation. The cap should be pulled along the axis of the syringe. Do not touch the needle or press the plunger.

2. There may be a small amount of air bubbles in the filled syringe. If air bubbles are present, gently tap the syringe with your fingers until the air bubbles rise to the top of the syringe. Pointing the syringe upwards, remove air from the syringe by slowly pressing the plunger upwards.

3. There is a scale on the syringe barrel. Press the plunger to the unit (IU) of the scale corresponding to the dose of Eporatio prescribed by the doctor.

4. Re-check the correctness of the set dose of Eporatio on the syringe scale.

5. Now the filled syringe is ready for use.

Choosing an injection site

The most suitable sites for injections are the following areas

• Upper thigh,
• Abdomen, excluding the navel area.

Injection into the back and side of the upper arm is possible if the injection is performed by another person. It is preferable to change injection sites each time to avoid the risk of developing pain in the same area.

How to perform the injection

1. Disinfect the skin area at the injection site with an alcohol swab and gently gather the skin into a fold with the thumb and forefinger, without squeezing it.

2. Insert the needle completely under the skin. The angle between the syringe and the skin should not be too acute (not less than 45°C (113°F)).

3. Gently pull back the plunger to ensure that a blood vessel has not been punctured. If blood appears in the syringe, remove the needle and reinsert it in another location.

4. Slowly and evenly inject the drug solution under the skin, holding the fold.

5. After administering the drug, remove the needle and release the skin.

4. Press on the injection site with a piece of gauze bandage or a sterile gauze pad and hold for a few seconds.

7. Use the syringe for only one injection. Do not use the remaining Eporatio solution in the syringe.

What to do before injecting the drug with a SurGuard2 needle with a needle safety device (needle protective cover)

1. Take one blister of Eporatio from the refrigerator.

2. Open the blister and remove the filled syringe and the container with the needle from it. Do not pull the pre-filled syringe by the plunger or protective cap.

3. Check the expiration date on the label of the filled syringe (Expiry date:). Do not use the drug if the date of the last day of the month indicated on the label has passed.

4. Assess the appearance of Eporatio. It should be a clear and colorless liquid. Do not use the drug if it contains particles or if the solution is cloudy.

5. Open the blister and remove the SurGuard2 needle with the needle safety device.

6. Remove the protective cap from the filled syringe.

7. Connect the needle to the syringe. Do not remove the needle protective cap yet.

8. For a more comfortable injection procedure, leave the filled syringe for 30 minutes to warm to room temperature (not above 25°C (77°F)) or, carefully, hold the syringe in your hand for a few minutes. Do not warm Eporatio in any other way (for example, do not heat it in a microwave or in hot water).

9. Do not remove the protective cap from the needle if you are not yet ready to perform the injection.

10. Choose a comfortable, well-lit place. The materials necessary for the injection (filled syringe with Eporatio, alcohol swab, a piece of gauze bandage or a sterile gauze pad) should be laid out so that they are easily within reach.

11. Wash hands thoroughly.

How to prepare for the injection

Before performing the injection of Eporatio, the following must be done

1. Move the protective device away from the SurGuard2 needle towards the syringe barrel.

2. Take the syringe and carefully remove the protective cap from the needle, avoiding rotation. The cap should be pulled along the axis of the syringe.

3. There may be a small amount of air bubbles in the filled syringe. If air bubbles are present, gently tap the syringe with your fingers until the air bubbles rise to the top of the syringe. Pointing the syringe upwards, remove air from the syringe by slowly pressing the plunger upwards.

4. There is a scale on the syringe barrel. Press the plunger to the unit (IU) of the scale corresponding to the dose of Eporatio prescribed by the doctor.

5. Re-check the correctness of the set dose of Eporatio on the syringe scale.

6. Now the filled syringe is ready for use.

Selection of the injection site

The most suitable sites for injections are the following areas:

• The upper part of the thigh;
• The abdomen, excluding the navel area.

It is possible to inject into the posterior or lateral surface of the shoulder if the injection is administered by another person. It is preferable to change the injection sites each time to avoid the risk of developing painful sensations in the same area.

How to perform the injection

1. Disinfect the skin area at the injection site with a cotton swab soaked in alcohol and gently grasp the skin into a fold using the thumb and index finger, without squeezing it.

2. Fully insert the needle, protected by the cover, under the skin. The angle between the syringe and the skin should not be too acute (not less than 45°C (113°F)).

3. Slowly and evenly inject the drug solution under the skin, while holding the fold.

4. After administering the drug, remove the needle and release the skin. Bring the SurGuard2 needle into the safe state by lowering the protective device until a characteristic click is heard.

5. Press on the injection site with a piece of gauze bandage or a sterile gauze swab and hold for a few seconds.

6. Use the syringe for only one injection. Do not use the remaining Eporatio drug solution in the syringe.

Adverse Reactions

Side effects are classified by frequency according to WHO recommendations: very common (≥10%); common (≥1%, but <10%); uncommon (≥0.1%, but <1%); rare (≥0.01%, but <0.1%); very rare (<0.01%, including isolated reports).

From the hematopoietic system common – shunt thrombosis (may occur mainly in patients who are prone to hypotension or in the presence of arteriovenous fistula complications: stenosis or aneurysm); very rare – thrombocytosis, thromboembolic disorders, PRCA.

From the immune system common – skin rash, itching, urticaria; very rare – anaphylactoid reactions.

From the CNS: common – headache.

From the cardiovascular system: common – onset or worsening of pre-existing arterial hypertension, hypertensive crisis with manifestations of encephalopathy (headaches, confusion, sensory and motor disturbances up to tonic-clonic seizures).

From the skeletal, muscular and joint tissue common – arthralgia.

Other common – flu-like syndrome (especially at the start of therapy), the symptoms of which are usually mild or moderate and disappear after a few hours or days, including fever, chills, headache, pain in the limbs or bones, general malaise.

Contraindications

• Hypersensitivity to epoetin theta or one of the components of the drug;
• Pure red cell aplasia (PRCA);
• Uncontrolled arterial hypertension;
• Hepatic insufficiency;
• Sickle cell anemia;
• Anemia in patients with malignant tumors not receiving chemotherapy and radiation therapy;
• Anemia with a hemoglobin (Hb) concentration of more than 12 g/dl (7.45 mmol/l) in patients with malignant tumors receiving chemotherapy and radiation therapy;
• Pregnancy;
• Breastfeeding period;
• Age over 75 years;
• Age under 18 years (there is no experience with the drug).

With caution: cardiovascular diseases, including cerebrovascular and peripheral vascular diseases; patients at risk of thrombosis and thromboembolism.

Use in Pregnancy and Lactation

Information on the efficacy and safety of using the drug Eporatio during pregnancy and breastfeeding is not available.

Use in Hepatic Impairment

The use of the drug is contraindicated in patients with hepatic insufficiency.

Pediatric Use

The use of the drug is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

The use of the drug is contraindicated in patients over 75 years of age.

Special Precautions

For all patients with serum ferritin levels less than 100 µg/l or transferrin saturation less than 20%, additional treatment with iron preparations is recommended. To ensure effective erythropoiesis, iron status should be carefully assessed in each patient before and during therapy. Lack of effect during therapy with Eporatio should be considered a basis for searching for other etiopathogenetic factors of anemia development. Therefore, before starting treatment, it is necessary to exclude cyanocobalamin and folic acid deficiency, which can reduce the effectiveness of epoetins.

The erythropoietic response may also be weakened by intercurrent infections, inflammatory processes or injuries, occult blood loss, hemolysis of red blood cells, aluminum intoxication, occult hematological disorders, or bone marrow fibrosis.

If the most common causes of lack of erythropoietic response are excluded, and a sharp decrease in Hb concentration associated with reticulocytopenia is detected in a patient, testing for anti-erythropoietin antibodies and a bone marrow examination should be performed for differential diagnosis with PRCA, which is an indication for discontinuation of treatment with Eporatio. Cases have been described where PRCA was caused by the neutralizing effect of anti-erythropoietin antibodies associated with therapy with Eporatio. It has been shown that these antibodies cross-react with all epoetins, therefore, patients with suspected or confirmed presence of neutralizing antibodies should not use Eporatio.

During therapy with Eporatio, patients may experience an increase in BP, especially at the initial stage of treatment. BP should be monitored before and during therapy to avoid acute complications such as hypertensive crisis with symptoms of encephalopathy (headache, confusion, speech impairment, gait disturbance) and associated complications (seizures), which can also occur in patients with both normal and low BP. Particular attention should be paid to sudden acute migraine-like headache as a possible warning signal.

An increase in BP may require treatment with antihypertensive drugs or an increase in their dose. If BP remains high, temporary discontinuation of therapy with Eporatio may be required. After stabilization and successful control of BP, therapy with Eporatio should be restarted at a reduced dose.

Incorrect use of Eporatio in healthy individuals may lead to an excessive increase in Hb concentration and hematocrit, which can cause life-threatening cardiovascular complications.

Due to limited clinical experience, the efficacy and safety of Eporatio have not been established in patients with impaired liver function or homozygous sickle cell anemia.

In clinical studies in patients over 75 years of age, a higher frequency of serious and severe adverse events was observed, regardless of causal relationships with Eporatio therapy. Furthermore, fatal outcomes were more frequent in this patient group compared to younger patients.

Anemia associated with CRF, including in patients on hemodialysis

The possibility of using Eporatio in patients with nephrosclerosis not undergoing dialysis should be determined individually, as possible accelerated development of renal failure cannot be excluded.

During hemodialysis, patients taking Eporatio may require an increased dose of anticoagulant to prevent arteriovenous shunt thrombosis.

In patients with CRF, the Hb concentration in the stabilization phase should not exceed the upper limit of the Hb concentration recommended in the “Dosage Regimen” section. In clinical studies, increased mortality and serious cardiovascular complications were observed when epoetins were administered to patients with an Hb concentration of more than 12 g/dl (7.45 mmol/l).

Anemia in patients with non-myeloid tumors receiving chemotherapy

Erythropoietins are growth factors that primarily stimulate the production of red blood cells. Erythropoietin receptors may be expressed on the surface of various tumor cells. As with any growth factor, there is a concern that erythropoietins may stimulate the growth of malignant neoplasms of any type.

A number of controlled clinical studies of epoetins in patients with cancer-associated anemia have not demonstrated an increase in overall survival or a reduction in the risk of tumor progression. According to controlled clinical studies, the use of epoetins may lead

• To a reduction in the time to tumor progression in patients with head and neck cancer receiving radiation therapy, when achieving a target Hb concentration of more than 14 g/dl (8.69 mmol/l);
• To a reduction in overall survival and an increase in the number of deaths associated with disease progression within 4 months from the start of treatment in patients with metastatic breast cancer receiving chemotherapy, when achieving a target Hb concentration from 12 to 14 g/dl (from 7.45 to 8.69 mmol/l);
• To an increased risk of death in patients with active malignant tumor not receiving chemotherapy and radiation therapy, when achieving a target Hb concentration of 12 g/dl (7.45 mmol/l).

The drug Eporatio is contraindicated for use in these patients.

Based on the above, in some clinical situations, blood transfusion is preferable for the treatment of anemia in patients with cancer.

The decision to use recombinant erythropoietins should be based on an assessment of the expected benefit to possible risk for the individual patient, taking into account the specific clinical picture.

Effect on the ability to drive vehicles and operate machinery

The drug Eporatio does not have a significant effect on the ability to drive vehicles and perform potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms the therapeutic index of Eporatio is very wide, however, the individual response to therapy at the beginning of treatment should be taken into account. An excessive pharmacodynamic response is possible, i.e., polycythemia with life-threatening cardiovascular complications.

Treatment in case of polycythemia, therapy with Eporatio is discontinued. If necessary, phlebotomy is performed.

Drug Interactions

Based on the data obtained to date, no interaction of epoetin theta with other drugs has been identified.

To avoid incompatibility or reduced activity, Epoetin theta should not be mixed with other drugs or injectable solutions.

Storage Conditions

The drug should be stored out of the reach of children at a temperature of 2 to 8°C (46.4°F).

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

EPOR-RU-00046-DOK

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.