Prescribing Information of Recormon

Indications / Uses of Recormon

• Erythropoietin available for use as therapeutic agents are produced by recombinant DNA technology in cell culture, and include Epogen/Procrit (epoetin alfa) and Aranesp (darbepoetin alfa); they are used in treating anemia resulting from chronic kidney disease, chemotherapy-induced anemia in patients with cancer, inflammatory bowel disease (Crohn’s disease and ulcerative colitis) and myelodysplasia from the treatment of cancer (chemotherapy and radiation).
• The package inserts include boxed warnings of increased risk of death, myocardial infarction, stroke, venous thromboembolism, and tumor recurrence, particularly when used to increase the hemoglobin levels to more than 11 g/dL to 12 g/dL.
• Treatment of anemia associated with chronic renal failure (renal anemia) in patients on dialysis.

Treatment of symptomatic renal anemia in patients not yet undergoing dialysis.

• Prevention of anemia of prematurity in infants with a birth weight of 750g to 1500 g and gestational age of fewer than 34 weeks.
• Treatment of anemia in adult patients with solid tumors and treated with platinum-based chemotherapy prone to induce anemia (cisplatin: 75 mg/m²/cycle; carboplatin: 350 mg/m²/cycle).
• Treatment of symptomatic anemia in adult patients with multiple myeloma, low-grade non-Hodgkin’s lymphoma or chronic lymphocytic leukemia, who have a relative erythropoietin deficiency and are receiving anti-tumor therapy. Deficiency is defined as an inappropriately low serum erythropoietin level in relation to the degree of anemia.
• Increasing the yield of autologous blood from patients in a pre-donation program.
• Its use in this indication must be balanced against the reported increased risk of thromboembolic events. Treatment should only be given to patients with moderate anemia (Hb 10 to 13 g/dl [6.21 to 8.07 mmol/l], no iron deficiency) if blood conserving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units of blood for females or 5 or more units for males).

Dosage / Direction for Use of Recormon

• Therapy with Recormon should be initiated by physicians experienced in the previously mentioned indications. As anaphylactoid reactions were observed in isolated cases, it is recommended that the first dose be administered under medical supervision.
• Substitution by any other biological medicinal product requires the consent of the prescribing physician. The Recormon pre-filled syringe is ready for use. Under no circumstances should more than one dose be administered per syringe; the medicinal product is for single use only (see Special Instructions for Use, Handling and Disposal under Cautions for Usage).

• The solution can be administered subcutaneously or intravenously. In the case of intravenous administration, the solution should be injected over approximately 2 minutes, e.g. in hemodialysis patients via the arteriovenous fistula at the end of dialysis. For non-hemodialysis patients, subcutaneous administration should always be preferred in order to avoid puncture of peripheral veins.
• In CKD patients, the aim of treatment is to reach a target Hb level of 10-12 g/dl). A Hb level of 12 g/dl should not be exceeded. If the rise in hemoglobin is greater than 2 g/dl (1.3 mmol/l) in 4 weeks, an appropriate dose reduction 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. Patients should be monitored closely to ensure that the lowest dose of Recormon is used to provide adequate control of the symptoms of anemia.

Treatment with Recormon is divided into two stages

Correction phase:  Subcutaneous administration

• The initial dosage is 3 x 20 IU/kg body weight per week. The dosage may be increased every 4 weeks by 3 x 20 IU/kg per week if the increase of Hb is not adequate (< 0.25 g/dl per week). The weekly dose can also be divided into daily doses.

Intravenous administration

• The initial dosage is 3 x 40 IU/kg per week. The dosage may be raised after 4 weeks to 80 IU/kg – three times per week- and by further increments of 20 IU/kg if needed, three times per week, at monthly intervals.
  For both routes of administration, the maximum dose should not exceed 720 IU/kg per week.

Maintenance phase

• To maintain a target Hb value of approximately 10-12 g/dl, the dosage is initially reduced to half of the previously administered amount. Subsequently, the dose is adjusted at intervals of two to four weeks individually for the patient (maintenance dose).
• In the case of subcutaneous administration, the weekly dose can be given as one injection per week or in divided doses three or seven times per week. Patients who are stable on a once-weekly dosing regimen may be switched to once every two weeks of administration. In this case dose increases may be necessary.
• Treatment with Recormon is normally a long-term therapy. It can, however, be interrupted, if necessary, at any time. Data on the once-weekly dosing schedule are based on clinical studies with a treatment duration of 24 weeks.

Prevention of anemia of prematurity:

• The solution is administered subcutaneously at a dose of 3 x 250 IU/kg body weight per week. Recormon treatment should start as early as possible, preferably by day 3 of life. Premature infants who have received a transfusion before starting Recormon treatment are not likely to benefit as much as infants who have not had a transfusion. The treatment should last for 6 weeks.

Treatment of symptomatic anemia in cancer patients receiving chemotherapy

• The solution is administered subcutaneously; 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 the average weighted patient).
• Recormon treatment is indicated if the hemoglobin value is ≤ 11g/dl (6.83 mmol/l). Hemoglobin levels should not exceed 13 g/dl (8.07 mmol/l) (see Pharmacology: Pharmacodynamics: Clinical / Efficacy Studies under Actions).
  If, after 4 weeks of therapy, the hemoglobin has increased by at least 1 g/dl (0.62 mmol/l), the current dose should be continued. If the hemoglobin 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 hemoglobin value has not been increased by at least 1 g/dl (0.62 mmol/l), responses are 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 hemoglobin at that level. If required, further dose reduction may be instituted to ensure that hemoglobin level does not exceed 13 g/dl.
  If the rise in hemoglobin is greater than 2 g/dl (1.3 mmol/l) in 4 weeks, the dose should be reduced by 25 to 50%.

Treatment for increasing the amount of autologous blood

• The solution is administered intravenously over approximately 2 minutes, or subcutaneously.
  Recormon is administered twice weekly for over 4 weeks. On those occasions where the patient’s PCV allows blood donation, i.e. PCV ≥ 33%, Recormon 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 donated blood and the endogenous red cell reserve: The required amount of 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 predominated blood is expressed in units whereby one unit in the nomogram is equivalent to 180 ml red cells.
• 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 Recormon treatment and, if given, the single dose should be determined from the required amount of predominated 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.

Special Dosage Instructions: Pediatric use

• Results of pediatric clinical studies in children have shown that, on average, the younger the patients, the higher the Recormon doses required. Nevertheless, the recommended dosing schedule should be followed as the individual response cannot be predicted (see Use in Children under Precautions).

Geriatric use

• No dedicated studies in geriatric patients were performed. A large proportion of geriatric patients were included in clinical trials with Recormon. A need for special dose adjustments in the geriatric population was not identified.

Hepatic impairment

• No dedicated clinical trials were conducted in patients with hepatic impairment. No special dosage instructions are available.

Overdosage

• The therapeutic range of Recormon is a wide and individual response to therapy that must be considered when Recormon treatment is initiated. Overdose can result in manifestations of an exaggerated pharmacodynamic effect, e.g. excessive erythropoiesis which may be associated with life-threatening complications of the cardiovascular system. In the case of excessive hemoglobin levels, Recormon should be temporarily withheld (see Dosage & Administration). If clinically indicated, phlebotomy may be performed.

Contraindications of Recormon

• Recormon is contraindicated in patients with: Known hypersensitivity to the active substance or to any of the excipients.
  Poorly controlled hypertension.
• In the indication “increasing the yield of autologous blood”, Recormon must not be used in patients who, in the month preceding treatment, have suffered a myocardial infarction or stroke, patients with unstable angina pectoris, or patients who are at risk of deep venous thrombosis such as those with a history of venous thromboembolic disease.

Warnings

• Cancer: ESAs shortened overall survival and/or time to tumor progression in clinical studies in patients with breast, non-small cell lung, head, and neck, lymphoid and cervical cancers when dosed to target a hemoglobin of ≥12g/dl.
  The risks of shortened survival and tumor progression have not been excluded when ESAs are dosed to target a hemoglobin of <12g/dl.
• To minimize these risks, as well as the risk of serious cardio-and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusions.
• Use only for the treatment of anemia due to concomitant myelosuppressive chemotherapy.
  Discontinue following the completion of a chemotherapy course.

Special Precautions

• General, In order to improve the traceability of biological medicinal products, the trade name and the batch number of the administered product, should be clearly recorded (or stated) in the patient file.
• Recormon 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 Recormon.
• 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.
• Recormon contains phenylalanine as an excipient. Therefore this should be taken into consideration in patients affected with severe forms of phenylketonuria.
• The indication for Recormon 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.

Lack of Effect of Recormon

• The most common reasons for an incomplete response to ESAs are iron deficiency and chronic inflammation (e.g. due to uremia or advanced metastatic cancer). The following conditions may also compromise the effectiveness of
• ESAs therapy: chronic blood loss, bone marrow fibrosis, severe aluminum overload due to treatment of renal failure, folic acid or vitamin B12 deficiencies, and hemolysis. If all the conditions mentioned are excluded and the patient has a sudden drop of hemoglobin associated with reticulocytopenia and anti-erythropoietin antibodies, the examination of the bone marrow for the diagnosis of Pure Red Cell Aplasia (PRCA) should be considered. If PRCA is diagnosed, therapy with epoetin beta must be discontinued and patients should not be switched to another ESA.
  Pure red cell aplasia caused by neutralizing anti-erythropoietin antibodies has been reported in association with erythropoietin therapy, including Recormon.
• These antibodies have been shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have neutralizing antibodies to erythropoietin should not be switched to Recormon (see Adverse Reactions).

Effect on tumor growth

• Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumor cells. As with all growth factors, there is a concern that epoetins could stimulate the growth of any type of malignancy.
• A controlled clinical study in which epoetin beta was administered to patients with head and neck cancer, has shown a shorter locoregional progression-free survival in patients receiving epoetin beta. Another clinical study in breast cancer designed to show a positive effect of epoetin beta on overall survival compared to untreated controls, showed no statistically significant effects in terms of overall survival or tumor progression. Furthermore, meta-analysis data from randomized, controlled clinical studies with epoetin beta in the treatment of anemia in cancer patients did not show any statistically significant negative effects on survival or tumor progression.
• In CKD patients and patients with cancer receiving chemotherapy an increase in blood pressure (hypertensive episodes) or aggravation of existing hypertension, especially in cases of rapid Hb increase can occur. Increases in blood pressure can be treated with antihypertensive drugs. If blood pressure rises cannot be controlled by drug therapy, transient interruption of Recormon therapy is recommended. Particularly at the beginning of therapy, regular monitoring of the blood pressure is recommended, including between dialyzes in patients with renal anemia. In patients with CKD, a hypertensive crisis with encephalopathy-like symptoms may also occur in individual patients with otherwise normal or low blood pressure. This requires 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.
• Severe aluminum overload due to the treatment of renal failure may compromise the effectiveness of Recormon.
  In CKD patients an increase in heparin dose during hemodialysis is frequently required during the course of therapy with Recormon as a result of the increased Hb. The occlusion of the dialysis system is possible if heparinization is not optimal. Early shunt revision and thrombosis prophylaxis by the administration of acetylsalicylic acid, for example, should be considered in CKD patients at risk of shunt thrombosis.
• In CKD patients there may be a moderate dose-dependent rise in the platelet count within the normal range during treatment with Recormon, 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.
• In patients in an autologous blood pre-donation 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 Recormon should be discontinued.
• For use of Recormon in an autologous pre-donation program, the official guidelines on principles of blood donation must be considered, in particular: only patients with a PCV ≥ 33 % (hemoglobin ≥ 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.
  In patients treated for anemia of prematurity, there may be a slight rise in platelet counts, particularly up today 12 – 14 of life, therefore platelets should be monitored regularly.
• Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported in association with epoetin treatment.
• More severe cases have been observed with long-acting epoetins. At the time of prescription, patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, Recormon should be withdrawn immediately and an alternative treatment considered. If the patient has developed a severe cutaneous skin reaction such as SJS or TEN due to the use of Recormon, treatment with Recormon must not be restarted in this patient at any time.

Laboratory tests

• Platelet counts and hematocrit/hemoglobin levels should be monitored at regular intervals in all patients.
• In patients with chronic kidney disease, serum potassium elevation has been reported in patients receiving Recormon, though causality has not been established. If an elevated or rising potassium level is observed then consideration should be given to interrupting Recormon administration until the level has been corrected.

Drug Abuse and Dependence

• Misuse by non-anemic persons may lead to an excessive increase in Hb. This may be associated with life-threatening complications of the cardiovascular system.
  There are no reports on dependence when using epoetin beta.

Ability to Drive and Use Machines

Recormon has no or negligible influence on the ability to drive and use machines.

• Renal Impairment.
• Hepatic Impairment.

Use in Children

• Clinical registration trials have been performed in children and adolescents with anemia due to chronic kidney disease and in neonates for the prevention of anemia due to prematurity.
  In the indication anemia due to chronic kidney disease, Recormon should not be used in infants (i.e. below 2 years of age) (see Special Dosage Instructions under Dosage & Administration, General as previously mentioned).
  In the indications anemia in cancer patients receiving chemotherapy and treatment for increasing the amount of autologous blood, Recormon is not indicated in the pediatric population.

Use in Elderly

• Use In Pregnancy & Lactation

• Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development (see Pharmacology: Toxicology: Nonclinical Safety under Actions).
• For epoetin beta, all safety information with regard to exposure to Recormon during pregnancies has 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 Recormon. However, in the absence of clinical study data, caution should be exercised when prescribing to pregnant women.

• Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development (see Pharmacology: Toxicology: Nonclinical Safety under Actions).
• For epoetin beta, all safety information with regard to exposure during labor and delivery has been gained from post-marketing experience. No evidence of harmful effects with respect to labor and delivery have been observed. However, in the absence of clinical study data, caution should be exercised when prescribing to pregnant women in labor.

Lactation

• Only limited experience in human lactation has been gained. Endogenous erythropoietin is excreted in breast milk and readily absorbed by neonatal gastrointestinal tract. A decision on whether to continue or discontinue breastfeeding or to continue or discontinue therapy with epoetin beta should be made taking into account the benefit of breastfeeding to the child and the benefit of epoetin beta therapy to the woman.

Clinical / Efficacy Studies

Not applicable.

Elimination 

• Pharmacokinetic investigations in healthy volunteers and uremic patients show that the half-life of intravenously administered epoetin beta is between 4 and 12 hours.
• After subcutaneous administration of epoetin beta to uremic patients, the terminal half-life is higher than after intravenous administration, with an average of 13 – 28 hours.

References