Mircera

Mircera

methoxy polyethylene glycol-epoetin beta

Manufacturer:

Roche

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Methoxy polyethylene glycol-epoetin β.
Description
Single dose pre-filled syringes: containing 30 μg, 50 μg, 75 μg, 100 μg, 120 μg, 150 μg, 200 μg methoxy polyethylene glycol-epoetin beta in 0.3 ml or 360 μg, or 800 μg of methoxy polyethylene glycol-epoetin beta in 0.6 ml.
The active substance, methoxy polyethylene glycol-epoetin beta, is a covalent conjugate of a protein produced by recombinant DNA technology in Chinese Hamster Ovarian cells and a linear methoxy-polyethylene glycol (PEG). This results in an approximate molecular weight of 60 kDa. The dosage strength in μg indicates the quantity of the protein moiety of the methoxy polyethylene glycol-epoetin beta molecule without consideration of the glycosylation.
Excipients/Inactive Ingredients: sodium phosphate monobasic monohydrate, sodium sulphate, mannitol, methionine, poloxamer 188 and water for injections.
Action
Pharmacotherapeutic Group: MIRCERA is the first molecule of a new class of Continuous Erythropoietin Receptor Activators called methoxy polyethylene glycol-epoetin beta. ATC Code: B03XA03.
Pharmacology: Pharmacodynamics: MIRCERA is a chemically synthesized continuous erythropoietin receptor activator. Methoxy polyethylene glycol-epoetin beta differs from erythropoietin through integration of an amide bond between either the N-terminal amino group or the ε-amino group of lysine, predominantly Lys52 and Lys45 and methoxy polyethylene glycol butanoic acid. This results in a molecular weight of approximately 60,000 daltons for methoxy polyethylene glycol-epoetin beta with the PEG-moiety having an approximate molecular weight of 30,000 daltons.
In contrast with erythropoietin, MIRCERA shows a different activity at the receptor level characterized by a slower association to and faster dissociation from the receptor, a reduced specific activity in vitro with an increased activity in vivo, as well as an increased half-life. These differential pharmacological properties are relevant in order to achieve a once monthly dosing regimen with MIRCERA in patients.
Mechanism of Action: MIRCERA stimulates erythropoiesis by interaction with the erythropoietin receptor on progenitor cells in the bone marrow. As primary growth factor for erythroid development, the natural hormone erythropoietin is produced in the kidney and released into the bloodstream in response to hypoxia. In responding to hypoxia, the natural hormone erythropoietin interacts with erythroid progenitor cells to increase red cell production.
Clinical / Efficacy Studies: Adult Patients: In two randomized controlled studies in CKD patients not on dialysis BA16738 and NH20052, MIRCERA achieved correction of anemia in 97.5% and 94.1% of patients, respectively. During the first 8 weeks of treatment the proportion of patients experiencing a hemoglobin level greater than 13 g/dl was 11.4% in the MIRCERA group and 34% in the darbepoetin alfa group in study BA 16738, while the corresponding proportions of patients experiencing a haemoglobin level greater than 12 g/dl were 25.8 % in the MIRCERA group and 47.7 % in the darbepoetin alfa group in NH20052. In a randomized controlled study in CKD patients on dialysis, Mircera achieved correction of anemia in 93.3% of patients.
Four randomized controlled studies were performed in dialysis patients currently treated with darbepoetin alfa or epoetin. Patients were randomized to stay on their current treatment or to be converted to MIRCERA in order to achieve stable hemoglobin levels. At the evaluation period (week 29 to 36), the mean and median level of hemoglobin in patients treated with MIRCERA was virtually identical to the baseline hemoglobin level.
In a controlled, open label, multi-centre study, 490 patients (245 per treatment arm) were randomized to compare the efficacy and safety of MIRCERA with that of darbepoetin alfa for the maintenance treatment of anemia in patients with CKD who are on hemodialysis.
The proportion of responders was significantly higher in patients treated with MIRCERA once-monthly than with darbepoetin alfa once-monthly (p < 0.0001). Of the 245 patients in each group, 157 (64.1%) in the MIRCERA group were responders compared to 99 (40.4%) in the darbepoetin alfa group. Response was defined as patients with an average Hb > 10.5 g/dL and an average decrease from individual baseline not exceeding 1.0 g/dL during the evaluation period.
Paediatric Patients: A phase II, dose-finding, open-label, multiple dose, multicenter study was conducted in 64 paediatric patients (aged 5-17 years old) with CKD who were on hemodialysis, to determine the effective starting dose of MIRCERA IV when switching from maintenance treatment with another ESA (epoetin alfa/beta or darbepoetin alfa). The primary efficacy endpoint in this study (change in Hb concentration (g/dL) between the baseline and evaluation periods) has been met. Overall, the adverse event profile observed was consistent with the safety profile in adults.
Pharmacokinetics: In patients, the pharmacokinetic and the pharmacologic properties allow monthly administration of MIRCERA due to the long elimination half life. The elimination half-life after i.v. administration of MIRCERA is 15 to 20 times longer compared to recombinant human erythropoietin.
The pharmacokinetics of MIRCERA were studied in healthy volunteers and in anemic patients with CKD including patients on dialysis and not on dialysis.
In CKD patients, clearance and volume of distribution of methoxy polyethylene glycol-epoetin beta were not dose dependent.
In CKD patients, the pharmacokinetics of MIRCERA were studied after the first dose and after administrations on week 9 and on week 19 or 21. Multiple dosing had no effect on clearance, volume of distribution and bioavailability of methoxy polyethylene glycol-epoetin beta. After administration every 4 weeks in CKD patients, there was no meaningful accumulation of methoxy polyethylene glycol-epoetin beta, as demonstrated by a ratio of accumulation of 1.03. After administration every 2 weeks, the ratio of accumulation was 1.12.
A comparison of serum concentrations of methoxy polyethylene glycol-epoetin beta measured before and after hemodialysis in 41 CKD patients showed that hemodialysis has no effect on the pharmacokinetics of methoxy polyethylene glycol-epoetin beta.
An analysis in 126 CKD patients showed no pharmacokinetic difference between patients on dialysis and patients not on dialysis.
The results of a study in 42 healthy volunteers indicated that the site of subcutaneous injection (abdomen, arm or thigh) has no clinically relevant effect on the pharmacokinetics, pharmacodynamics or local tolerability of MIRCERA. Based on these results, all three sites are considered suitable for subcutaneous injection with MIRCERA.
Absorption: Absorption after subcutaneous administration: Following s.c. administration to CKD patients, the maximum serum concentrations of methoxy polyethylene glycol-epoetin beta were observed 72 hours (median value) after administration in dialysis patients and 95 hours after administration in patients not on dialysis.
The absolute bioavailability of methoxy polyethylene glycol-epoetin beta after s.c. administration was 62% and 54%, in dialysis patients and patients not on dialysis, respectively.
Distribution: A study in 400 CKD patients showed that the volume of distribution of methoxy polyethylene glycol-epoetin beta is approximately 5 L.
Metabolism: No data to report.
Elimination: Following IV administration to CKD patients, the t½ for methoxy polyethylene glycol-epoetin beta was 134 hours [or 5.6 days], and the total systemic clearance was 0.494 mL/h per kg. Following s.c. administration the observed terminal elimination half-life (t½) was 139 hours in dialysis patients and 142 hours in patients not on dialysis.
Pharmacokinetics in Special Populations: Hepatic Impairment: The pharmacokinetics of MIRCERA are similar in patients with severe hepatic impairment as compared to healthy subjects (see Special Dosage Instructions under Dosage & Administration).
Paediatric Population: The pharmacokinetics of MIRCERA were studied in 64 paediatric CKD patients (aged 5-17 years old) receiving hemodialysis. At steady state (following the third IV administration of MIRCERA) the maximum observed exposures were a geometric mean Cmax of 66.1 ng/mL and a geometric mean AUC0-tau of 7170 ng.hr/mL. Subsequently, Mircera serum concentrations declined with an apparent mean half-life of approximately 121 to 147 hours (geometric mean) comparable to adults.
Other special populations: Population analyses evaluated the potential effects of demographic characteristics on the pharmacokinetics of MIRCERA. Results of these analyses showed that no adjustments of the starting dose are necessary for age(>18 years), gender, or race. A population pharmacokinetic analysis also showed no pharmacokinetic differences between patients on dialysis and patients not on dialysis.
Toxicology: Preclinical Safety: Carcinogenicity: The carcinogenic potential of MIRCERA has not been evaluated in long-term animal studies. MIRCERA did not induce a proliferative response in non-hematological tumor cell lines in vitro. In a six-month rat toxicity study no tumorigenic or unexpected mitogenic responses were observed in non-hematological tissues. In addition, using a panel of human tissues, the in vitro binding of MIRCERA was only observed in target cells (bone marrow progenitor cells).
Mutagenicity: No data to report.
Impairment of Fertility: When MIRCERA was administered subcutaneously to male and female rats prior to and during mating, reproductive performance, fertility, and sperm assessment parameters were not affected.
Teratogenicity: Studies in animals have not shown any harmful effect of MIRCERA on pregnancy, embryonal/fetal development, parturition or postnatal development.
Indications/Uses
MIRCERA is indicated for the treatment of anemia associated with chronic kidney disease (CKD) including patients on dialysis and patients not on dialysis. The safety and efficacy of MIRCERA therapy in other indications has not been established.
Dosage/Direction for Use
Standard dosage: MIRCERA is administered less frequently than other erythropoiesis stimulating agents (ESAs) due to the longer elimination half-life.
Treatment with MIRCERA has to be initiated under the supervision of a healthcare professional.
Treatment of anemic patients with chronic kidney disease: The solution can be administered subcutaneously (SC) or intravenously (IV), according to clinical preference.
MIRCERA can be injected subcutaneously in the abdomen, arm or thigh. All three injection sites are equally suitable for subcutaneous injection with MIRCERA.
It is recommended that hemoglobin is monitored every two weeks until stabilized, and periodically thereafter.
As recommended in current guidelines, the rate of increase in Hb and the target Hb should be determined for each patient individually. In CKD patients, the aim of treatment is to reach a target Hb level of 10-12g/dL. Patients should be monitored closely to ensure that the lowest effective dose of MIRCERA is used to provide adequate control of the symptoms of anemia.
Patients currently not treated with an Erythropoiesis Stimulating Agent: Patient not on dialysis: The recommended starting dose is 1.2 microgram/kg body weight administered once every month as a single subcutaneous injection. Alternatively, a starting dose of 0.6 microgram/kg body weight may be administered once every two weeks as a single IV or SC injection.
Patients on dialysis: The recommended starting dose of 0.6 microgram/kg body weight may be administered once every two weeks as a single IV or SC injection.
The dose of MIRCERA may be increased by approximately 25 to 50% of the previous dose if the rate of rise in hemoglobin is less than 1.0 g/dl (0.621 mmol/l) over a month. Further increases of approximately 25 to 50% may be made at monthly intervals until the individual target hemoglobin level is obtained.
If the rate of rise in hemoglobin is greater than 2 g/dl (1.24 mmol/l) in one month or the haemoglobin levels exceed 12g/dL, the dose is to be reduced by approximately 25 to 50%. If the hemoglobin level exceeds 13 g/dl (8.07 mmol/l), therapy is to be interrupted until the hemoglobin level falls below 13 g/dl and then restarted with approximately 50% of the previously administered dose. After dose interruption a hemoglobin decrease of approximately 0.35 g/dl per week is expected.
Patients treated once every two weeks whose haemoglobin concentration is in target range may receive MIRCERA administered once monthly using the dose equal to twice the previous once every two weeks dose. Dose adjustments should not be made more often than once a month.
Patients currently treated with an Erythropoiesis Stimulating Agent: Patients currently treated with an ESA can be converted to MIRCERA administered once a month or, if desired, once every two weeks as a single IV or SC injection. The starting dose of MIRCERA is based on the calculated previously given weekly dose of darbepoetin alfa or epoetin at the time of substitution as described in Table 1, as follows. The first injection of MIRCERA should be administered at the next scheduled dose of the previously administered darbepoetin alfa or epoetin. (See Table 1.)

Click on icon to see table/diagram/image

If a dose adjustment is required to maintain the target hemoglobin concentration above 10 g/dl, the monthly dose may be adjusted by approximately 25%.
If the rate of rise in hemoglobin is greater than 2 g/dl (1.24 mmol/l) over a month or the haemoglobin levels exceed 12g/dL, the dose is to be reduced by approximately 25 to 50%. If the hemoglobin level exceeds 13 g/dl (8.07 mmol/l), therapy is to be interrupted until the hemoglobin level falls below 13 g/dl and then restarted with approximately 50% of the previously administered dose. After dose interruption a hemoglobin decrease of approximately 0.35 g/dl per week is expected.
Dose adjustments should not be made more often than once a month.
Treatment interruption: Treatment with MIRCERA is normally long-term. However, it can be interrupted at any time, if necessary.
Missed dose: If one dose of MIRCERA is missed, the missed dose should be administered as soon as possible and administration of MIRCERA is to be restarted at the prescribed dosing frequency.
Special Dosage Instructions: Pediatric use: No dose recommendations can be made for use in patients aged less than 18 years due to the limited data on safety and efficacy (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
Geriatric use: no adjustment of the starting dose is required in patients aged 65 years or older (see Geriatric Use under Precautions).
Hepatic Impairment: no adjustments of the starting dose nor dose modification rules are required in patients with any degree of hepatic impairment (see Pharmacology: Pharmacokinetics: Pharmacokinetics in special Populations under Actions).
Overdosage
The therapeutic range of MIRCERA is wide and individual response to therapy must be considered when MIRCERA treatment is initiated. Overdose can result in manifestations of an exaggerated pharmacodynamic effect, e.g. excessive erythropoiesis. In case of excessive hemoglobin levels, MIRCERA should be temporarily withheld (see Dosage & Administration). If clinically indicated, phlebotomy may be performed.
Contraindications
MIRCERA is contraindicated in patients with: Uncontrolled hypertension.
Known hypersensitivity to the active substance or any of the excipients.
Special Precautions
General: Supplementary iron therapy: 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 treatment guidelines.
Lack of effect: The most common reasons for incomplete response to ESAs are iron deficiency and inflammatory disorders. The following conditions may also compromise the effectiveness of ESAs therapy: chronic blood loss, bone marrow fibrosis, severe aluminium 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, examination of the bone marrow for the diagnosis of Pure Red Cell Aplasia (PRCA) should be considered. If PRCA is diagnosed, therapy with MIRCERA must be discontinued and patients should not be switched to another ESA.
PRCA: PRCA caused by anti-erythropoietin antibodies has been reported in association with ESAs including MIRCERA. These antibodies have been shown to cross-react with all ESAs, and patients suspected or confirmed to have antibodies to erythropoietin should not be switched to MIRCERA.
Blood pressure monitoring: As with other ESAs, blood pressure may rise during treatment of anemia with MIRCERA. Blood pressure should be adequately controlled before, at initiation of and during treatment with MIRCERA. If high blood pressure is difficult to control by drug treatment or dietary measures, the dose of MIRCERA must be reduced or withheld (see Dosage & Administration).
Effect on tumor growth: MIRCERA, like other ESAs, is a growth factor that primarily stimulates 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 ESAs could stimulate the growth of any type of malignancy. Controlled clinical studies in which epoetins were administered to patients with various cancers including head and neck cancers, and breast cancer, have shown an unexplained excess mortality.
The safety and efficacy of MIRCERA therapy has not been established in patients with hemoglobinopathies, seizures or with a platelet level greater than 500 x 109/l. Therefore, caution should be used in these patients.
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, Mircera 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 Mircera, treatment with Mircera must not be restarted in this patient at any time.
Drug Abuse and Dependence: Misuse by non-anaemic persons may lead to an excessive increase in Hb. This may be associated with life threatening complications of the cardiovascular system.
Laboratory Tests: No data to report.
Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed. However, no effects are expected based on the mechanism of action and the known safety profile of MIRCERA.
Renal Impairment: No data to report.
Hepatic Impairment: See Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Use in Children: No dose recommendations can be made for use in patients aged less than 18 years due to the limited data on safety and efficacy (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
Use in Elderly: Of the 1789 MIRCERA-treated CKD patients in Phase II and Phase III clinical studies of MIRCERA, 24% were age 65 to 74 years, while 20% were age 75 years and over. Based on population analyses, no adjustment of the starting dose is required in patients aged 65 years or older. See Special Dosage Instructions under Dosage & Administration.
Use In Pregnancy & Lactation
Pregnancy: There are no adequate data on the use of MIRCERA in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.
Caution should be exercised when prescribing MIRCERA to pregnant women.
Labor and Delivery: No data to report.
Nursing Mothers: It is unknown whether methoxy polyethylene glycol-epoetin beta is excreted in human breast milk. One animal study has shown excretion of methoxy polyethylene glycol-epoetin beta in maternal milk. A decision on whether to continue or discontinue breast-feeding or to continue or discontinue therapy with MIRCERA should be made taking into account the benefit of breastfeeding to the child and the benefit of MIRCERA therapy to the woman.
Adverse Reactions
Clinical Trials: The safety data base for MIRCERA from controlled clinical trials comprised 3042 CKD patients where 1939 were treated with MIRCERA and 1103 with an ESA.
Based on the results of 1939 patients, approximately 6% of patients treated with MIRCERA are expected to experience adverse drug reactions (ADRs). The most frequent reported adverse reaction was hypertension (common).
The following descriptors are used to describe the frequency of ADRs attributed to treatment with MIRCERA in controlled clinical trials: Common (≥1/100 and <1/10), Uncommon (≥1/1000 and <1/100), and Rare (≥1/10,000 and <1/1000). (See Table 2.)

Click on icon to see table/diagram/image

All other events attributed to MIRCERA were reported with rare frequency and were in the majority of mild to moderate severity. These events were consistent with comorbidities known in the population.
Laboratory Abnormalities: During treatment with MIRCERA, a slight decrease in platelet counts, remaining within the normal range, was observed in clinical studies.
A platelet count below 100 x 109/l was observed in 7.5% of patients treated with MIRCERA and 4.4% of patients treated with other ESAs.
Post Marketing: Neutralizing anti-erythropoetin antibody-mediated pure red cell aplasia (AEAB-PRCA) associated with MIRCERA therapy has been reported during post marketing experience (see also Precautions).
Stevens-Johnson syndrome/toxic epidermal necrolysis has been reported.
Laboratory Abnormalities: See Post Marketing as previously mentioned.
Drug Interactions
No interaction studies have been performed. The clinical results do not indicate any interaction of MIRCERA with other medicinal products. The effect of other drugs on the pharmacokinetics and pharmacodynamics of MIRCERA was explored using a population analysis approach. There was no indication of an effect of concomitant medications on the pharmacokinetics and pharmacodynamics of MIRCERA.
Caution For Usage
Special Instructions for Use, Handling and Disposal: MIRCERA should not be mixed with other products.
MIRCERA is a sterile but unpreserved product. Do not administer more than one dose per pre-filled syringe.
Only solutions which are clear, colorless to slightly yellowish and free of visible particles must be injected.
Do not shake.
Allow the product to reach room temperature before injecting.
Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Use established "collection systems", if available in the location.
Storage
Store in the refrigerator at 2°C to 8°C.
Keep the pre-filled syringe in the outer carton in order to protect from light.
Do not freeze.
For Pre-Filled Syringe: The patient may remove the product from refrigeration for storage at room temperature (not above 30°C) for one single period of 1 month. Once removed from the refrigerator the product must be used within this period.
Patient Counseling Information
MIRCERA PFS: Instructions for SC Use: Reminder: Store in a refrigerator (2 °C - 8 °C). Do not freeze.
Protect from light during preparation. MIRCERA maybe removed from the refrigerator and stored atroom temperature (not > 30ºC) for a single period up to 30 days. Once removed: 1. Break seal and remove needle cap: Use only needle supplied with the syringe.
2. Remove rubber tip cap: Grab tip cap firmly; bend and pull to remove cap from the prefilled syringe.
3. Attach needle: Attach needle without twisting. Press firmly to ensure tight fit.
4. Remove needle shield: Grab syringe and needle shield and pull firmly.
5. Start administration: Grasp the finger flange and start to depress the plunger.
6. Administer injection: Inject the entire dose. The needle guard will not activate unless the entire dose has been given. Do not release plunger.
7. Remove the syringe: Continue to depress the plunger while removing the syringe.
8. Release needle guard: Release grip slowly and allow needle guard to move forward.
9. Tear off label: Grab flap of label, turn plunger clockwise and peel the label off syringe.
Dispose of syringe properly in an approved sharps container.
ATC Classification
B03XA01 - erythropoietin ; Belongs to the class of other antianemic preparations. Used in the treatment of anemia.
B03XA03 - methoxy polyethylene glycol-epoetin beta ; Belongs to the class of other antianemic preparations. Used in the treatment of anemia.
Presentation/Packing
Inj (clear and colorless to slightly yellowish in pre-filled syringe) 50 mcg/0.3 mL x 1's. 75 mcg/0.3 mL x 1's. 100 mcg/0.3 mL x 1's. 120 mcg/0.3 mL x 1's. 150 mcg/0.3 mL x 1's. 200 mcg/0.3 mL x 1's.
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