2010/09/21

Aranesp

Composition, structure and packing

Solution for injection transparent, colorless.

1 ml of 1 syringe (0.4 ml) of darbepoetin alfa (recombinant) 25 mcg 10 mcg.

Excipients: sodium dihydrogen phosphate monohydrate, sodium hydrophosphate, sodium chloride, polysorbate 80, water d / and. Solution for injection transparent, colorless.

1 ml of 1 syringe (0.375 ml) darbepoetin alfa (recombinant) 40 mcg 15 mcg.

Excipients: sodium dihydrogen phosphate monohydrate, sodium hydrophosphate, sodium chloride, polysorbate 80, water d / and.

Solution for injection transparent, colorless.

1 ml of 1 syringe (0.5 ml) of darbepoetin alfa (recombinant) 40 mcg 20 mcg.

Excipients: sodium dihydrogen phosphate monohydrate, sodium hydrophosphate, sodium chloride, polysorbate 80, water d / and.

Solution for injection transparent, colorless.

1 ml of 1 syringe (0.3 ml) of darbepoetin alfa (recombinant) 100 mcg 30 mcg.

Excipients: sodium dihydrogen phosphate monohydrate, sodium hydrophosphate, sodium chloride, polysorbate 80, water d / and.

Solution for injection transparent, colorless.

1 ml of 1 syringe (0.4 ml) of darbepoetin alfa (recombinant) 100 mcg 40 mcg.

Excipients: sodium dihydrogen phosphate monohydrate, sodium hydrophosphate, sodium chloride, polysorbate 80, water d / and.

Solution for injection transparent, colorless.

1 mL 1 syringe (0.5 ml) of darbepoetin alfa (recombinant) 100 ug 50 ug.

Excipients: sodium dihydrogen phosphate monohydrate, sodium hydrophosphate, sodium chloride, polysorbate 80, water d / and.

Solution for injection transparent, colorless.

1 ml of 1 syringe (0.3 ml) of darbepoetin alfa (recombinant) 200 mcg 60 mcg.

Excipients: sodium dihydrogen phosphate monohydrate, sodium hydrophosphate, sodium chloride, polysorbate 80, water d / and.

Solution for injection transparent, colorless.

1 ml of 1 syringe (0.4 ml) of darbepoetin alfa (recombinant) 200 mcg 80 mcg.

Excipients: sodium dihydrogen phosphate monohydrate, sodium hydrophosphate, sodium chloride, polysorbate 80, water d / and.

Solution for injection transparent, colorless.

1 ml of 1 syringe (0.5 ml) of darbepoetin alfa (recombinant) 200 mcg 100 mcg.

Excipients: sodium dihydrogen phosphate monohydrate, sodium hydrophosphate, sodium chloride, polysorbate 80, water d / and.

Solution for injection transparent, colorless.

1 ml of 1 syringe (0.3 ml) of darbepoetin alfa (recombinant) 500 mcg 150 mcg.

Excipients: sodium dihydrogen phosphate monohydrate, sodium hydrophosphate, sodium chloride, polysorbate 80, water d / and.

Solution for injection transparent, colorless.

1 ml of 1 syringe (0.6 ml) of darbepoetin alfa (recombinant) 500 mcg 300 mcg.

Excipients: sodium dihydrogen phosphate monohydrate, sodium hydrophosphate, sodium chloride, polysorbate 80, water d / and.

Solution for injection transparent, colorless.

1 ml of 1 syringe darbepoetin alfa (recombinant) 500 mcg 500 mcg.

Excipients: sodium dihydrogen phosphate monohydrate, sodium hydrophosphate, sodium chloride, polysorbate 80, water d / and.

Clinico-pharmacological group: stimulator of erythropoiesis.

Pharmacological action

Stimulator of hematopoiesis, antianemic drug. Darbepoetin alfa is produced using gene technology in the cells of Chinese hamster ovary (CHO-K1). Stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Darbepoetin alfa contains five N-linked carbohydrate chains, whereas the endogenous hormone and recombinant human erythropoietin (rhEPO) have only three chains. Additional sugar residues, with a molecular point of view, no different from those presented in the endogenous hormone.

Due to the increased carbohydrate content of darbepoetin alfa has a longer T1 / 2, compared with rhEPO, and consequently, greater activity in vivo. Despite these changes the molecular structure of darbepoetin alfa maintains a very narrow specificity to eritropoetinovomu receptor.

Pharmacokinetics

Due to the high carbohydrate concentration in the circulating blood of darbepoetin alfa than the minimum concentration required for stimulation of erythropoiesis over a longer time, compared with equivalent doses of rhEPO, which reduces the frequency of the introduction of darbepoetin alfa in maintaining an equivalent level of biological response.

Patients with chronic renal failure

Distribution Vd is roughly equivalent plasma volume (50 ml / kg). When s / c injection of the drug bioavailability was 37%. In clinical trials minimal accumulation of the drug was observed with any method of administration.

Withdrawal

T1 / 2 was 21 h (standard deviation (CO) 7.5) with a / in the introduction. Clearance of darbepoetin alfa - 1.9 ml / hr / kg (CO 0.56). With monthly s / c administration darbepoetin alfa at a dose of 0.6 to 2.1 mg / kg to T1 / 2 was 73 h (SB 24). Longer T1 / 2 darbepoetin alfa in n / a introduction, compared with a / c, due to the kinetics of absorption. In preclinical studies have demonstrated that the renal clearance of darbepoetin alfa is minimal (up to 2% of total clearance) and no effect on T1 / 2 of the drug from the serum. Route of administration does not affect the dose of darbepoetin alfa required to maintain the achieved hemoglobin.

Cancer patients receiving chemotherapy

Absorption

After sc injection of the drug at a dose of 2.25 mg / kg of adult cancer patients the mean Cmax darbepoetin alfa, amounting to 10.6 ng / ml (CO 5.9), achieved on average for 91 h (CO 19.7). These options are consistent with linear pharmacokinetics over a wide range of doses (from 0.5 to 8 mg / kg weekly dose and from 3 to 9 mg / kg of the introduction of 1 every 2 weeks).

Distribution and excretion

Pharmacokinetic parameters did not change after repeated administration for 12 weeks. (Weekly introduction or imposition of one every 2 weeks). It was expected a modest increase (<2-fold) serum concentration of the drug upon reaching the equilibrium state, but found no signs of accumulation in the re-appointment.

Pharmacokinetic studies were performed involving patients during chemotherapy-induced anemia, which in combination with chemotherapy n / a received injections of darbepoetin alfa at a dose of 6.75 mg / kg 1 every 3 weeks. In this study, the mean value of T1 / 2 was 74 h (SB 27).

Statement
treatment of anemia associated with chronic renal failure in adults and children 11 years and older;
treatment of symptomatic anemia in adult cancer patients with nemieloidnymi malignancies receiving chemotherapy.

Dosage regimen

Treatment with Aranesp should hold physicians with experience in its application according to testimony. Aranesp is supplied ready for use in pre-filled syringe (PZSH). Treatment of anemia in patients with chronic renal failure. Aranesp can enter n / a or / in. P / to the introduction preferable for patients not receiving hemodialysis, in order to avoid puncture of peripheral veins. The aim of therapy is to raise hemoglobin to a level above 110 g / liter. For each patient requires individual selection of the desired hemoglobin above 110 g / liter. Avoid raising hemoglobin more than 20 g / l for 4 weeks or hemoglobin above 140 g / liter.

Clinical studies have shown that an individual patient's response may be different. Nevertheless, in the initial stages should follow the recommendations below for adults and children alike, with further optimization of therapy depending on clinical indications.

Treatment with Aranesp includes two phases: phase correction and maintenance phase.

Phase correction

The initial dose s / c or / in the introduction of 0.45 mg / kg of body weight at a single weekly injection. Alternatively, for patients not receiving dialysis, allowed sc injection of the drug in an initial dose of 0.75 mg / kg of body weight every 2 weeks. If the increase in hemoglobin concentration is insufficient (less than 10 g / l for 4 weeks), dose increased approximately 25%. Increasing the dose should be no more than 1 time in 4 weeks.

If the concentration of hemoglobin increases by more than 25 g / l for 4 weeks, a dose of Aranesp should be reduced by 25-50% depending on the rate of increase of hemoglobin. If the hemoglobin exceeds 140 g / l therapy should be interrupted to reduce the hemoglobin below 130 g / l, and then resume the introduction of the drug in doses, decreased by approximately 25% relative to the previous one. Hemoglobin should be measured weekly or 1 every 2 weeks until it is stabilized. Subsequently, the hemoglobin can be evaluated periodically.

Maintenance phase

During the maintenance phase can be continued once weekly injection of the drug Aranesp, or go to the introduction of every two weeks. When transferring patients on dialysis, with weekly injection regime for introduction of a single dose every 2 weeks, the initial dose should be twice the dose, injected 1 time per week.

For patients not receiving dialysis, after reaching the desired concentration on the background of the drug every 2 weeks, its subcutaneous injection can be performed 1 time per month with the initial dose of twice the previous dose, injected once every 2 weeks. Titration of dose to maintain the desired hemoglobin concentration should be made as often as required.

For each patient requires individual selection of the desired hemoglobin above 110 g / liter. If you want to maintain the hemoglobin should be optimized dose of Aranesp, it is recommended to increase by approximately 25%.

If the observed increase in hemoglobin of more than 20 g / l for 4 weeks, dose should be reduced by approximately 25%, depending on the rate increase. If the hemoglobin exceeds 140 g / l, therapy should be interrupted to reduce the concentration below 130 g / l, and then resume the introduction of the drug at a dose of less than about 25% relative to the previous one. After any change in dose or mode of administration, the hemoglobin should be monitored every 1 or 2 weeks.

Changing the dose during the maintenance phase should be carried out not more than 1 time in 2 weeks.

If you change the route of administration of the drug should be used the same dose and monitor the concentration of hemoglobin every 1-2 weeks to maintain the required level of hemoglobin. Patients receiving weekly for 1, 2 or 3 injections of rhEPO can be transferred to a single mode of weekly administration Aranesp or the introduction of 1 every 2 weeks. The initial weekly dose of Aranesp (ug / week) is determined by dividing the total weekly dose of rhEPO (IU / week) at 200.

The starting dose of Aranesp (mg / in 2 weeks) during the regime introduced on 1 every 2 weeks is determined by dividing the total cumulative dose of rhEPO, introduced the two-week period, at 200. Given the well-known individual variability, for individual patients may need to titrate doses to obtain optimal therapeutic effect.

At replacement of rhEPO on the drug Aranesp measurement of hemoglobin level should be performed at least 1 time a week or 2 weeks, and the way the drug should remain unchanged. Treatment of symptomatic anemia in cancer patients with Aranesp should be administered sc in patients with hemoglobin ≤ 110 g / liter. The recommended initial dose is 500 mcg (6.75 mg / kg), the introduction of 1 every 3 weeks.

If clinical response is inadequate after 9 weeks (fatigue, hemoglobin content), further therapy may be ineffective. Alternatively, a weekly drug can be administered in a dose of 2.25 mg / kg body weight.

The use of Aranesp stopped after about 4 weeks after completion of chemotherapy. The content of hemoglobin should not exceed 130 g / liter. After achieving the target hemoglobin level dose should be reduced by 25-50% to maintain hemoglobin at an appropriate level.

If necessary, may further reduce the dose to prevent the increase in hemoglobin concentration over 130 g / liter. If the rate of increase of hemoglobin exceeds 20 g / l for 4 weeks, the dose should be reduced by 25-50%.

Rules injection

To make the s / c injection is required: a new pre-filled syringe containing Aranesp and moistened with alcohol swabs or similar materials.

Pre-injections of Aranesp
Pre-filled syringe from the refrigerator, not shaken.
Check that the dose of the drug in pre-filled syringe dose prescribed by your doctor.
Check the expiry date of the drug in pre-filled syringe on the label. You should not use pre-filled syringe, if expired last day of the month.
Check the appearance of the drug Aranesp. The liquid must be transparent or slightly "pearl". If the solution is cloudy or contains particles, the drug should be used.
To feel more comfortable, pre-filled syringe should hold about 30 minutes at room temperature or gently hold in your hand a few minutes. Not be pre-filled syringe heated in other ways (for example, in the microwave or in hot water).
Do not remove the protective cap from the needle to the completion of preparations for the injection.
Wash hands thoroughly.
Choose a comfortable, well lit and clean surface, where you can arrange all the necessary materials so that they are easily within reach.

Immediately prior to injection
Hold the syringe cylinder, carefully remove the cap from the needle, not screwing. Pull it in a straight line without touching the needle and pressing the plunger of the syringe. If within a pre-filled syringe visible air bubbles, there is no need to remove them prior to injection. Introduction of the solution with air bubbles can not cause harm. The syringe is ready for use.
The most ideal location for the drug are: the upper region of the thighs, and abdomen, except the area around the navel. Every time should change the injection site, that there are no ill effects in one area. If the injection does the other person, then the drug can also use the back of the shoulder.

The introduction of the drug
Disinfect the skin, without pressure, using moistened with alcohol swab, and take the skin fold between thumb and index finger.
Introduce the needle into the skin (doctor or nurse should teach the patient from completing this procedure).
Gently pull the plunger of the syringe to make sure that there had been a puncture of the vessel. If blood appears in the syringe, remove the needle and put it in another place.
Gently and slowly enter the solution, keeping the skin in the crease.
After the introduction of the solution to remove the needle and release the fold of skin.
One pre-filled syringe intended for single use.

Do not use the remainder of the syringe drug Aranesp. Patients should be warned that if problems arise with the introduction of the drug should consult your doctor or nurse.

The destruction of used syringes

Do not put back the gray coating on the needle of a used syringe. Dispose of used syringes should be in accordance with generally accepted rules.

Side effect

Allergic reactions: seldom - dyspnoea, skin rashes and urticaria.

Predominantly in patients with chronic renal failure

Since the cardiovascular system: frequent (> 1%, ≤ 10%) - arterial hypertension, thrombosis of vascular access. However, when analyzing the results of safety studies, such reactions have not been associated with changes in hemoglobin (<120> 120 g / l) or a rate increase in hemoglobin levels (<10, 10 to <20, 20 to <30 and ≥ 30 g / l hemoglobin within 4 weeks).

From the side of the central nervous system: frequent (> 1%, ≤ 10%) - headache, very rarely - seizures.

Local reactions: common (> 1%, ≤ 10%) - pain at the site of subcutaneous injection (recorded more frequently than with rhEPO). Discomfort at the injection site was usually slight and temporary, and developed mainly after the first injection.

On the part of the hemopoietic system: in some cases - partial red cell aplasia (PKKA), caused by the neutralizing effect of anti-eritropoetinovyh antibodies.

Predominantly in patients with cancer

The incidence of hypertension and cardiovascular events was comparable in cancer patients treated with placebo, rhEPO or Aranesp, when administered Aranesp n / k. In addition, such adverse reactions were not associated with any content of hemoglobin (<130> 130 g / l), nor at a speed of increase in hemoglobin levels (> 20 g / l for 4 weeks).

From the blood coagulation system: increased frequency of thromboembolic complications, including deep vein thrombosis and pulmonary embolism, compared with patients receiving placebo. In general, adverse events in the application of Aranesp in cancer patients receiving concomitant chemotherapy, are consistent with the underlying disease and used for its treatment of chemotherapy.

Adverse effects that are considered to be related with the use of Aranesp, the following:

Since the cardiovascular system: frequent (> 1%, ≤ 10%) - thromboembolic reaction.

On the part of the musculoskeletal system: frequent (> 1%, ≤ 10%) - arthralgia.

Local reactions: common (> 1%, ≤ 10%) - pain at the injection site.

Discomfort at the injection site was usually slight and temporary

On the part of the body as a whole: frequent (> 1%, ≤ 10%) - peripheral edema.

Contraindications
poorly controlled hypertension;
Hypersensitivity to darbepoetin alfa, rhEPO, or any component of the drug.

Pregnancy and lactation

There are no adequate and strictly controlled clinical studies on the safety of the drug during pregnancy has not been made.

With caution and after careful assessment of the expected benefit of therapy for the mother and the potential risk to the fetus should be prescribed the drug to pregnant women.

If necessary, the appointment during lactation breastfeeding should be discontinued. In experimental studies on animals were not observed a direct damaging effect of the drug on pregnancy, on embryo / fetal development, at birth or postnatal development. Penetrates through the placental barrier in minimal concentrations.

Application for violations of liver function

In all studies, Aranesp exclusion criteria were active liver disease, so data on the use of the drug in patients with hepatic impairment are absent.

Since liver is considered the main route of excretion darbepoetina alpha and rhEPO, patients with pathology of the liver medication should be prescribed with caution.

Application for violations of renal function

In patients with chronic renal failure and clinical symptoms of heart disease or congestive heart failure, target hemoglobin levels should be determined individually.

Cautions

With care use in patients with liver disease, sickle-cell anemia, epilepsy. In order to confirm the effectiveness of erythropoiesis in all patients should determine the content of iron before and during treatment with a view to the appointment, if necessary, additional therapy with iron. In the absence of response to Aranesp should be used to identify the cause.

The effectiveness of erythropoiesis stimulating agents reduced the shortage of iron, folic acid or vitamin B12, as a consequence the level of their contents must be adjusted. Erythropoetic response may also be weakened in the presence of opportunistic infections, symptoms of inflammation or trauma cases, hidden blood loss, hemolysis, severe aluminum intoxication associated hematologic diseases or fibrosis of the bone marrow. The number of reticulocytes should be regarded as one of the options assessment.

If the typical reasons for lack of response are excluded, and the patient is detected reticulopenia, should undertake a study of the bone marrow. If the picture of the bone marrow PKKA corresponds to the picture, we recommend that you study for the presence of antibodies to erythropoietin. PKKA caused neutralize antieritropoetinovyh antibodies, has been described in connection with the use of recombinant erythropoietic proteins, including darbepoetin alfa.

It was shown that these antibodies cross-react with all erythropoietic proteins. In the case of PKKA diagnosis, treatment, drug Aranesp should be discontinued without further transfer the patient to the therapeutic regimen, including other recombinant protein erythropoetic. In all studies, Aranesp exclusion criteria were active liver disease, so data on the use of the drug in patients with hepatic impairment are absent.

Since liver is considered the main route of elimination of darbepoetin alfa and rhEPO, patients with pathology of the liver medication should be used with caution. Abuse of Aranesp in healthy persons may lead to excessive increase of hematocrit.

Similar phenomena may be associated with life-threatening complications with the cardiovascular system. The protective needle cap in the pre-filled syringe contains in its composition dehydrated natural rubber (a derivative of latex), which may cause allergic reactions.

Patients with chronic renal failure

The use of additional therapy with iron is recommended for all patients who have serum ferritin concentration less than 100 mg / l or transferrin saturation levels below 20%. BP should be monitored in all patients, especially in the beginning of Aranesp. Patients should be aware of the importance of compliance with recommendations for use of antihypertensive medications and dietary restrictions. If blood pressure difficult to control during the procedures, can reduce the hemoglobin content by reducing the dose of Aranesp or suspension of its introduction.

In patients with chronic renal failure and clinical symptoms of heart disease or congestive heart failure, target hemoglobin levels should be determined individually. In such cases the maximum hemoglobin should not exceed 120 g / l, except in cases where the seriousness of symptoms (eg, angina) requires a different solution. During the application of Aranesp should regularly monitor the serum potassium content. Higher concentrations of potassium have been described in several patients receiving Aranesp, but a causal relationship has not been installed.

If there are high or rising concentration of potassium, the introduction of Aranesp should be discontinued prior to its normalization. Patients suffering from epilepsy, Aranesp should be administered with caution, because there are reports on the development of seizures in patients with chronic renal failure treated with Aranesp. Patients with cancer effect on tumor growth. Erythropoietin is a growth factor that primarily stimulates red blood cell production. Receptors for erythropoietin are expressing at the surface of various tumor cells.

As in the case of any growth factors, there is an assumption that erythropoietins can stimulate the growth of malignant neoplasms of any type. In two controlled clinical studies on the use of erythropoietin in patients with various forms of cancer, including cancer of the head and neck cancer and breast cancer, demonstrated unexplained increase in mortality.

In patients with solid tumors or lymphoproliferative malignant diseases with increasing levels of hemoglobin above 130 g / l should strictly observe the recommended regimen for dose adjustment in order to minimize the potential risk of thromboembolic events. It is also necessary to regularly monitor the number of platelets and the concentration of hemoglobin in the blood.

Effects on ability to drive vehicles and management mechanisms

There were no effects of the drug Aranesp's ability to drive vehicles and handling equipment.

Experimental Results

In experimental studies in rats and dogs in the application of Aranesp significantly increased the concentration of hemoglobin, hematocrit, red blood cells and reticulocytes, which corresponds to the expected pharmacological effects. Adverse events with the introduction of the drug in very high doses were considered as a consequence of enhanced pharmacological effect (decrease in tissue blood flow due to increased blood viscosity).

These were classified as myelofibrosis and hypertrophy of the spleen, as well as expansion of QRS complex on ECG in dogs without cardiac arrhythmias and the influence of the interval QT. Aranesp is not possessed by any genotoxic potential and no effect on cell proliferation negematologicheskogo series or in vitro, or in vivo. In studies of chronic toxicity was observed tumorogennogo or unexpected mitogenic response in any type of tissue studied. In the extended animal studies, assessment of the carcinogenic potential of darbepoetin alfa is not performed.

Rules of the drug Aranesp is a sterile product made without preservatives. A syringe should be injected no more than one dose of the drug. Any amount of drug remaining in the pre-filled syringe should be discarded. Before the introduction of the solution of the drug Aranesp should be monitored for the presence of visible particles.

You can use only a colorless, transparent or slightly opalescent solution. The solution can not be shaken. Before the introduction should wait for pre-filled syringe warm to room temperature. To avoid discomfort at the injection site, it is necessary to change the place of the drug.

Any amount of unused product or waste to be destroyed in accordance with local requirements.

Overdose

Aranesp is characterized by a wide range of therapeutic doses. Even at very high drug concentration in blood serum were observed symptoms of overdose.

Treatment: In case of detection of polycythemia introduction of Aranesp should be temporarily discontinued. In the presence of clinical indications can be performed phlebotomy.

Drug Interactions

Clinical data obtained so far do not indicate interaction Aranesp with other substances. However, it is known that the capacity of its interaction with drugs, characterized by high affinity for red blood cells, such as tacrolimus.

In case of simultaneous appointment of darbepoetin alfa with any such drugs, should monitor the level of serum with a modification of the dose in the case of increasing the concentration of hemoglobin. Given that the studies were not conducted on the compatibility of the drug Aranesp should not be confused or put into the form of infusion, together with other drugs.

Terms and Conditions of storage

The product should be stored out of reach of children protected from light, at temperatures from 2 ° to 8 ° C Do not freeze. Shelf life - 2 years.

Prior outpatient use of Aranesp can be once moved from the place of storage at room temperature (25 ° C) for a maximum period of 7 days.

One time extracted from the refrigerator and has reached room temperature (25 ° C) syringe should be used within 7 days or destroy.