4.1. Therapeutic indications

Atgam is indicated for use in adults and in children aged 2 years and older for the treatment of acquired moderate to severe aplastic anaemia of known or suspected immunologic aetiology as part of standard immunosuppressive therapy in patients who are unsuitable for haematopoietic stem cell transplantation (HSCT) or for whom a suitable haematopoietic stem cells (HSCs) donor is not available.

4.2. Posology and method of administration

Only physicians experienced in immunosuppressive therapy should use Atgam. Facilities equipped and staffed with adequate laboratory and supportive inpatient medical resources should be used.

Posology

Adult patients and children aged 2 years and older

Dosage recommendations are based on body weight (bw).

The recommended total dose is 160 mg/kg bw, administered as part of standard immunosuppressive therapy, as follows (see sections 4.4, 4.8 and 5.1):

• 16 mg/kg bw/day over 10 days or

• 20 mg/kg bw/day over 8 days or

• 40 mg/kg bw/day over 4 days

Monitoring and management of adverse events

Patients should be carefully monitored during and after treatment for adverse events. Recommendations for monitoring and management of adverse events are included in Table 1. Treatment of the adverse events should be instituted in accordance with local guidelines.

Table 1. Recommendations for Monitoring and Management of Adverse Events

Adverse Event

Recommendations for Monitoring and Management

Anaphylaxis, including respiratory distress

To identify those at greatest risk of systemic anaphylaxis, skin testing of potential recipients before commencing treatment is strongly recommended, especially if the patient is atopic.

Patients should be carefully monitored for anaphylaxis, including respiratory distress, and treatment should be discontinued if anaphylaxis occurs (see section 4.4).

Cytokine Release Syndrome (CRS)

If CRS occurs, discontinuation of treatment should be considered (see section 4.4).

Thrombocytopenia and neutropenia

If there is evidence of severe and unremitting thrombocytopenia or neutropenia, discontinuation of treatment should be considered (see section 4.4).

Special populations

Renal and hepatic impairment

Specific clinical studies have not been performed to assess the effect of renal or hepatic impairment on the pharmacokinetics of Atgam.

Paediatric population

Currently available data in children less than 18 years of age are described in sections 4.8 and 5.1.

Elderly (> 65 years)

Clinical experience in elderly patients has not identified differences in responses between the elderly and younger patients. Therefore, no dose adjustment is recommended for elderly patients.

Method of administration

Atgam is intended for intravenous use and should be administered preferably, via a high flow central vein.

Pre-medication

It is recommended to administer pre-medication with corticosteroids and antihistamines prior to infusion of Atgam in accordance with local treatment guidelines. Anti-pyretics may also increase the tolerability of Atgam infusion (see section 4.4).

Administration

Atgam should be diluted prior to infusion and administered using appropriate aseptic technique (see sections 6.3 and 6.6).

Diluted Atgam should be at room temperature (20°C - 25°C) prior to infusion. Atgam should be administered into a high flow central vein through an in-line filter (0.2-1.0 micron). An in-line filter (not supplied) must be used with all infusions of Atgam to prevent the administration of any insoluble material that may develop during storage. The use of high flow veins will minimize the incidence of phlebitis and thrombosis.

The recommended infusion duration for the 40 mg/kg dose regimen is 12 to 18 hours. Atgam should not be infused in less than 4 hours. Increasing the infusion duration may minimize adverse reactions. The patient should be kept under continuous observation during and after the infusion for possible allergic reactions (see sections 4.4 and 4.8). Following administration, it is recommended to flush the intravenous line.

The infusion volume of the diluted solution should take into consideration factors such as patient's haemodynamic status, age and weight.

Concomitant immunosuppressive therapy

Atgam is most commonly administered with ciclosporin A.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity to any other horse gamma globulin preparation.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Special considerations for Atgam infusion

Atgam should be administered into a high flow central vein through an in-line filter (not supplied). Atgam should not be infused in less than 4 hours. Increasing the infusion duration may minimize adverse reactions. The patient should be kept under continuous observation during and after the infusion for possible allergic reactions (see section 4.8).

Infection

Due to the nature of the disease and the immunosuppressive effects of Atgam, opportunistic infections (bacterial and fungal) are very common. Sepsis has also been reported. The risk of infections is increased when Atgam is combined with other immunosuppressants. There is an increased risk of viral reactivation (e.g., cytomegalovirus [CMV], Epstein–Barr virus [EBV], herpes simplex virus [HSV]). Patients should be carefully monitored for evidence of infection and treatment should be instituted in accordance with local guidelines.

Immune-mediated reactions

In rare instances, serious immune-mediated reactions have been reported with the use of Atgam. Clinical signs associated with anaphylaxis, other infusion-associated reactions, serum sickness and associated symptoms such as rash, arthralgia, pyrexia, chills, and pain have been reported (see section 4.8).

A systemic reaction such as a generalized rash, tachycardia, dyspnoea, hypotension, or anaphylaxis precludes any additional administration of Atgam.

It is recommended to administer corticosteroids and antihistamines prior to infusion of Atgam (see sections 4.2 and 4.5). Antipyretics may also be administered to increase the tolerability of Atgam infusion.

Cytokine release syndrome

There is a potential risk of cytokine release syndrome, which can be fatal (see section 4.2).

Anaphylaxis/skin testing

To identify those at greatest risk of systemic anaphylaxis, especially if the patient is atopic, skin testing of potential recipients before commencing treatment is strongly recommended. A conservative, conventional approach would first employ epicutaneous testing with undiluted Atgam. If the subject does not show a wheal ten minutes after pricking, proceed to intradermal testing with 0.02 ml of a saline dilution (1:1000 v/v) of Atgam with a separate saline control injection of similar volume. Read the result at 10 minutes. A wheal at the Atgam site of 3 millimetres or larger in diameter than that at the saline control site (or a positive prick test) suggests clinical sensitivity and an increased possibility of a systemic allergic reaction.

The predictive value of this test has not been proven clinically. Allergic reactions can also occur in patients whose skin test is negative. Also, skin testing done as described above is not predictive of future development of serum sickness. In the presence of a locally positive skin test to Atgam, serious consideration to alternative forms of therapy should be given. The benefit-risk ratio must be carefully assessed. If therapy with Atgam is deemed appropriate following a locally positive skin test, treatment should be administered in a setting where intensive life support facilities are immediately available and a physician familiar with the treatment of potentially life-threatening allergic reactions is in attendance (see section 4.2).

Thrombocytopenia and neutropenia

Treatment with Atgam may exacerbate thrombocytopenia and neutropenia (see section 4.2).

Renal and liver function tests

In patients with aplastic anaemia and other haematologic abnormalities who have received Atgam abnormal test results of liver function and renal function have been observed.

Concomitant use of vaccines

The safety and effectiveness of immunisation with vaccines and treatment with Atgam have not been studied. Vaccination is not recommended in conjunction with Atgam therapy as the effectiveness of the vaccines could be reduced. The prescribing information for the respective vaccine should be consulted to determine the appropriate interval for vaccination in relation to immunosuppressive therapy.

Excipients

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per total dose, that is to say is essentially 'sodium-free'.

Atgam may be further prepared for administration with sodium-containing solutions (see section 6.6) and this should be considered in relation to the total daily intake from all sources that will be administered to the patient.

Transmissible Agents

Atgam is made from horse plasma and also employs human blood-derived reagents in the process.

Effective manufacturing steps for the inactivation/removal of viruses are employed in the Atgam process and these steps have been validated to clear a wide range of both human blood-borne and horse viruses, using a virus panel approach. This covers the complete virus spectrum from small, non-enveloped viruses such as parvoviruses and Hepatitis A to large enveloped viruses like Herpes Simplex Virus. Despite this, when medicinal products prepared from horse and human blood are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

When tapering corticosteroids and other immunosuppressants, some previously masked reactions to Atgam may appear. Under these circumstances, patients should be observed carefully during and after treatment with Atgam.

4.6. Fertility, pregnancy and lactation

Pregnancy

There is a limited amount of data from the use of horse anti-human T lymphocyte immunoglobulin in pregnant women. The outcome of pregnancies cannot be determined. Studies in animals have shown reproductive toxicity (see section 5.3). These effects are not considered relevant to humans.

As a precautionary measure, it is preferable to avoid the use of Atgam during pregnancy.

Women of childbearing potential should use effective contraception during and up to 10 weeks after cessation of therapy.

Breast-feeding

It is unknown whether horse anti-human T lymphocyte immunoglobulin is excreted in human milk. Available toxicological data in animals have not shown excretion of horse anti-human T lymphocyte immunoglobulin in milk (see section 5.3). As a risk to the breast-fed child cannot be excluded, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Atgam therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Administration of horse anti-human T lymphocyte immunoglobulin to cynomolgus monkeys (Macaca fascicularis) at doses comparable to those used in clinical studies was not associated with impairment of male or female fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

No studies on the effect or ability to drive or use machines have been performed. Horse anti-human T lymphocyte immunoglobulin has a moderate influence on the ability to drive and use machines. Given the potential adverse reactions that may be experienced (e.g., dizziness, convulsion, confusional state, syncope), caution should be taken when driving or using machinery.

4.8. Undesirable effects

The most commonly reported adverse reactions from clinical studies (occurring in greater than 10% of patients) are infections, neutropenia, serum sickness, headache, hypertension, diarrhoea, rash, arthralgia, pyrexia, chills, pain, oedema and abnormal liver function test (see section 4.4). Adverse reactions listed as frequency unknown are from post-marketing experience.

For safety information with respect to transmissible agents, see section 4.4.

Tabulated list of adverse reactions

In the following table, adverse reactions are listed by MedDRA system organ class and preferred term.

Note: Frequency categories are defined using the following convention: very common (≥1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2. Adverse Reactions

System Organ Class

Very Common

Common

Uncommon

Frequency Not Known

Infections and infestations

Infection, Localized Infection

Sepsis, Herpes simplex

Hepatitis viral, Epstein–Barr Virus

Cytomegalovirus infection

Blood and lymphatic system disorders

Neutropenia

Haemolysis, Leukopenia, Lymphadenopathy

Thrombocytopenia

Pancytopenia, Granulocytopenia, Haemolytic anaemia, Anaemia, Eosinophilia

Immune system disorders

Serum sickness

Anaphylactic reaction

Metabolism and nutrition disorders

Hyperglycaemia

Psychiatric disorders

Agitation

Confusional state, Disorientation

Nervous system disorders

Headache

Convulsion, Syncope, Paraesthesia, Dizziness

Encephalitis, Dyskinesia, Tremor

Eye disorders

Periorbital oedema

Cardiac disorders

Bradycardia, Tachycardia

Cardiac failure congestive

Vascular disorders

Hypertension

Hypotension, Thrombophlebitis

Vasculitis, Iliac vein occlusion, Deep vein thrombosis

Respiratory, thoracic and mediastinal disorders

Pleural effusion, Dyspnoea, Epistaxis, Cough

Laryngospasm, Pulmonary oedema, Apnoea, Oropharyngeal pain, Hiccups

Gastrointestinal disorders

Diarrhoea

Gastrointestinal haemorrhage, Abdominal pain, Abdominal pain upper, Vomiting, Stomatitis, Nausea

Gastrointestinal perforation, Oral pain

Skin and subcutaneous tissue disorders

Rash

Pruritus, Urticaria

Dermatitis allergic

Toxic epidermal necrolysis, Night sweats, Hyperhidrosis

Musculoskeletal and connective tissue disorders

Arthralgia

Myalgia, Back pain

Muscle rigidity, Flank pain, Pain in extremity

Renal and urinary disorders

Proteinuria

Renal failure acute, Renal artery thrombosis, Kidney enlargement

Congenital, familial and genetic disorders

Aplasia

General disorders and administration site conditions

Oedema, Pyrexia, Pain, Chills

Chest pain, Malaise

Infusion site erythema

Infusion site swelling, Infusion site pain, Asthenia

Investigations

Liver function test abnormal

Renal function test abnormal

Injury, poisoning and procedural complications

Kidney rupture, Arteriovenous fistula thrombosis, Wound dehiscence

Paediatric population

Data from published studies of differing designs suggest that the safety of Atgam in paediatric patients with aplastic anaemia is similar to that of adults, when treated with dosages comparable to those used in adults over similar treatment durations.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The maximum tolerated dose of Atgam would be expected to vary from patient to patient due to the biological nature of the product.

A maximum therapeutic dose has not been established therefore the definition of overdose for Atgam has not been clearly defined. Some aplastic anaemia patients have received up to 21 doses as additional alternate day therapy for another 14 days. The incidence of toxicologic manifestations did not increase with any of these regimens; however close monitoring of the patient is recommended.

No signs of acute intoxication or late sequelae have been observed at a single dose 7,000 mg in one renal transplant recipient treated with Atgam.

There is no known antidote. Treatment should be symptomatic.