CinnaPoietin®


(Erythropoietin β)

Provide RBC; Provide Life


Description

Epoetin beta rch (recombinant human erythropoietin)

CAS registry number: 122312-54-3

CinnaPoietin® (epoetin beta rch) is a sterile, purified, stable recombinant human erythropoietin concentrate produced from genetically engineered Chinese hamster ovary (CHO) cells containing a cloned human erythropoietin gene.

The active ingredient, epoetin beta rch, is a highly purified glycoprotein, identical in amino acid sequence to endogenous erythropoietin, with a mean molecular weight of approximately 30kDa. Epoetin beta rch is 98% pure, with no detectable cell line residues.

CinnaPoietin® is available in pre-filled syringes containing the excipients urea, sodium chloride, sodium phosphate - monobasic, sodium phosphate - dibasic, calcium chloride, polysorbate 20, glycine, leucine, isoleucine, threonine, glutamic acid and phenylalanine.

 

Dosage Forms and Strengths

CinnaPoietin® is available as pre-filled syringes in the following strengths:

  • 2,000 IU
  • 4,000 IU
  • 10,000 IU

Indication and Usage

  1. Treatment of anemia associated with chronic kidney disease in adults and children on dialysis and symptomatic patients who have not undergone dialysis yet.
  2. Prevention of anemia of prematurity in infants with a birth weight of 750 gr to 1500 gr and a gestational age of less than 34 weeks.
  3. Treatment of anemia and reduction of transfusion requirements in adult patients with non-myeloid malignancies who are receiving chemotherapy, when the chemotherapy stops the bone marrow producing enough blood cells.
  4. It can also be used in patients who are going to have an operation and donate their own blood before surgery (autologous blood transfusion) to increase the amount of blood that can be taken.

Dosage and Administration

2.1 administration

  • Administer subcutaneously or intravenously infusion.
  • Do not administer as an intravenous push or bolus.
  • Premedicate before each infusion.
  • Therapy with CinnaPoietin® should be initiated by physicians experienced in the above mentioned indications. As anaphylactoid reactions were observed in isolated cases, it is recommended that the first dose be administered under medical supervision.
  • Incompatibilities: In the absence of compatibility studies, CinnaPoietin® should not be mixed with other medicinal products.
  • Remove the cap from the syringe and affix the needle provided. Only solutions which are clear or slightly opalescent, colourless and practically free of visible particles should be injected. CinnaPoietin® pre-filled syringes are sterile but do not contain preservatives. Product is for single use in one patient only.

2.2 The recommended dose for Treatment of symptomatic anemia in adult and paediatric chronic renal failure patients

Anemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a physician’s evaluation of the individual patient’s clinical course and condition is necessary.

CinnaPoietin® should be administered either subcutaneously or intravenously in order to increase haemoglobin to not greater than 12 g/dl (7.5 mmol/l). Subcutaneous use is preferable in patients who are not receiving haemodialysis to avoid puncture of peripheral veins. In case of intravenous administration, the solution should be injected over approx. 2 minutes, e.g. in haemodialysis patients via the arterio-venous fistula at the end of dialysis.

Due to intra-patient variability, occasional individual haemoglobin values for a patient above and below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed through dose management, with consideration for the haemoglobin target range of 10 g/dl (6.2 mmol/l) to 12 g/dl (7.5 mmol/l). A sustained haemoglobin level of greater than 12 g/dl (7.5 mmol/l) should be avoided; guidance for appropriate dose adjustment for when haemoglobin values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.

A rise in haemoglobin of greater than 2 g/dl (1.25 mmol/l) over a four week period should be avoided.

If it occurs, appropriate dose adjustment should be made as provided. If the rate of rise in haemoglobin is greater than 2 g/dl (1.25 mmol/l) in one month or if the haemoglobin level is increasing and approaching 12 g/dl (7.45 mmol/l), the dose is to be reduced by approximately 25 %. If the haemoglobin level continues to increase, therapy should be interrupted until the hemoglobin level begins to decrease, at which point therapy should be restarted at a dose approximately 25 % below the previously administered dose.

Patients should be monitored closely to ensure that the lowest approved effective dose of CinnaPoietin® is used to provide adequate control of the symptoms of anemia whilst maintaining a haemoglobin concentration below or at 12g/dl (7.45mmol/l).

Caution should be exercised with escalation of CinnaPoietin® doses in patients with chronic renal failure. In patients with a poor haemoglobin response to CinnaPoietin®, alternative explanations for the poor response should be considered.

In the presence of hypertension or existing cardiovascular, cerebrovascular or peripheral vascular diseases, the weekly increase in Hb and the target Hb should be determined individually taking into account the clinical picture.

Treatment with CinnaPoietin® is divided into two stages.

  1. Correction phase

Subcutaneous administration:

The recommended starting dose is 60 IU/kg body weight/week, administered as a single weekly injection or in up to 7 divided doses. The dose may be increased every 4 weeks by 60 IU/kg body weight/week if the hemoglobin increase is not adequate (Hb < 0.15 g/dL per week).

Intravenous administration:

The initial dose is 120 IU/kg body weight/week, administered in 3 divided doses. The dose may be raised after 4 weeks to 240 IU/kg body weight/week. If further increments are needed they should be at 60 IU/kg body weight/week, at monthly intervals.

For both routes of administration, the maximum dose should not exceed 720 IU/kg per week.

  1. Maintenance phase

To maintain an Hb of between 10 and 12 g/dl, the dosage is initially reduced to half of the previously administered amount. Subsequently, the dose is adjusted at intervals of one or two weeks individually for the patient (maintenance dose).

The dose that mentioned above, is due to first approval of drug. Today the initial dose of epoetin beta is similar to epoetin alfa that consider by KDIGO guideline. Epoetin-alfa or epoetin-beta dosing usually starts at 20 to 50 IU/kg body weight three times a week.

 

2.3 The recommended dose for Treatment of symptomatic chemotherapy-induced anemia in cancer patients

CinnaPoietin® should be administered by the subcutaneous route to patients with anemia (e.g. haemoglobin concentration ≤ 10g/dl (6.2 mmol/l)). Anemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a physician’s evaluation of the individual patient’s clinical course and condition is necessary.

The weekly dose can be given as one injection per week or in divided doses 3 to 7 times per week.

The recommended initial dose is 30,000 IU per week (corresponding to approximately 450 IU/kg body weight per week, based on an average weighted patient).

Due to intra-patient variability, occasional individual haemoglobin values for a patient above and below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed through dose management, with consideration for the haemoglobin target range of 10 g/dl (6.2 mmol/l) to 12 g/dl (7.5 mmol/l). A sustained haemoglobin level of greater than 12 g/dl (7.5 mmol/l) should be avoided; guidance for appropriate dose adjustment for when haemoglobin values exceeding 12 g/dl (7.5 mmol/l) are observed are described below.

If, after 4 weeks of therapy, the haemoglobin value has increased by at least 1 g/dl (0.62 mmol/l), the current dose should be continued. If the haemoglobin value has not increased by at least 1 g/dl (0.62 mmol/l), a doubling of the weekly dose should be considered. If, after 8 weeks of therapy, the haemoglobin value has not increased by at least 1 g/dl (0.62 mmol/l), response is unlikely and treatment should be discontinued.

The therapy should be continued up to 4 weeks after the end of chemotherapy.

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

Once the therapeutic objective for an individual patient has been achieved, the dose should be reduced by 25 to 50 % in order to maintain haemoglobin at that level. Appropriate dose titration should be considered.

If the haemoglobin exceeds 12 g/dl (7.5 mmol/l), the dose should be reduced by approximately 25 to 50 %. Treatment with CinnaPoietin® should be temporarily discontinued if haemoglobin levels exceed 13 g/dl (8.1 mmol/l). Therapy should be reinitiated at approximately 25 % lower than the previous dose after haemoglobin levels fall to 12 g/dl (7.5 mmol/l) or below.

If the rise in haemoglobin is greater than 2 g/dl (1.3 mmol/l) in 4 weeks, the dose should be reduced by 25 to 50 %.

Patients should be monitored closely to ensure that the lowest approved dose of CinnaPoietin® is used to provide adequate control of the symptoms of anemia.

2.4 The recommended dose for increasing the amount of autologous blood

The reconstituted solution is administered intravenously over approx. 2 minutes or subcutaneously.

CinnaPoietin® is administered twice weekly over 4 weeks. On those occasions where the patient's PCV allows blood donation, i.e. PCV ≥ 33 %, CinnaPoietin® is administered at the end of blood donation.

During the entire treatment period, a PCV of 48 % should not be exceeded.

The dosage must be determined by the surgical team individually for each patient as a function of the required amount of pre-donated blood and the endogenous red cell reserve:

  1. The required amount of pre-donated blood depends on the anticipated blood loss, use of blood conserving procedures and the physical condition of the patient.

This amount should be that quantity which is expected to be sufficient to avoid homologous blood transfusions.

The required amount of pre-donated blood is expressed in units whereby one unit in the nomogram is equivalent to 180 ml red cells.

  1. The ability to donate blood depends predominantly on the patient's blood volume and baseline PCV. Both variables determine the endogenous red cell reserve, which can be calculated according to the following formula.

Endogenous red cell reserve = blood volume [ml] x (PCV - 33) ÷ 100

Women: blood volume [ml] = 41 [ml/kg] x body weight [kg] + 1200 [ml]

Men: blood volume [ml] = 44 [ml/kg] x body weight [kg] + 1600 [ml] (body weight ≥ 45 kg)


The indication for CinnaPoietin® treatment and, if given, the single dose should be determined from the required amount of pre-donated blood and the endogenous red cell reserve according to the following graphs.

The single dose thus determined is administered twice weekly over 4 weeks. The maximum dose should not exceed 1600 IU/kg body weight per week for intravenous or 1200 IU/kg per week for subcutaneous administration.

2.5 Recommended concomitant medications

Not applicable

2.6 Preparation for administration

  • CinnaPoietin® therapy is started by a doctor who is an expert on your condition. The first dose is usually given to you under medical supervision, because of the possibility of an allergic reaction.
  • CinnaPoietin® injections can then be given by a trained nurse, doctor or other professional.
  • To avoid the risk of cross-infection always follow aseptic techniques and use disposable sterile syringes and needles to administer each dose.
  • Do not mix CinnaPoietin® with other injections or infusion solutions.
  • Use only plastic materials for injection.
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use Syringe if particulates or discoloration is present. Only solutions which are clear or slightly opalescent, colorless and practically free of visible particles should be injected.
  • Discard any unused portion left in the syringe.
  • Remove the cap from the syringe and affix the needle provided.
  • CinnaPoietin® pre-filled syringes are sterile but do not contain preservatives.
  • Product is for single use in one patient only.

Instructions for use

First wash your hands!

1. Remove one syringe from the pack and check that the solution is clear, colourless and practically free from visible particles. Remove the cap from the syringe.

2. Remove one needle from the pack, fix it on the syringe and remove the protective cap from the needle.

3. Clean the skin at the site of injection using an alcohol wipe. Form a skin fold by pinching the skin between thumb and forefinger. Hold the syringe barrel near to the needle, and insert the needle into the skin fold with a quick, firm action. Inject the CinnaPoietin® solution. Withdraw the needle quickly and apply pressure over the injection site with a dry, sterile pad.

This medicinal product is for single use only. Any unused product or waste material should be disposed of in accordance with local requirements.

Contraindications

  • Hypersensitivity to the active substance or any of the excipients.
  • Poorly controlled hypertension.
  • In the indication "increasing the yield of autologous blood": myocardial infarction or stroke in the month preceding treatment, unstable angina pectoris, and increased risk of deep venous thrombosis such as history of venous thromboembolic disease.

Warning and Precautions

  • 5.1 infusion reactions

    CinnaPoietin® should be used with caution in the presence of refractory anemia with excess blasts in transformation, epilepsy, thrombocytosis, and chronic liver failure. Folic acid and vitamin B12 deficiencies should be ruled out as they reduce the effectiveness of CinnaPoietin®.

    Caution should be exercised with escalation of CinnaPoietin® doses in patients with chronic renal failure since high cumulative epoetin doses may be associated with an increased risk of mortality, serious cardiovascular and cerebrovascular events. In patients with a poor haemoglobin response to epoetins, alternative explanations for the poor response should be considered.

    In order to ensure effective erythropoiesis, iron status should be evaluated for all patients prior to and during treatment and supplementary iron therapy may be necessary and conducted in accordance with therapeutic guidelines.

    Severe aluminium overload due to treatment of renal failure may compromise the effectiveness of CinnaPoietin®.

    The indication for CinnaPoietin® treatment of nephrosclerotic patients not yet undergoing dialysis should be defined individually, as a possible acceleration of progression of renal failure cannot be ruled out with certainty.

    A paradoxical decrease in haemoglobin and development of severe anemia associated with low reticulocyte counts should prompt to discontinue treatment with epoetin and perform anti-erythropoietin antibody testing.

    5.2 In patients with chronic renal failure

    In chronic renal failure patients an increase in blood pressure or aggravation of existing hypertension, especially in cases of rapid PCV increase can occur. These increases in blood pressure can be treated with medicinal products. If blood pressure rises cannot be controlled by drug therapy, a transient interruption of CinnaPoietin® therapy is recommended. Particularly at beginning of therapy, regular monitoring of the blood pressure is recommended, including between dialyses. Hypertensive crisis with encephalopathy-like symptoms may occur and require the immediate attention of a physician and intensive medical care. Particular attention should be paid to sudden stabbing migraine like headaches as a possible warning sign.

    In chronic renal failure patients there may be a moderate dose-dependent rise in the platelet count within the normal range during treatment with CinnaPoietin®, especially after intravenous administration. This regresses during the course of continued therapy. It is recommended that the platelet count be monitored regularly during the first 8 weeks of therapy.

    5.3 Haemoglobin concentration

    In patients with chronic renal failure, maintenance haemoglobin concentration should not exceed the upper limit of the target haemoglobin concentration recommended in section 2.2.

    5.4 Effect on tumour growth

    Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, there is a concern that epoetins could stimulate the growth of tumours.

    In view of the above, in some clinical situations blood transfusion should be the preferred treatment for the management of anemia in patients with cancer. The decision to administer recombinant erythropoietins should be based on a benefit-risk assessment with the participation of the individual patient, which should take into account the specific clinical context. Factors that should be considered in this assessment should include the type of tumour and its stage; the degree of anemia; life expectancy; the environment in which the patient is being treated; and patient preference.

    There may be an increase in blood pressure which can be treated with drugs. It is therefore recommended to monitor blood pressure, in particular in the initial treatment phase in cancer patients.

    Platelet counts and haemoglobin level should also be monitored at regular intervals in cancer patients.

    5.5 In patients in an autologous blood predonation program

    There may be an increase in platelet count, mostly within the normal range. Therefore, it is recommended that the platelet count be determined at least once a week in these patients. If there is an increase in platelets of more than 150 x 109/l or if platelets rise above the normal range, treatment with CinnaPoietin® should be discontinued.

    5.6 In chronic renal failure patients

    An increase in heparin dose during haemodialysis is frequently required during the course of therapy with CinnaPoietin® as a result of the increased packed cell volume. Occlusion of the dialysis system is possible if heparinisation is not optimum.

    Early shunt revision and thrombosis prophylaxis by administration of acetylsalicylic acid, for example, should be considered in chronic renal failure patients at risk of shunt thrombosis.

    Serum potassium and phosphate levels should be monitored regularly during CinnaPoietin® therapy. Potassium elevation has been reported in a few uraemic patients receiving CinnaPoietin®, though causality has not been established. If an elevated or rising potassium level is observed then consideration should be given to ceasing CinnaPoietin® administration until the level has been corrected.

    For use of CinnaPoietin® in an autologous predonation program, the official guidelines on principles of blood donation must be considered, in particular:

    - Only patients with a PCV ≥ 33 % (haemoglobin ≥ 11 g/dl [6.83 mmol/l]) should donate;

    - Special care should be taken with patients below 50 kg weight;

    - The single volume drawn should not exceed approx. 12 % of the patient's estimated blood volume.

    Treatment should be reserved for patients in whom it is considered of particular importance to avoid homologous blood transfusion taking into consideration the risk/benefit assessment for homologous transfusions.

    Misuse by healthy persons may lead to an excessive increase in packed cell volume. This may be associated with life-threatening complications of the cardiovascular system.

    This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium free”. In order to improve the traceability of ESAs, the name of the prescribed ESA should be clearly recorded (or: stated) in the patient file.

Adverse Reactions / Side Effects

  • Anemic patients with chronic renal failure

The most frequent adverse reaction during treatment with CinnaPoietin® is an increase in blood pressure or aggravation of existing hypertension, especially in cases of rapid PCV increase. Hypertensive crisis with encephalopathy-like symptoms (e.g. headaches and confused state, sensorimotor disorders - such as speech disturbance or impaired gait - up to tonoclonic seizures) may also occur in individual patients with otherwise normal or low blood pressure.

Shunt thromboses may occur, especially in patients who have a tendency to hypotension or whose arteriovenous fistulae exhibit complications (e.g. stenoses, aneurisms).

In case anti-erythropoietin antibody mediated PRCA is diagnosed, therapy with CinnaPoietin® must be discontinued and patients should not be switched to another erythropoietic protein.

The incidences of undesirable effects in clinical trials, considered related to treatment with Erythropoietin beta are shown in below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Vascular disorders:

Common (>1%, <10%): Hypertension, Headache.

Uncommon (>0.1%, <1%): Hypertensive crisis.

Nervous system disorders:

Common (>1%, <10%): Headache.

Blood and the lymphatic system disorders:

Common (> 1%): decrease of ferritin values and transferrin saturation.

Uncommon (>0.1%, <1%): vascular access thromboses in hypotensive patients or those with vascular access complications, increase in platelet count.

Rare (>0.01%, <0.1%): Shunt thrombosis.

Very rare (< 0.01%): thrombocytosis, transient increase in potassium and phosphate

 
  • Patients with cancer

Epoetin beta treatment-related headache and hypertension which can be treated with drugs are common (>1 %, <10 %).

In some patients, a fall in serum iron parameters observed.

Clinical studies have shown a higher frequency of thromboembolic events in cancer patients treated with Erythropoietin beta compared to untreated controls or placebo. In patients treated with Erythropoietin beta, this incidence is 7 % compared to 4 % in controls; this is not associated with any increase in thromboembolic mortality compared with controls.

The incidences of undesirable effects in clinical trials, considered related to treatment with Erythropoietin beta are shown in below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Vascular disorders:

Common (>1%, <10%): Hypertension

Blood and the lymphatic system disorders:

Common (>1%, <10%): Thromboembolic event

Nervous system disorders:

Common (>1%, <10%): Headache

 

  • Patients in an autologous blood predonation program

Patients in an autologous blood predonation program have been reported to show a slightly higher frequency of thromboembolic events. However, a causal relationship with treatment with CinnaPoietin® could not be established.

The incidences of undesirable effects in clinical trials, considered related to treatment with Erythropoietin beta are shown in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Headache Common (>1%, <10%)

  • Premature infants

A fall in serum ferritin values is very common (>10%)

  • All indications

In common (≥1/100 to <1/10):

Data from a controlled clinical trial with epoetin alfa or darbepoetin alfa, reported an incidence of stroke.

Rarely (≥1/10.000 to ≤1/1.000):

Epoetin beta treatment-related skin reactions such as rash, pruritus, urticaria or Injection site reactions may occur.

In very rare cases (≤1/10.000):

Epoetin beta treatment related anaphylactoid reactions have been reported. However, in controlled clinical studies no increased incidence of hypersensitivity reactions was found.

In very rare cases (≤1/10.000):

Particularly when starting treatment, epoetin beta treatment-related flulike symptoms such as fever, chills, headaches, pain in the limbs, malaise and/or bone pain have been reported. These reactions were mild or moderate in nature and subsided after a couple of hours or days.

Drug Interactions

Clinical results to date do not indicate any interaction with other substances.

Animal experiments revealed that epoetin beta does not increase the myelotoxicity of cytostatic medicinal products like etoposide, cisplatin, cyclophosphamide, and fluorouracil.

 

 

Overdosage

The therapeutic margin of CinnaPoietin® is very wide. Even at very high serum levels, no symptoms of poisoning have been observed.

Overdose can result in manifestations of an exaggerated pharmacodynamic effect e.g. excessive erythropoiesis, which may be associated with life-threatening complications to the cardiovascular system. In cases of excessive haemoglobin levels, CinnaPoietin® should be temporarily withheld. If clinically indicated, phlebotomy may be performed.

Use in Specific Populations

Pediatric use

Clinical trials have been performed in children and adolescents with anemia due to chronic kidney disease (CKD) and in neonates for prevention of anemia due to prematurity. For CKD, NEORECORMON should not be used in infants (i.e. below 2 years of age). NEORECORMON is not indicated for paediatric patients to increase autologous blood yield; nor for anemic paediatric patients with non-myeloid malignancies receiving chemotherapy.

Geriatric use

No dedicated studies in elderly patients have been performed.

Pregnancy and Lactation

Pregnancy

Pregnancy category: B

Epoetin beta rch was not teratogenic in rats and rabbits at doses of up to 3000 IU/kg/day I.V. when administered during the period of organogenesis. Epoetin beta rch caused post-implantation loss and decreased fetal weight in animals dosed prior to mating right through gestation at doses of 160 U/kg/day S.C. and above. Kinked tails were observed in rat pups and fetuses (from 160 U/kg S.C. upwards). These effects are thought to be related to the pharmacodynamic action of the drug.

All safety information with regards to exposure of Erythropoietin beta during pregnancy have been gained from post marketing experience. A review of the available post marketing data does not show evidence of a causal association between harmful effects with respect to pregnancy, embryonal/fetal development or postnatal development and treatment with CinnaPoietin®. However in the absence of clinical study data, caution should be exercised when prescribing to pregnant women.

Nursing mothers

Postnatal observations of the live offspring (F1 generation) of female rats treated with epoetin beta rch during gestation and lactation revealed no effect of epoetin beta rch at doses up to 1280 U/kg s.c. There were, however, decreases in body weight gain, eyelid opening, and delayed testicular descent and vaginal opening in the F1 fetuses at doses of 320 IU/kg s.c. and above.

Only limited experience in human lactation has been gained. Endogenous erythropoietin is excreted into breast milk but it is not known whether it is absorbed by the neonatal gastrointestinal tract in functional form. A decision on whether to continue or discontinue breast-feeding or to continue or discontinue therapy with CinnaPoietin® should be made taking into account the benefit of breast-feeding to the child and the benefit of CinnaPoietin® therapy to the woman.

Clinical Pharmacology

Mechanism of action

Epoetin beta’s protein sequence, biological activity and immunological reactivity were found to be indistinguishable from erythropoietin isolated from the urine of anemic patients. Its mechanism of action lies in the stimulation of erythropoiesis.

Erythropoietin is a glycoprotein that stimulates the formation of erythrocytes from its committed progenitors. It acts as a mitosis stimulating factor and differentiation hormone Epoetin beta, the active substance of CinnaPoietin®, is identical in its amino acid and carbohydrate composition to erythropoietin that has been isolated from the urine of anemic patients.

The biological efficacy of epoetin beta has been demonstrated after intravenous and subcutaneous administration in various animal models in vivo (normal and uraemic rats, polycythaemic mice, dogs).

After administration of epoetin beta, the number of erythrocytes, the Hb values and reticulocyte counts increase as well as the 59Fe-incorporation rate.

An increased 3H-thymidine incorporation in the erythroid nucleated spleen cells has been found in vitro (mouse spleen cell culture) after incubation with epoetin beta.

Investigations in cell cultures of human bone marrow cells showed that epoetin beta stimulates erythropoiesis specifically and does not affect leucopoiesis. Cytotoxic actions of epoetin beta on bone marrow or on human skin cells were not detected.

After single dose administration of epoetin beta no effects on behaviour or locomotor activity of mice and circulatory or respiratory function of dogs were observed.

 

 

Non-Clinical Toxicology

12.1 Single dose toxicity studies

In acute toxicity study performed in mice and single dose intravenous pilot study in beagle dogs no effect was observed with 6000 IU/kg BW. In acute toxicity study performed in rats (intravenous administration) accelerated erythropoiesis was seen from 3,000 IU/kg BW. The acute lethal dose in mice was found over 45,000 IU/kg and in guinea pigs over 14,000 IU/kg.

12.2 Repeated dose toxicity studies

Four week study in rats (subcutaneous administration) in order to investigate myelofibrosis in early stage and its relation with increase PCV showed an increase in hematopoiesis and hyperaemia of bone marrow.

In a 3-month S.C. test of Erythropoietin beta in dogs and rats, deaths were occurred in the middle and high dose groups attributed to renal and myocardial thrombosis. Drug-induced polycythemia was developed from the first week due to the high doses administrated. Antibodies were developed in some animals from each dose level. Severe but reversible myelofibrosis occurred. Bone marrow was the target in chronic toxicity studies both after I.V. and S.C. administration. In the 3-month I.V. study in dogs myelofibrosis was the only adverse effect in 7/10 animals after 3,000 IU/kg which often aggravated by osteosclerosis but did not influence the clinical or haematological parameters. It was concluded that development of myelofibrosis is dependent on the level of the PCV.

12.3 Reproductive function, embryo-fetal and perinatal toxicity

No reproductive risks were revealed in I.V. and S.C. reproductive toxicology studies of Erythropoietin beta in animals. The only finding observed was kinked tails. Polysorbate 20, an ingredient in the formulation of epoetin beta did not elicit any adverse effects in pregnant rats and is not responsible for the kinked tail malformation observed. Treatment of female rats with epoetin beta caused adverse effects in both the maternal and F1 generation.

12.4 Mutagenic potential

Epoetin beta did not exhibit any genotoxic potential in the Ames test and a micronucleus test. Neither gene mutations were triggered nor chromosome breakage recorded.

In an in vitro mammalian test conducted to amplify and complete the test battery, no evidence of mutagenic activity with Erythropoietin beta was shown either in the presence or the absence of metabolic activation. In an in vitro metaphase analysis in human lymphocytes, there was no indication in chromosomal damage either in the presence or the absence of metabolic activation.

It can be concluded that there is no evidence of either mutagenic or clastogenic activity with Erythropoietin beta administration.

12.5 Carcinogenic potential

The following studies were performed with Erythropoietin beta: Investigation of the carcinogenic potential of murine epoetin during long term administration in mice, effect of epoetin beta on proliferation and colony formation of human tumour cell lines in vitro and in vivo, as well as proliferation of human myeloma cells and a rat study in which implanted tumours were treated with cyclophosphamide and epoetin beta. These studies have demonstrated that epoetin beta has no tumourigenic potential, especially there was no influence on tumour progression.

12.6 Local tolerance

Reports on local intravenous or subcutaneous tolerance revealed no problems with intravenous or subcutaneous administration of epoetin beta in the applied formulations.

Clinical Studies

Not applicable

How Supplied / Storage and Handling

  • Storage Conditions
  • CinnaPoietin® must not be used after the expiry date.
  • Store in a refrigerator (2°C – 8°C).
  • Keep the pre-filled syringe in the outer carton, in order to protect from light.
  • For the purpose of ambulatory use, the patient may remove the product from the refrigerator and store it at room temperature (not above 25°C) for one single period of up to 3 days.
  • Disposal of Medicines
  • The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Unused or expired medicine should be returned to a pharmacy for disposal.
  • Disposal of syringes/sharps

The following points should be strictly adhered to regarding the use and disposal of the pre-filled syringe and medicinal sharps:

  • Needles and syringes should never be reused.
  • Place all used needles and syringes into a sharps container (puncture-proof disposable container).
  • Keep this container out of the reach of children.
  • Avoid placing used sharps containers in the household waste.
  • Dispose of the full container according to local requirements or as instructed by your healthcare provider.

 

 

Patients can be advised to get in touch with Orchid Pharmed Patient Support Center for asking any question or reporting any Adverse Drug event.

Phone: +982122382641

24/7 hotline: +989363094949

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