Mircera: Indications, Dosage, Precautions, Adverse Effects
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Mircera - Product Information

Manufacture: Roche
Country: Australia
Condition: Anemia Associated with Chronic Renal Failure
Class: Recombinant human erythropoietins
Form: Liquid solution, Subcutaneous (SC)
Ingredients: methoxy polyethylene glycolepoetin beta, sodium phosphate - monobasic, monohydrate, sodium sulfate, mannitol, methionine, poloxamer 188, water for injection

Methoxy polyethylene glycol-epoetin beta


CAS registry number: 677324-53-7

Description

MIRCERA (methoxy polyethylene glycol-epoetin beta) is a chemically synthesised Erythropoiesis Stimulating Agent (ESA) with a much longer half-life than erythropoietin.

It is produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells and differs from erythropoietin through the 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 kDa with the polyethylene glycol-moiety having an approximate molecular weight of 30 kDa. The dosage strength in g indicates the quantity of the protein moiety of the methoxy polyethylene glycol-epoetin beta molecule without consideration of glycosylation.

MIRCERA is available in prefilled syringes containing a sterile, preservative-free solution with the following excipients; sodium phosphate-monobasic, monohydrate; sodium sulfate; mannitol; methionine; Poloxamer 188 and water for injection. The solution is clear, colourless to slightly yellowish and the pH is 6.2.

Pharmacology

Pharmacodynamics

MIRCERA shows different activity to recombinant erythropoietin at the receptor level. It is characterised by slower association to the receptor and slightly faster dissociation, resulting in a lower affinity for the receptor. This lower affinity may result in less receptor-mediated endocytosis and contribute together with reduced subsequent lysosomal degradation and/or increased recycling to the slower elimination. MIRCERA thus has a longer half-life than erythropoietin which enables MIRCERA to be administered in a once monthly dosing regimen.

Erythropoietin is a growth factor for erythroid development. It is produced in the kidney and released into the bloodstream in response to hypoxia, interacting with erythroid progenitor cells to increase red blood cell production. Production of endogenous erythropoietin is impaired in patients with chronic kidney disease (CKD), and erythropoietin deficiency is the primary cause of their anaemia.

The onset of haemoglobin increase (defined as an increase > 4 g/L from baseline) is observed in CKD patients after 7 to 15 days following a single dose of MIRCERA.

Pharmacokinetics

The pharmacokinetics of MIRCERA was studied in healthy volunteers and in anaemic CKD patients, including patients on dialysis and not on dialysis.

A comparison of serum concentrations of MIRCERA measured before and after haemodialysis in 41 CKD patients showed that haemodialysis had no effect on MIRCERA serum concentrations in vivo.

The results of a study in 42 healthy volunteers indicated that the site of subcutaneous (SC) injection (abdomen, arm or thigh) had no clinically relevant effect on the pharmacokinetics, pharmacodynamics, or local tolerability of MIRCERA. Based on these results, all three sites are considered suitable for SC injection with MIRCERA.

An analysis in 126 CKD patients showed no pharmacokinetic difference between patients on dialysis and patients not on dialysis.

Multiple dosing in CKD patients was found to have no effect on the clearance, volume of distribution and bioavailability of MIRCERA.

Absorption and Bioavailability

Following SC administration in CKD patients, the maximum serum concentrations of MIRCERA 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 MIRCERA after SC 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 MIRCERA is approximately 5 L.

After administration every 4 weeks in CKD patients, there was virtually no accumulation of MIRCERA, as demonstrated by a ratio of accumulation of 1.03. After administration every 2 weeks, the ratio of accumulation in serum was 1.12.

Elimination

The pharmacokinetic and the pharmacological properties of MIRCERA allow for monthly administration due to the longer elimination half-life. The elimination half-life after intravenous (IV) administration of MIRCERA is 15 to 20 times longer compared to recombinant human erythropoietin.

Following IV administration in CKD patients, the observed terminal elimination half-life (t1/2) for MIRCERA was 134 hours, and the total systemic clearance was 0.494 mL/hr/kg. Following SC administration the t1/2 was 139 hours in dialysis patients and 142 hours in patients not on dialysis.

Data on methoxy polyethylene glycol-epoetin beta metabolism in animals is not available. In rat, both unchanged methoxy polyethylene glycol-epoetin beta (about 1% of administered dose) and polyethylene glycol-like material were found in urine. In humans, it is unknown whether a significant proportion of methoxy polyethylene glycol-epoetin beta is catabolised. In clinical trials with healthy volunteers, unchanged methoxy polyethylene glycol-epoetin beta was not detected in the urine. Due to its high molecular weight, renal excretion of methoxy polyethylene glycol-epoetin beta would not be expected.

Pharmacokinetics in Special Populations

Population analyses evaluated the potential effects of demographic characteristics on the pharmacokinetics of MIRCERA. Results of these analyses showed that no dose adjustments are necessary for age, gender, or race.

From a single dose study, it was shown that following IV administration, the pharmacokinetics of MIRCERA are similar in patients with severe hepatic impairment compared to healthy subjects.

Clinical trials

Chronic Kidney Disease Anaemia

MIRCERA has been evaluated in patients not currently treated with an ESA (including patients on dialysis and not on dialysis) and those currently treated with an ESA.

Patients Not Currently Treated with an Erythropoiesis Stimulating Agent (ESA)

Table 1 Summary of phase III trials in anaemic CKD patients not currently treated with an ESA
CORDATUS
(n = 307)
ARCTOS
(n = 324)
AMICUS
(n = 181)
Study design /
Patient group
Open-label, randomised,
CKD patients not on
dialysis
No prior ESA treatment
Open-label, randomised
CKD patients not on
dialysis
No prior ESA treatment
Open-label, randomised
CKD patients on dialysis
No prior ESA treatment
Patient numbers MIRCERA (n = 153)
Darbepoetin alfa (n = 154)
MIRCERA (n = 162)
Darbepoetin alfa (n = 162)
MIRCERA (n = 135)
Epo alfa or epo beta (n=46)
Duration of
treatment
28 wk
20 wk initiation,
8 wk maintenance
52 wk
28 wk initiation, 24 wk
maintenance
52 wk
24 wk initiation, 28 wk
maintenance
Route/
Starting dose/
Dosage regimen
MIRCERA:
SC: 1.2 μg­g/kg, q4w



Darbepoetin alfa:
SC: 0.45 пЃ­g/kg, q1w
or 0.75 пЃ­g/kg, q2w




Target Hb: 100 to 120 g/L
MIRCERA: SC: 0.6 пЃ­g/kg
Initiation: q2w Maintenance: q2w or q4w


Darbepoetin alfa:
SC: 0.45 пЃ­g/kg
Initiation: q1w
Maintenance: 1w or q2w




Target Hb: 110 to 130 g/L.
MIRCERA:
IV: 0.4 μg­g/kg
Initiation: q2w
Maintenance: q2w or q4w
Epo alfa or epo beta
IV: dose per label
Initiation and maintenance:
3x/wk



Target Hb: 110 to 130 g/L.
Efficacy results Hb response*
MIRCERA: 94.1%
(95% CI: 89.1, 97.3)
Darbepoetin alfa: 93.5%
(95% CI: 88.4, 96.8)
Hb response*
MIRCERA: 97.5%
(95% CI: 93.8, 99.3)
Darbepoetin alfa: 96.3%
(95% CI: 92.1, 98.6)
Hb response*
MIRCERA: 93%
(95% CI: 87.7, 96.9)
Epo alfa or epo beta: 91%
(95% CI: 79.2, 97.6)
Median time to Hb
response

MIRCERA: 43 days
Darbepoetin alfa: 29 days
Median time to Hb
response
MIRCERA: 43 days
Darbepoetin alfa: 29 days
Median time to Hb response
MIRCERA: 57 days
Epo alfa or epo beta: 31
days
Hb change from baseline
MIRCERA: 16.2 g/L
Darbepoetin alfa: 16.6 g/L
(p < 0.0001)
Hb change from baseline
MIRCERA: 21.5 g/L
Darbepoetin alfa: 19.9 g/L
(p < 0.0001)
Incidence of RBC transfusion
MIRCERA:3.3%
Darbepoetin alfa: 6.5%
Incidence of RBC
transfusion

MIRCERA: 2.5%
Darbepoetin alfa: 6.8%
Incidence of RBC transfusion
MIRCERA: 5.2%
Epo alfa or beta: 4.3%

# Hb response defined as at least a 10 g/L increase in Hb concentration to a level of at least 100 g/L without RBC transfusion.

* Hb response defined as at least a 10 g/L increase in Hb concentration to a level of at least 110 g/L without RBC transfusion.

CKD = Chronic Kidney Disease, ESA = Erythropoiesis Stimulating Agent, q1w = once weekly, q2w = once every two weeks, q4w = once every four weeks, Hb = haemoglobin, RBC = red blood cell, Epo = epoetin, IV = intravenous,

SC = subcutaneous, wk = week, CI = confidence interval.

The change in haemoglobin levels (from baseline) observed in these clinical trials demonstrated MIRCERA to be clinically non-inferior to darbepoetin alfa (p < 0.0001). The time to haemoglobin response was longer with MIRCERA than the comparator. For the ARCTOS and AMICUS trials the observed median dose of MIRCERA (once every two weeks) was 0.6 μg/kg.

A lower proportion of patients treated with MIRCERA experienced a haemoglobin level greater than 130 g/L during the first 8 weeks of treatment compared to the reference arms in the AMICUS and ARCTOS studies (7.5% in the MIRCERA group compared to 17.8% for epoetin alfa or beta and 34% in the darbepoetin alfa arm compared to 11.4% for MIRCERA). The corresponding proportions of patients experiencing a haemoglobin level greater than 120 g/L during the first 8 weeks of treatment in the CORDATUS study were 25.8% in the MIRCERA group and 47.7% in the darbepoetin alfa group.

Patients Currently Treated with an Erythropoiesis Stimulating Agent (ESA)

CKD patients currently receiving an ESA were randomised to stay on their current treatment or switched to MIRCERA to maintain stable haemoglobin levels. For patients randomised to receive MIRCERA (either once every two weeks or once every four weeks) the initial dose was determined based on the patient’s previous weekly ESA dose.

Table 2 Summary of phase III trials in anaemic CKD patients currently receiving an ESA
MAXIMA
(n = 673)
PROTOS
(n = 572)
STRIATA
(n = 313)
RUBRA
(n = 336)
Study design/
Patient group
Open-label,
randomised
CKD dialysis patients
with stable Hb* receiving epo (IV)
Open-label,
randomised
CKD dialysis patients
with stable Hb*receiving epo (SC)
Open-label,
randomised
CKD dialysis patients
with stable Hb*
on darbepoetin (IV)
Open-label,
randomised
CKD dialysis patients
with stable Hb*
receiving epo (SC or
IV)
Patient numbers MIRCERA
(n = 447)
Epo alfa or epo beta
(n = 226)
MIRCERA
(n = 381)
Epo alfa or epo beta
(n = 191)
MIRCERA
(n = 157)
Darbepoetin alfa
(n = 156)
MIRCERA
(n = 168)
Epo alfa or epo beta
(n = 168)
Duration of treatment 52 wk52 wk52 wk 36 wk
Route/
Dosage
regimen
Dosage
regimen
MIRCERA:
IV: 30, 50, or 90
μg­g/wk.
q2w, q4w

Epo alfa or epo beta
IV at previous dose
and schedule
MIRCERA:
SC: 30, 50, or 90
μg­g/wk.
q2w, q4w

Epo alfa or epo beta
SC at previous dose
and schedule
MIRCERA:
IV: 60, 100, or 180
μg­g/ q2w

Darbepoetin alfa
IV at previous dose
and schedule
MIRCERA:
IV or SC: 60, 100,
or 180 μg­g/q2w
Epo alfa or epo beta
IV or SC: at previous
dose and schedule
Efficacy resultsNo difference in Hb
change from baseline
(p < 0.0001)
No difference in Hb
change from baseline
(p < 0.0001)
No difference in Hb
change from baseline
(p < 0.0001)
No difference in Hb
change from baseline
(p < 0.0001)

* stable Hb baseline Hb concentration between 105 and 130 g/L

CKD = Chronic Kidney Disease, ESA = Erythropoiesis Stimulating Agent, q2w = once every two weeks, q4w = once every 4 weeks, Hb = haemoglobin, Epo = epoetin, IV = intravenous, SC = subcutaneous, wk = week.

The results from these studies demonstrated the ability of MIRCERA to maintain haemoglobin concentrations within the study target range of 110 - 130 g/L.

The most frequently reported adverse effect in clinical trials (both comparators and MIRCERA) was hypertension (see PRECAUTIONS).

Other Clinical Trials

In a randomised, placebo-controlled, single-blind, three-way crossover study, pain scores after SC injection with MIRCERA were similar to placebo and significantly less compared to other ESAs.

Indications

MIRCERA is indicated for the treatment of anaemia associated with chronic kidney disease (CKD).

Contraindications

MIRCERA is contraindicated in patients with:

  • Uncontrolled hypertension.
  • Known hypersensitivity to the active substance or any of the excipients.

Precautions

Cardiovascular and Thrombotic Events / Increased Mortality

Cardiovascular and thrombotic events such as myocardial ischaemia and infarction, cerebrovascular haemorrhage and infarction, transient ischaemic attacks, deep venous thrombosis, arterial thrombosis, pulmonary emboli, retinal thrombosis and haemodialysis graft occlusion have been reported in patients receiving ESAs.

In controlled clinical trials, ESAs increased the risk for death in oncology patients and for serious cardiovascular events in oncology and CKD patients when administered to target a haemoglobin of > 120 g/L. There was an increased risk of serious arterial and venous thromboembolic events, including myocardial infarction, stroke, congestive heart failure and haemodialysis graft occlusion. A rate of haemoglobin rise of > 10 g/L over 2 weeks may also contribute to these risks.

ESAs also increased the risk of thrombosis in patients undergoing orthopaedic procedures or coronary artery bypass.

The safety and efficacy of MIRCERA have not been established in patients with anaemia due to cancer chemotherapy or in the peri-surgical setting.

To reduce cardiovascular risks, use the lowest dose of MIRCERA that will gradually increase the haemoglobin concentration. The haemoglobin concentration should not exceed 120 g/L and the rate of haemoglobin increase should not exceed 10 g/L in a 2 week period. Haemoglobin levels should be checked at regular intervals and dosages adjusted (see DOSAGE and ADMINISTRATION).

Growth Factor Potential / Increased Tumour Progression

MIRCERA, like other ESAs, is a growth factor that primarily stimulates red blood cell (RBC) production. As with all growth factors, there is a theoretical concern that epoetins could act as a growth factor for any type of malignancy. ESAs, when administered to target haemoglobin of > 120 g/L, shortened the time to tumour progression in patients with advanced head and neck cancer receiving radiation therapy. ESAs also shortened the time to tumour progression and/or survival in patients with breast cancer, cervical cancer, lymphoid malignancy or non- small cell lung cancer when administered to a target haemoglobin ≥ 120 g/L. Although the target haemoglobin was ≥ 120 g/L, the risk of accelerated tumour progression and shortened survival has not been excluded when ESAs are used to target haemoglobin < 120 g/L.

ESAs have been associated with an increased risk of thrombosis (see PRECAUTIONS, Cardiovascular and Thrombotic Events / Increased Mortality) and accelerated tumour progression. MIRCERA is not indicated for the treatment of anaemia in patients with cancer.

Hypertension

Patients with uncontrolled hypertension should not be treated with MIRCERA; blood pressure should be adequately controlled before initiation of therapy. Blood pressure may rise during treatment of anaemia with MIRCERA as with other ESAs. Hypertensive encephalopathy and seizures have been observed in patients treated with MIRCERA as with other ESAs.

Special care should be taken to closely monitor and control blood pressure in patients treated with MIRCERA. During MIRCERA therapy, patients should be advised of the importance of compliance with antihypertensive therapy and dietary restrictions. If blood pressure is difficult to control after initiation of appropriate measures, the dose of MIRCERA should be reduced or temporarily withheld until haemoglobin begins to decrease (see DOSAGE and ADMINISTRATION).

Pure Red Cell Aplasia (PRCA)

PRCA caused by neutralising anti-erythropoietin antibodies has been reported in association with ESA therapy including MIRCERA. These antibodies have been shown to cross-react with all erythropoietic proteins, and patients suspected or confirmed to have neutralising antibodies to erythropoietin should not be switched to MIRCERA. If anti-erythropoietin antibody-mediated PRCA develops whilst on MIRCERA, therapy with MIRCERA must be discontinued and patients should not be switched to another ESA.

Seizures

ESAs should be used with caution in patients with epilepsy.

General

The safety and efficacy of MIRCERA therapy have not been established in patients with haemoglobinopathies or with a platelet level greater than 500 x 109/L. Therefore, caution should be used in these patients.

Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/L or whose transferrin saturation is below 20%, as per Caring for Australasians with Renal Impairment (CARI) Guidelines. To ensure effective erythropoiesis, iron status should be evaluated for all patients prior to, and during treatment.

A lack of response or failure to maintain haemoglobin response with MIRCERA within the recommended dose range should prompt a search for causative factors. Deficiencies of iron, folic acid, and vitamin B12 should be excluded or corrected. The following conditions may also compromise the effectiveness of ESA therapy: chronic blood loss, bone marrow fibrosis, haemolysis, and severe aluminium overload due to treatment of renal failure. If all these conditions are excluded and the patient has a sudden drop of haemoglobin associated with reticulocytopenia and anti-erythropoietin antibodies, examination of the bone marrow for the diagnosis of PRCA should be considered. If PRCA is diagnosed, therapy with MIRCERA must be discontinued and patients should not be switched to another ESA.

Effects on Fertility

When MIRCERA was administered subcutaneously to male and female rats prior to, and during mating, at 6 times the clinical systemic exposure, based on AUC values, fertility, and sperm count and motility were not affected.

Use in Pregnancy - Category B3

Methoxy polyethylene glycol-epoetin beta crossed the rat placenta and was distributed to foetal tissues, particularly the reproductive organs, spleen and kidneys. A reduction in foetal weights occurred in rats and rabbits at systemic exposures 1 to 3 times clinical exposure, with an increase in reversible developmental delays, such as incomplete ossification, in both species. In rabbits there was an increase in the incidence of flat ribs at 29 times the clinical systemic exposure (based on AUC values). All doses tested in both species caused exaggerated pharmacodynamic effects in dams. Post-implantation loss was increased in rabbits and sometimes in rats. MIRCERA should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Use in Lactation

It is unknown whether MIRCERA is excreted in human breast milk. Methoxy polyethylene glycol-epoetin beta was excreted into the milk of rats. MIRCERA treatment of lactating rats was associated with some adverse effects on the offspring, which included reduced pup bodyweight gain, developmental delay, slightly increased pup mortality, increased incidence of pale livers and/or lungs and an increase in the incidence of abdominal distension post weaning. A decision on whether to discontinue breast-feeding or therapy with MIRCERA should be made taking into account the benefit of MIRCERA therapy to the woman and the potential risks to the child.

Paediatric Use

MIRCERA is not recommended for use in patients aged less than 18 years due to a lack of data on safety and efficacy.

Use in the Elderly

Of the 1789 CKD patients treated with MIRCERA in clinical trials, 24% were aged 65 to 74 years, while 20% were aged 75 years and over. Based on population analyses, no adjustment of the starting dose is required in patients aged 65 years or older.

Carcinogenicity

The carcinogenic potential of MIRCERA has not been evaluated in long-term animal studies. As with all growth factors, there is a concern that ESAs could stimulate the growth of any type of malignancy (see PRECAUTIONS, Growth Factor Potential/Increased Tumour Progression).

Genotoxicity

The genotoxic potential of MIRCERA has not been evaluated.

Interactions with Other Medicines

No interaction studies have been performed. The results from clinical trials do not indicate any interaction of MIRCERA with other medicinal products. There was no indication of an effect of concomitant medications on the pharmacokinetics and pharmacodynamics of MIRCERA using a population analysis approach.

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.

Effects on Laboratory Tests

Platelet counts and thrombocytopenia

During treatment with MIRCERA, a slight decrease (median 5.7%) in platelet counts, remaining within the normal range, was observed in clinical studies. The decline was observed after the first dose and there was a partial recovery over the course of the studies.

A platelet count below 100 x 109/L was observed in 9.0% of patients treated with MIRCERA and 6.2% of patients treated with other ESAs.

Adverse effects

The safety database for MIRCERA (based on data from the completed phase II and III studies and long-term follow-up information from safety extension studies) comprised of 2737 CKD patients, where 1789 were treated with MIRCERA and 948 with another ESA.

Based on the results of 1789 patients, approximately 8% of patients treated with MIRCERA experienced adverse reactions. The most frequently reported adverse reaction was hypertension.

Adverse events (irrespective of causal relationship) with ≥ 5% incidence in patients treated with MIRCERA or a reference drug (epoetin or darbepoetin alfa) are presented in Table 3.

Table 3 Adverse events (irrespective of causal relationship) occurring in ≥ 5% of CKD patients
Adverse EventMIRCERA
(n = 1789)
Epoetin or
Darbepoetin alfa
(n = 948)
VASCULAR
Hypertension19%21%
Hypotension7%7%
GASTROINTESTINAL
Diarrhoea17%19%
Vomiting9%11%
Constipation7%9%
Nausea7%8%
Abdominal Pain5%5%
Dyspepsia4%5%
INFECTIONS AND INFESTATIONS
Nasopharyngitis15%15%
Upper Respiratory Tract Infection11%12%
Urinary Tract Infection9%10%
Bronchitis7%8%
Pneumonia7%9%
Influenza6%6%
Gastroenteritis5%6%
NERVOUS SYSTEM
Headache13%13%
Dizziness6%6%
Dizziness6%6%
INJURY, POISONING AND PROCEDURAL COMPLICATIONS
Procedural Hypotension13%11%
Arteriovenous Fistula Thrombosis8%8%
Arteriovenous Fistula Site Complication8%9%
Arteriovenous Graft Thrombosis6%7%
Arteriovenous Fistula Site Haemorrhage5%5%
Contusion4%5%
MUSCULOSKELETAL AND CONNECTIVE TISSUE
Muscle Spasms11%12%
Back Pain10%9%
Pain in Extremity8%9%
Arthralgia7%8%
Back Pain10%9%
Pain in Extremity8%9%
Arthralgia7%8%
RESPIRATORY, THORACIC AND MEDIASTINAL
Cough10%10%
Dyspnoea6%8%
METABOLISM AND NUTRITION
Fluid Overload10%9%
Hyperkalaemia5%6%
Hypoglycaemia3%6%
GENERAL AND ADMINISTRATION SITE COMPLICATIONS
Pyrexia7%7%
Oedema Peripheral4%7%
Asthenia5%4%
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Pruritus6%7%
PSYCHIATRIC DISORDERS
Insomnia6%6%
CARDIAC DISORDERS
Angina Pectoris6%5%
Cardiac Failure Congestive4%5%
RENAL AND URINARY DISORDERS
Renal Failure Chronic5%7%
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anaemia5%4%

The adverse event of thrombocytopenia was reported in 0.8% of MIRCERA treated patients and 0.5% of patients receiving epoetin or darbepoetin alfa, irrespective of causal relationship. However, the incidence of platelet count less than 100 x 109/L was considerably higher in both treatment groups (see PRECAUTIONS, Effects on Laboratory Tests).

Some of the adverse events reported are typically associated with CKD, or recognised complications of dialysis, and may not necessarily be attributable to MIRCERA therapy.

The following descriptors are used to describe the frequency of adverse reactions 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).


Vascular disorders: common hypertension; rare hot flush

Injury, poisoning and procedural complications: uncommon vascular access thrombosis

Immune system disorders: rare hypersensitivity

Nervous system disorders: uncommon headache; rare hypertensive encephalopathy

Skin and subcutaneous tissue disorders: rare rash (maculo-papular, serious)

All other events attributed to MIRCERA were reported with rare frequency and were of mild to moderate severity in the majority of patients. These events were consistent with co- morbidities known in the population.

Post-Marketing Experience

Neutralising anti-erythropoietin antibody-mediated pure red cell aplasia (AEAB-PRCA) associated with MIRCERA therapy has been reported during post marketing experience (see PRECAUTIONS, Pure Red Cell Aplasia). Stevens-Johnson syndrome / toxic epidermal necrolysis has been reported.

Dosage and administration

General

Use the lowest dose of MIRCERA that will gradually increase the haemoglobin concentration. MIRCERA is administered less frequently than Aranesp, Eprex and NeoRecormon due to the longer elimination half-life.

Treatment with MIRCERA is to be initiated under the supervision of a healthcare professional.

Treatment of Anaemic Patients with Chronic Kidney Disease

The solution can be administered by subcutaneous (SC) or intravenous (IV) injection, according to clinical preference. MIRCERA can be injected SC in the abdomen, arm or thigh. All three injection sites are equally suitable for SC injection with MIRCERA.

Patients being changed from SC to IV administration of MIRCERA (or vice-versa) should have their haemoglobin levels monitored to ensure that the haemoglobin concentration stays within the desired target of 100 and 120 g/L.

Patients not currently treated with an Erythropoiesis Stimulating Agent (ESA):

Patients not on dialysis - In order to target a haemoglobin between 100 - 120 g/L, the recommended starting dose is 1.2 μg/kg body weight administered once every month as a single SC injection. Alternatively, a starting dose of 0.6 μg/kg body weight may be administered once every two weeks as a single IV or SC injection.

Patients on dialysis – In order to target a haemoglobin between 100 - 120 g/L, the recommended starting dose of 0.6 μg/kg body weight may be administered once every two weeks as a single IV or SC injection.

It is recommended that haemoglobin is monitored every two weeks until stabilised, and periodically thereafter (see PRECAUTIONS, Cardiovascular and Thrombotic Events/Increased Mortality).

The dose of MIRCERA may be increased by approximately 25 to 50% of the previous dose if the rate of rise in haemoglobin is less than 10 g/L over a month. Further increases of approximately 25 to 50% may be made at monthly intervals until the individual target haemoglobin level is obtained.

Dose adjustments should not be made more frequently than once a month. The dose for each patient should be adjusted so that the haemoglobin level does not exceed 120 g/L. If the haemoglobin is increasing and approaching 120 g/L, the dose should be reduced by approximately 25 to 50%. If the haemoglobin continues to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which point therapy should be reinitiated at a dose approximately 25 to 50% below the previous dose. If the haemoglobin increases by more than 10 g/L in any 2 week period, the dose should be decreased by approximately 25 to 50%. After dose interruption, a haemoglobin decrease of approximately 3.5 g/L per week is expected.

Patients treated once every two weeks whose target haemoglobin has been reached may receive MIRCERA administered once monthly using the dose equal to twice the previous fortnightly dose.

Patients currently treated with an Erythropoiesis Stimulating Agent (ESA):

When converting from epoetin or darbepoetin alfa, MIRCERA can be administered once monthly or, if desired, once every two weeks as a single IV or SC injection. The starting dose of MIRCERA is calculated based on the previously-given ESA weekly dose at the time of conversion, as described in Table 4 below. The two-weekly dose should be approximately half the once monthly dose. The first injection of MIRCERA should be administered at the next scheduled dose of the previously administered darbepoetin alfa or epoetin.

Table 4 MIRCERA dose when converting from another ESA
Previous Weekly
Darbepoetin Alfa Dose
(μg­g/week)
Previous Weekly Epoetin
Dose (Units/week)
MIRCERA Starting Dose
(μg­g/month)
< 40
40-80
> 80
< 8000
8000-16000
> 16000
120
200
360

It is recommended that haemoglobin is monitored every month until stabilised, and periodically thereafter (see PRECAUTIONS, Cardiovascular and Thrombotic Events/Increased Mortality).

If a dose adjustment is required to maintain the target haemoglobin concentration between 100 - 120 g/L, the monthly dose may be adjusted by approximately 25%.

Dose adjustments should not be made more frequently than once a month. The dose for each patient should be adjusted so that the haemoglobin level does not exceed 120 g/L. If the haemoglobin is increasing and approaching 120 g/L, the dose should be reduced by approximately 25 to 50%. If the haemoglobin continues to increase, the dose should be temporarily withheld until the haemoglobin begins to decrease, at which point therapy should be reinitiated at a dose approximately 25 to 50% below the previous dose. If the haemoglobin increases by more than 10 g/L in any 2 week period, the dose should be decreased by approximately 25 to 50%. After dose interruption, a haemoglobin decrease of approximately 3.5 g/L per week is expected.

Hepatic Impairment

No adjustments of the starting dose or dose modification rules are required in patients with any degree of hepatic impairment.

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 restarted at the prescribed dosing frequency.

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 haemoglobin levels, MIRCERA should be temporarily withheld. If clinically indicated, phlebotomy may be performed.

Contact the Poisons Information Centre for advice on management of overdosage.

Presentation and storage conditions

MIRCERA is supplied in a pack containing one single-use prefilled syringe and a 27 gauge, ½ inch needle. Each prefilled syringe is equipped with a needle guard that covers the needle during disposal to reduce the risk of needle stick injury after application.

MIRCERA is available in the following strengths and plungers are colour coded for easy identification as indicated below:

Strength
(μg­g)
Volume
(mL)
Colour
300.3aqua
500.3yellow
750.3red
1000.3turquoise
1200.3lime
150*0.3grey
2000.3purple
250*0.3green
3600.6salmon

* not currently distributed in Australia

Storage Conditions

MIRCERA must not be used after the expiry date.

Store continuously in the refrigerator at 2°C to 8°C. Do not freeze. Do not shake. Protect from light.

The prefilled syringes contain no antimicrobial preservative and are for single-use in one patient only. Discard any residue.

The end user may remove MIRCERA from refrigeration (2°C to 8°C) for storage at room temperature (up to 30°C) for one single period of 1 month. Once removed from the fridge, the product must be used within 1 month and not returned to the fridge for storage.

MIRCERA should not be mixed with other products.

Allow the product to reach room temperature before injecting.

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.

Name and address of sponsor

Roche Products Pty Limited

ABN 70 000 132 865

4-10 Inman Road

Dee Why NSW 2099

AUSTRALIA


Customer enquiries: 1800 233 950

Poison schedule of the medicine

S4. Prescription only medicine.


TGA Approval Date: 09 May 2011

Date of Most Recent Amendment: 03 September 2015