Epoetin Theta

Epoetin theta is a recombinant form of human erythropoietin, the endogenous glycoprotein hormone that is the primary regulator of red blood cell production (erythropoiesis). Its amino acid sequence is identical to that of endogenous human erythropoietin, and its carbohydrate composition (glycosylation) is similar. Eporatio and Biopoin are two EU brands of epoetin theta.

Mechanism of Action

• Receptor interaction: erythropoietin acts through specific interaction with the erythropoietin receptor on erythroid progenitor cells in the bone marrow, as a mitosis-stimulating factor and differentiation hormone. DrugBank adds that receptor binding activates JAK2 and STAT5, which switch on genes for cell division and differentiation.
• Natural regulation: it is made mainly in the kidney and regulated by changes in tissue oxygenation.
• Renal failure: endogenous erythropoietin production is impaired, and erythropoietin deficiency is the primary cause of the anaemia.
• Cancer on chemotherapy: the causes of anaemia are multifactorial; erythropoietin deficiency and a reduced response of erythroid progenitors to endogenous erythropoietin both contribute significantly.
• Preclinical effect: after intravenous or subcutaneous dosing in mice, rats and dogs, erythrocyte numbers, haematocrit values and reticulocyte counts increased.

Pharmacokinetics

• Age and sex: the pharmacokinetics do not depend on age or gender.
• Absorption, subcutaneous: after 40 IU/kg in healthy volunteers, profiles were similar at the upper arm, abdomen and thigh, with slightly greater absorption (AUC) from the abdomen. The peak is reached after 10 to 14 hours on average, the terminal half-life is about 22 to 41 hours, and average bioavailability is about 31% of the intravenous route.
• Pre-dialysis renal failure: after a subcutaneous dose of 40 IU/kg, slow absorption gives a plateau with the maximum at about 14 hours. The terminal half-life averages 25 hours after a single dose and 34 hours at steady state on three-times-weekly dosing, with no accumulation.
• Cancer patients on chemotherapy: after repeated subcutaneous doses of 20,000 IU once weekly, the terminal half-life is 29 hours after the first dose and 28 hours at steady state, with no accumulation.
• Intravenous: in haemodialysis patients on 40 IU/kg three times weekly, the elimination half-life is 6 hours after a single dose and 4 hours at steady state, with no accumulation. The volume of distribution approximates the total blood volume.
• Metabolism: after binding its receptor, erythropoietin is internalised and degraded (DrugBank).

• Chronic renal failure: treatment of symptomatic anaemia associated with chronic renal failure in adult patients.
• Chemotherapy-induced anaemia: treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving chemotherapy.

• Hypersensitivity to the active substance, other epoetins and derivatives, or any excipient.
• Uncontrolled hypertension.

About 9% of patients can be expected to have an adverse reaction. The most frequent are hypertension, influenza-like illness and headache. The table in the SmPC rests on clinical studies in 972 patients and separates symptomatic anaemia in chronic renal failure from anaemia in cancer patients on chemotherapy.

Common (≥1/100 to <1/10): headache; hypertension; hypertensive crisis and shunt thrombosis (renal failure patients); skin reactions (rash, pruritus, injection site reactions); arthralgia (cancer patients); influenza-like illness.

Not known: pure red cell aplasia (renal failure patients, after marketing); hypersensitivity reactions; thromboembolic events (cancer patients).

Hypertension occurs more often in the correction phase than in the maintenance phase of renal failure treatment. Hypertensive crisis with encephalopathy-like symptoms (headache, confusion, speech disturbance, impaired gait) and related complications (seizures, stroke) may also occur in patients with otherwise normal or low blood pressure. Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can be life-threatening or fatal and have been reported with epoetins.

• No interaction studies have been performed.
• Antihypertensive medicines: a rise in blood pressure may call for antihypertensive treatment or a higher dose of existing antihypertensives.
• Anticoagulation: during haemodialysis, increased anticoagulation may be needed to prevent clotting of the arteriovenous shunt.
• Interferon and ribavirin: severe anaemia with low reticulocyte counts has been reported in hepatitis C patients when epoetins were used with interferon and ribavirin; epoetins are not approved for anaemia associated with hepatitis C.
• Iron: supplementary iron is recommended when serum ferritin is below 100 µg/L or transferrin saturation is below 20%; DrugBank also advises checking iron stores when starting an ESA.

Treatment must be started by a physician experienced in the indications above. The solution can be given subcutaneously or intravenously. Subcutaneous use is preferable in patients not on haemodialysis, to avoid puncturing peripheral veins. In cancer patients on chemotherapy it is given only subcutaneously. When switching from another epoetin, use the same route and monitor haemoglobin closely. Subcutaneous injections go into the abdomen, arm or thigh, with the sites rotated and the injection given slowly to avoid discomfort. See the SmPC for handling instructions before administration.

Chronic Renal Failure (Adults)

• Target: haemoglobin 10 to 12 g/dL and never above 12 g/dL. Avoid a rise of more than 2 g/dL over four weeks. In hypertension or existing cardiovascular, cerebrovascular or peripheral vascular disease, the rise and the target are set individually.
• Dose changes: if haemoglobin rises by more than 2 g/dL in 4 weeks or exceeds 12 g/dL, reduce the dose by 25 to 50%. Check haemoglobin every two weeks until stable and periodically afterwards. If it keeps rising, interrupt until it begins to fall, then restart about 25% below the previous dose.
• Correction phase, subcutaneous: 20 IU/kg three times a week, raised after 4 weeks to 40 IU/kg three times a week if the haemoglobin rise is below 1 g/dL, then by 25% of the previous dose at monthly intervals until the target is reached.
• Correction phase, intravenous: 40 IU/kg three times a week, raised after 4 weeks to 80 IU/kg three times a week, then by 25% of the previous dose at monthly intervals if needed.
• Maintenance phase: adjust the dose, usually by about 25%, to hold haemoglobin in the individual target within 10 to 12 g/dL. Subcutaneously, the weekly dose can be one injection a week or three a week. Intravenously, patients stable on three-times-weekly dosing may move to twice weekly. Monitor haemoglobin closely when the frequency changes.
• Maximum: 700 IU/kg per week, by either route.
• Dose escalation: use the lowest effective dose, take caution when escalating, and consider other explanations for a poor response.

Anaemia in Cancer Patients on Chemotherapy (Adults)

• Start: subcutaneously, in patients with anaemia (for example haemoglobin 10 g/dL or less), 20,000 IU once weekly regardless of body weight.
• After 4 weeks: if haemoglobin has risen by at least 1 g/dL, continue. If not, consider doubling to 40,000 IU weekly, and after a further 4 weeks of insufficient rise consider 60,000 IU weekly. The maximum is 60,000 IU per week. If haemoglobin has not risen by at least 1 g/dL after 12 weeks, a response is unlikely and treatment should stop.
• Dose changes: if haemoglobin rises by more than 2 g/dL in 4 weeks or exceeds 12 g/dL, reduce the dose by 25 to 50%. Interrupt if it exceeds 13 g/dL, and restart about 25% lower once it is 12 g/dL or less.
• Duration: continue up to 4 weeks after chemotherapy ends.

Special Populations

• Children and adolescents up to 17 years: safety and efficacy have not been established, and no data are available.
• Patients over 75 years: in clinical trials they had more serious and severe adverse events, and more deaths, than younger patients, irrespective of any causal link to treatment.
• Liver disease and sickle cell disease: because of limited experience, efficacy and safety could not be assessed in impaired liver function or homozygous sickle cell anaemia.

Hypertension

Blood pressure may rise or existing hypertension worsen, particularly early in treatment, so it must be monitored closely and well controlled before and during therapy to avoid acute complications such as hypertensive crisis with encephalopathy-like symptoms and related seizures or stroke. These can also occur in patients with normal or low blood pressure and need immediate medical attention and intensive care; sudden sharp, migraine-like headache is a possible warning signal. Antihypertensive treatment may need to be started or increased, and a lower epoetin theta dose should be considered. If blood pressure stays high, treatment may be interrupted temporarily and restarted at a reduced dose once it is controlled.

Haemoglobin Targets in Renal Failure

Maintenance haemoglobin must not exceed the upper limit of the recommended target (12 g/dL). In clinical trials, an increased risk of death and serious cardiovascular events was observed when epoetins were given to target a haemoglobin above 12 g/dL (7.45 mmol/L). Controlled trials have not shown significant benefit from raising haemoglobin beyond the level needed to control symptoms and avoid transfusion. High cumulative doses may be associated with a higher risk of death and of serious cardiovascular and cerebrovascular events.

Effect on Tumour Growth

Epoetins are growth factors that mainly stimulate red blood cell production, and erythropoietin receptors may be present on a variety of tumour cells. As with all growth factors, there is a concern that epoetins could stimulate the growth of any type of malignancy. In several controlled studies, epoetins have not been shown to improve overall survival or lower the risk of tumour progression in patients with cancer-related anaemia. In controlled clinical studies, epoetins showed:

• shortened time to tumour progression in advanced head and neck cancer treated with radiation therapy, when targeting haemoglobin above 14 g/dL;
• shortened overall survival and more deaths attributed to disease progression at 4 months in metastatic breast cancer treated with chemotherapy, when targeting haemoglobin of 12 to 14 g/dL;
• increased risk of death at a target haemoglobin of 12 g/dL in patients with active malignant disease receiving neither chemotherapy nor radiation therapy (epoetins are not indicated for this population).

Because of this, blood transfusion should in some clinical situations be the preferred treatment of anaemia in cancer patients. The decision to give a recombinant erythropoietin should rest on a benefit-risk assessment made with the patient, taking account of tumour type and stage, degree of anaemia, life expectancy, the setting in which the patient is treated and patient preference.

Pure Red Cell Aplasia (PRCA)

If typical causes of non-response are excluded and haemoglobin drops suddenly with reticulocytopenia, anti-erythropoietin antibodies and the bone marrow should be examined for PRCA, and stopping treatment should be considered. PRCA caused by neutralising anti-erythropoietin antibodies has been reported with erythropoietin therapy, including epoetin theta. These antibodies cross-react with all epoetins, so patients suspected or confirmed to have them should not be switched to epoetin theta. A paradoxical fall in haemoglobin with severe anaemia and low reticulocyte counts should prompt stopping the epoetin and testing for antibodies; this has been reported in hepatitis C patients on interferon and ribavirin.

Iron and Non-Response

Iron status must be checked before and during treatment, and supplementary iron is recommended when serum ferritin is below 100 µg/L or transferrin saturation is below 20%. Non-response should prompt a search for causes: deficiencies of iron, folic acid or vitamin B12 reduce effectiveness, and infections, inflammation or injury, occult blood loss, haemolysis, aluminium intoxication, underlying haematological disease or bone marrow fibrosis may compromise the response. Consider a reticulocyte count. The name of the epoetin given should be clearly recorded in the patient file.

Severe Cutaneous Reactions

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can be life-threatening or fatal and have been reported with epoetins; more severe cases were seen with long-acting epoetins. Patients should be told the signs and symptoms at the time of prescription and be monitored closely for skin reactions. If such signs appear, epoetin theta should be withdrawn immediately and an alternative considered. After such a reaction attributed to epoetin theta, it must never be restarted.

Monitoring, Renal Failure and Misuse

• Laboratory monitoring: haemoglobin, a complete blood count and a platelet count should be done regularly.
• Nephrosclerosis: in patients not yet on dialysis, the indication is decided individually, as a possible acceleration of renal failure cannot be ruled out with certainty.
• Haemodialysis: more anticoagulation may be needed to prevent clotting of the arteriovenous shunt.
• Misuse: misuse by healthy people may excessively raise haemoglobin and haematocrit, with life-threatening cardiovascular complications.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: data are limited (fewer than 300 pregnancy outcomes). Animal studies with other epoetins do not indicate direct harmful effects on reproduction. As a precaution, it is preferable to avoid epoetin theta in pregnancy.
• Breastfeeding: it is unknown whether epoetin theta or its metabolites pass into human milk, but data in neonates show no absorption or pharmacological activity of erythropoietin given with breast milk. Decide whether to stop breastfeeding or to stop or withhold treatment, weighing the benefit of breastfeeding for the child against the benefit of therapy for the woman.
• Fertility: no data are available.

Sodium

Each pre-filled syringe contains less than 1 mmol (23 mg) sodium, that is, it is essentially sodium-free.

Effect on Driving

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

Store in a refrigerator at 2 °C to 8 °C. Do not freeze. Keep the pre-filled syringe in the outer carton to protect it from light. Keep the cold chain unbroken during transport and delivery.

For ambulatory use, the patient may take the product out of the refrigerator and keep it at a temperature not above 25 °C for a single period of up to 7 days, without exceeding the expiry date. Once removed from the refrigerator, it must be used within this period or disposed of.

2 years for the 1,000, 2,000, 3,000 and 4,000 IU syringes, and 30 months for the 5,000, 10,000, 20,000 and 30,000 IU syringes. The single period of up to 7 days outside the refrigerator is allowed within the expiry date.

Prescription only (Rx). Treatment is started by a physician experienced in managing anaemia in chronic renal failure or in cancer patients on chemotherapy. It is injected under the skin, or into a vein in renal failure, and is supplied as pre-filled syringes on prescription to the hospital, dialysis unit or clinic that administers it, or to the patient or treating clinic for ambulatory use, with cold-chain delivery at 2–8 °C. See the SmPC for pack sizes.