Document: document 1 change

• document 0
• document 1

---

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

SUBCUVIA 160 g/l Solution for Injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Human Normal Immunoglobulin 1 l solution contains: human protein 160 g

(of which at least 90% are immunoglobulin G)

3 PHARMACEUTICAL FORM

Solution for subcutaneous or intramuscular administration.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Replacement therapy in adults and children in primary immunodeficiency syndromes such as:

-    congenital agammaglobulinaemia and hypogammaglobulinaemia

-    common variable immunodeficiency

-    severe combined immunodeficiency

-    IgG subclass deficiencies with recurrent infections

Replacement therapy in myeloma or chronic lymphatic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections.

4.2 Posology and method of administration

Replacement therapy

Treatment should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency.

The dosage may need to be individualised for each patient dependent on the pharmacokinetic and clinical response. The following dosage regimens are given as a guideline.

Adults and elderly:

The dosage should be adjusted to maintain trough level of at least 4-6 g/L of circulating IgG.

The dosage regimen using the subcutaneous route should achieve a sustained level of IgG (measured before the next infusion). A loading dose of at least 0.2-0.5 g/kg given over the course of one week (0.1 - 0.15 g/kg bodyweight on any given day) may be required. After steady state IgG levels have been attained, maintenance doses are administered at repeated intervals to reach a cumulative monthly dose of the order of 0.4-0.8 g/kg.

Trough levels should be measured in order to adjust the dose and dosage interval.

SUBCUVIA may also be injected by the intramuscular route. In such cases, the cumulative monthly dose should be divided up into weekly or bi-weekly applications, in order to keep the injected volume low. To further minimize the discomfort for the patient, each single dosage may need to be injected at different anatomic sites.

Children:

Administration of Subcuvia to children should use the same dosage recommendation as stated above for adults.

Human normal immunoglobulin is administered via the subcutaneous or intramuscular route.

SUBCUVIA should be administered via the subcutaneous route. In exceptional cases, where subcutaneous administration is not possible SUBCUVIA can be given intramuscularly.

Subcutaneous infusion for home treatment should be initiated by a physician experienced in the guidance of patients for home treatment. The patient will be instructed in the use of a syringe driver, infusion techniques, the keeping of a treatment diary and measures to be taken in case of severe adverse events.

It is recommended to use an initial speed of 10 ml/h/pump.

The infusion speed can be increased by 1 ml/h/pump every subsequent infusion. The recommended maximum speed is 20 ml/h/pump. More than one pump can be used simultaneously. The infusion site should be changed every 5-15 ml.

Intramuscular injection must be given by a physician or nurse.

4.3 Contraindications

Hypersensitivity to any of the components.

SUBCUVIA must not be given intravenously.

SUBCUVIA must not be administered intramuscularly in cases of severe thrombocytopenia and in other disorders of haemostasis.

4.4 Special warnings and precautions for use

If SUBCUVIA is accidentally administered into a blood vessel, patients could develop shock. Therefore, it must be ensured that SUBCUVIA is not administered into a blood vessel.

The recommended infusion rate stated under “4.2 Method of Administration” should be adhered to. Patients should be closely monitored and carefully be observed for any adverse events throughout the infusion period.

Patients receiving treatment at home, and/or their guardian must be trained to detect the early signs of hypotensive reactions that may seldom occur. Suspicion of allergic or anaphylactic type reactions requires immediate discontinuation of the injection. If severe anaphylactoid reactions do occur, standard medical treatment should be implemented and the patient or guardian should contact a doctor immediately.

Certain adverse reactions may occur more frequently in patients who receive human normal immunoglobulin for the first time or, in rare cases, when the human normal immunoglobulin product is switched or when treatment has been stopped for more than eight weeks.

True hypersensitivity reactions are rare. They can particularly occur in very rare cases of IgA deficiency with anti-IgA antibodies and these patients should be treated with caution.

Rarely, human normal immunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin.

Potential complications can often be avoided by ensuring that:

•    patients are not sensitive to human normal immunoglobulin by first injecting the product slowly (see 4.2)

•    patients are carefully monitored for any symptoms throughout the infusion period. In particular, patients naive to human normal immunoglobulin, patients switched from an alternative product or when there has been a long interval since the previous infusion should be monitored during the first infusion and for the first hour after the first infusion, in order to detect potential adverse signs. All other patients should be observed for at least 20 minutes after administration.

Suspicion of allergic or anaphylactic type reactions requires immediate discontinuation of the injection. In case of shock, standard medical treatment should be administered.

SUBCUVIA is made from human plasma.

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV.

The measures taken may be of limited value against non-enveloped viruses such as HAV and parvovirus B19.

Parvovirus B19 infection may be serious for pregnant women (fetal infection) and for individuals with immunodeficiency or increased red blood cell turnover (e.g., haemolytic anaemia).

There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to the viral safety.

It is strongly recommended that every time that SUBCUVIA is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Interference with serological testing:

After injection of immunoglobulin the transitory rise in the various passively transferred antibodies in the patient's blood may result in misleading positive results in serological testing.

Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D may interfere with some serological tests for red cell antibodies, for example the antiglobulin test (Coombs test), or other laboratory tests, e.g. reticulocyte count and haptoglobulin test.

This medicinal product contains 1.2 mg sodium per ml. This should be taken into account by patients on a low sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Live attenuated virus vaccines

Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After administration of this product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year.

Therefore patients receiving measles vaccine should have their antibody status checked.

4.6 Fertility, Pregnancy and lactation

The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials and therefore should only be given with caution to pregnant women and breast-feeding mothers. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected.

Continued treatment of the pregnant woman is important to ensure that the neonate is born with appropriate passive immunity.

See section 4.4 for information on Parvovirus B19 infection.

4.7 Effects on ability to drive and use machines

No effects on ability to drive and use machines have been observed.

4.8 Undesirable effects

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Rarely human normal immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration.

Adverse reactions such as chills, headache, fever, vomiting, allergic reactions, nausea, dizziness, hyperhidrosis, pallor, paraesthesia, tachycardia, arthralgia, low blood pressure and moderate low back pain may occur occasionally.

Local reactions at infusion site: swelling, soreness, redness, induration, local heat, local pain, itching, bruising and rash.

In very rare cases anaphylactic/anaphylactoid reactions, such as dyspnoea, chest tightness, flushing of the face and skin, feeling of heat, and urticaria, may occur.

The adverse reactions presented in this section have been identified from clinical trials (IMAG-069 and IMAG-147) and from post-marketing experience with subcutaneous administration of human normal immunoglobulin.

System Organ Class (SOC)	Preferred MedDRA Term	Frequency
IMMUNE SYSTEM DISORDERS	Anaphylactic shock	Not known
	Anaphyl acti c/ Anaphyl actoi d reactions	Not known
	Hypersensitivity reactions	Not known
NERVOUS SYSTEM DISORDERS	Dizziness	Uncommon
	Headache	Uncommon
	Tremor	Rare
	Paresthesia	Not known
CARDIAC DISORDERS	Heart rate increased	Rare
	Tachycardia	Not known
VASCULAR DISORDERS	Peripheral coldness	Rare
	Hypotension	Not known
	Hypertension	Not known

System Organ Class (SOC)	Preferred MedDRA Term	Frequency
	Flushing	Not known
	Pallor	Not known
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS	Dyspnea	Not known
GASTROINTESTINAL DISORDERS	Nausea	Uncommon
	Abdominal pain	Rare
	Vomiting	Not known
	Paresthesia oral	Not known
SKIN AND SUBCUTANEOUS TISSUE DISORDERS	Pruritus	Uncommon
	Erythema	Uncommon
	Swelling face	Not known
	Urticaria	Not known
	Rash macula-papular	Not known
	Dermatitis allergic	Not known
	Hyperhidrosis	Not known
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS	Arthralgia	Rare
	Musculoskeletal stiffness	Rare
	Myalgia	Rare
	Back pain	Not known
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS	Injection site hemorrhage	Common
	Injection site pain	Common
	Injection site hematoma	Common
	Injection site erythema	Common
	Chills	Common
	Injection site swelling	Uncommon
	Injection site pruritus	Uncommon
	Pain	Uncommon
	Fatigue	Uncommon
	Feeling hot	Uncommon

System Organ Class (SOC)	Preferred MedDRA Term	Frequency
	Injection site rash	Rare
	Chest discomfort	Not known
	Pyrexia	Not known
	Malaise	Not known
	Injection site reaction	Not known
	Injection site urticaria	Not known
	Injection site induration	Not known
	Injection site warmth	Not known
INVESTIGATIONS	Alanine aminotransferase increased	Rare

• Legend: ADR frequency is based upon the following scale: Very Common (>1/10); Common (>1/100 - <1/10), Uncommon (>1/1,000 - <1/100), Rare (>1/10,000 -<1/1,000), Very Rare (<1/10,000)

For safety with respect to transmissible agents, see 4.4 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.

4.9 Overdose

Consequences of an overdose are not known.

5    PHARMACOLOGICAL PROPERTIES

SUBCUVIA is a liquid immunoglobulin concentrate for subcutaneous administration, which is manufactured from pooled human plasma.

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for extravascular administration. ATC code: J06BA01

Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents.

Human normal immunoglobulin contains the 1gG antibodies present in the normal population. It is usually prepared from pooled plasma from not fewer than 1000 donations. It has a distribution of immunglobulin G subclasses closely proportional to that in native human plasma.

Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the normal range.

5.2 Pharmacokinetic properties

With subcutaneous administration of human normal immunoglobulin, peak levels are achieved in the recipient’s circulation after a delay of about 4 days. Data from clinical trials show that trough levels of 7,24-7,86 g/l can be maintained by dosing regimens of 1,25 ml (0,2 g)/kg bw administered at intervals of 2 weeks.

The half-life of total IgG calculated in patients with hypo- or agammaglobulinemia after subcutaneous administration of SUBCUVIA was calculated to be approximately 40 days.

With intramuscular administration, human normal immunoglobulin is bioavailable in the recipient’s circulation after a delay of 2-3 days.

IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.

5.3 Preclinical safety data

Single dose toxicity studies demonstrate that the doses several times higher than the maximum recommended human dose had no toxic effects on laboratory animals.

Repeated dose toxicity testing in animals is impracticable due to interference with developing antibodies to heterologous protein.

Since human proteins have not been seen to cause tumorigenic or mutagenic effects, experimental studies particularly in a heterologous species are not considered necessary.

6.1 List of excipients

Glycine

Sodium chloride Water for Injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

30 months.

After opening of the vial the product must be used immediately.

6.4 Special precautions for storage

Store in a refrigerator (2°C - 8°C).

During the shelf life, the product may be stored at room temperature (not more than 25°C) for up to 3 months. The date of transfer to room temperature and the end of the 3 month period should be recorded on the outer carton. Once the product is stored at room temperature it must not be returned to the refrigerator and must be discarded, if not used by the end of the 3 month period.

Do not freeze.

Keep the container in the outer carton in order to protect from light.

Keep out of the reach and sight of children.

6.5 Nature and contents of container

The product is supplied in vials made of glass of hydrolytic type I that are closed with bromobutyl rubber stoppers.

SUBCUVIA is available in packages containing either:

1 vial with 5 ml solution for injection/infusion,

20 vials with 5 ml solution for injection/infusion each, or 1 vial with 10 ml solution for injection/infusion.

20 vials with 10 ml solution for injection/infusion

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

The product should be brought to room or body temperature before use.

Do not use heating devices.

The liquid preparation is clear and pale yellow to light brown; during storage it may show formation of slight turbidity or a small amount of particulate matter.

Do not use solutions that are more than just slightly turbid.

Entered vials must not be reused.

Any unused product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Baxalta Innovations GmbH Industriestrasse 67 A-1221 Vienna Austria

8    MARKETING AUTHORISATION NUMBER(S)

PL 34078/0010

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

06/11/2003 01/07/2015