What Hizentra is

Hizentra belongs to the class of medicines called human normal immunoglobulins. Immunoglobulins are also known as antibodies and are blood proteins.

How Hizentra works

Hizentra contains immunoglobulins that have been prepared from the blood of healthy people. Immunoglobulins are produced by human body’s immune system and help your body to fight infections caused by e.g. bacteria and viruses or maintain the balance in your immune system (referred to as

immunomodulation). The medicine works in exactly the same way as the immunoglobulins naturally present in your blood.

What Hizentra is used for

Replacement therapy

Hizentra is used to raise abnormally low immunoglobulin levels in your blood to normal levels (replacement therapy). The medicine is used in the following situations:

1. Treatment of adults, children and adolescents (0-18 years) who are born with a reduced ability or inability to produce immunoglobulins (primary immunodeficiency syndromes). This  includes conditions such as:

Ø  low immunoglobulin levels (hypogammaglobulinaemia) or absence of immunoglobulins (agammaglobulinaemia) in the blood

Ø  combination of low immunoglobulin levels, frequent infections and inability to produce adequate amounts of antibodies after vaccination (common variable immunodeficiency)

Ø  combination of low level or absence of immunoglobulins and absence or non-functional immune cells (severe combined immunodeficiency)

Ø  absence of certain immunoglobulin G subclasses causing recurrent infections.

2. Treatment of patients with low or dysfunctional immunoglobulin levels in acquired conditions (secondary immunodeficiency) who experience severe or recurrent infections due to a weakened immune system resulting from other conditions or treatments.

Immunomodulatory therapy in CIDP patients

Hizentra is also used in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), a form of autoimmune disease. CIDP is characterized by chronic inflammation of the peripheral nerves that causes muscle weakness and/or numbness mainly in the legs and arms. It is believed that the body’s defense attack underlines such inflammation, and immunoglobulins present in Hizentra help to protect the nerve from being attacked (immunomodulatory therapy).

Do NOT infuse Hizentra:

Ø  if you were allergic to human immunoglobulins, polysorbate 80 or L-proline in the past.

ETell your doctor or healthcare professional prior to treatment if you have experienced intolerance against one of these components earlier.

Ø  if you suffer from hyperprolinaemia (a genetic disorder causing high levels of the amino acid proline in the blood).

Warnings and precautions

ETalk to your doctor or healthcare professional before using Hizentra.

Route of administration

Administer Hizentra via the subcutaneous route only (under the skin). If Hizentra is accidentally administered into a blood vessel, you could develop severe allergic reaction (anaphylactic shock). The infusion rate recommended by your doctor should be adhered to. Closely monitor and carefully observe for any adverse events throughout the infusion period.

Hypersensitivity / Anaphylaxis

You may be allergic (hypersensitive) to immunoglobulins without knowing it. However, true allergic reactions are rare. They may occur even if you received human immunoglobulins previously and tolerated them well. It may happen particularly if you do not have enough of the immunoglobulin type A (IgA) in your blood (IgA deficiency).

ETell your doctor prior to treatment if you have an immunoglobulin type A (IgA) deficiency. Hizentra contains residual amounts of IgA which might cause an allergic reaction.

In these rare cases allergic reactions, such as a sudden fall in blood pressure or shock, may occur (see also section 4).

EIf you notice such signs during the infusion of Hizentra, stop the infusion and contact your doctor or go to the nearest hospital immediately.

Your doctor will avoid potential complications by ensuring:

Ø  that you are not sensitive to human normal immunoglobulin.

Ø  the medicine must be infused slowly at first.

Ø  that you are carefully monitored for any symptoms throughout the infusion period, especially if:

·                you receive human normal immunoglobulin for the first time

·                you have switched from a different medicine

·                there has been a long interval (more than eight weeks) since the previous infusion.

In these cases, it is recommended that you are monitored during the first infusion and for an hour afterwards. If the points above do not apply for you it is recommended that you are observed for at least 20 minutes after administration.

Blood clots

ETell your doctor if you have a history of heart or blood vessel disease or blood clots, have thick blood, or have been immobile for some time. These things may increase your risk of having a blood clot after using Hizentra. Also tell your doctor what drugs you are using, as some drugs, such as those that contain the hormone estrogen (for example, birth control pills), may increase your risk of developing a blood clot. Contact your doctor immediately if you experience signs and symptoms such as shortness of breath, chest pain, pain and swelling of a limb, weakness or numbness on one side of the body after receiving Hizentra.

Aseptic Meningitis Syndrome (AMS)

EContact your doctor if you experience the following signs and symptoms: severe headache, neck stiffness, drowsiness, fever, photophobia, nausea, and vomiting after receiving Hizentra. These symptoms might indicate aseptic meningitis (a temporary and reversible non-infectious inflammation of the protective membranes surrounding the brain and spinal cord). Your doctor will decide if further tests are necessary and whether Hizentra should be continued.

Renal complications

ETell your doctor if you have or had previously problems with your kidneys, take medicinal products that may harm your kidneys (nephrotoxic medicinal products), have diabetes (diabetes mellitus), hypovolemia (the liquid portion of your blood is too low), thick blood (hyperviscosity), are older than 65 years, or suffer from a condition called paraproteinaemia or sepsis. In these circumstances, immunoglobulin preparations, particularly those containing sucrose, may increase the risk of serious renal complications (acute renal failure, acute tubular necrosis, proximal tubulopathy, osmotic nephrosis), including rapid loss of the kidney function (acute renal failure). Hizentra does not contain sucrose.

Haemolytic anaemia

Immunoglobulin products can contain blood group antibodies that may affect certain blood tests (serological tests such as e.g. DAT, direct Coombs test) and, rarely, cause the breakdown of the red blood cells (haemolysis). It has been reported that this may lead to a subsequent decrease in the red blood cells (delayed haemolytic anaemia) during the immunoglobulin therapy.

Pathogen safety

Hizentra is made from human blood plasma. This is the liquid part of the blood. When medicines are made from human blood or plasma, certain measures are put in place to prevent infections being passed on to patients. These include:

Ø  careful selection of blood and plasma donors to make sure those at risk of carrying infections are excluded, and

Ø  the testing of each donation and pools of plasma for signs of virus/infections. Manufacturers of these medicines also include additional steps in the processing of the blood or plasma that can inactivate or remove viruses.

Despite these measures, when medicines prepared from human blood or plasma are administered, the possibility of passing on infection cannot be totally excluded. This also applies to any unknown or emerging viruses or other types of infections.

The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV, the AIDS virus), hepatitis B virus and hepatitis C virus (liver inflammation), and for the non-enveloped hepatitis A virus and parvovirus B19.

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

EIt is strongly recommended that every time you receive a dose of Hizentra the name and batch number of the product are recorded in order to maintain a record of the batches used (see section 3).

Other medicines and Hizentra

ETell your doctor if you are using, have recently used or might use any other medicines. You must not mix other medicines with Hizentra.

Live attenuated virus vaccines

ETell your vaccinating doctor prior to a vaccination about your treatment with Hizentra. Hizentra may impair the effect of some live virus vaccines such as measles, rubella, mumps and chicken pox. Therefore, after receiving this medicine you may have to wait up to 3 months before

receiving your live-attenuated vaccine. In the case of measles vaccinations the impairment may persist for up to 1 year.

Blood tests

After receiving Hizentra, the results of certain blood tests (serological tests) may be impaired for a certain time.

ETell your doctor about your treatment with Hizentra prior to any blood test.

Pregnancy, breastfeeding and fertility

ETell your doctor if you are pregnant, plan to become pregnant or are breastfeeding. Your doctor will decide whether you can receive Hizentra during your pregnancy or while you are breastfeeding.

No clinical studies have been performed with Hizentra in pregnant women. However, medicines that contain immunoglobulins have been used in pregnant or breastfeeding women for years, and no harmful effects on the course of pregnancy or on the baby have been observed.

If you are breastfeeding and receive Hizentra, the immunoglobulins of the medicine can also be found in the breast milk. Therefore, your baby may be protected from certain infections.

Driving and using machines

The ability to drive and operate machines may be impaired by some side effects associated with Hizentra. If you experience adverse reactions during treatment you should wait for these to resolve before driving or operating machines.

Hizentra contains proline

You must not take it if you suffer from hyperprolinaemia (see also section 2). Please tell your doctor prior to treatment.

Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

Dosage

Your doctor will calculate the correct dose for you taking into account your weight and response to treatment.

Do not change the dose or dosing interval without consulting with your doctor.

If you think you should receive Hizentra more or less frequently, please speak to your doctor. If you think you have missed a dose, speak to your doctor as soon as possible.

Replacement therapy

Your doctor will determine whether you need a loading dose (for adults, children and adolescents) of at least 1 to 2.5 ml/kg of body weight that may be divided over several days. Following this, maintenance doses may be given at repeated intervals, from daily to once every two weeks, to reach a cumulative monthly dose of about 2 to 4 ml/kg of body weight. Your healthcare professional may adjust the dose

based on your response to the treatment.

Immunomodulatory therapy

Your doctor will initiate the therapy with Hizentra 1 week after your last intravenous immunoglobulin infusion by administrating under the skin (subcutaneously) a weekly dose of 2.0 ml/kg of body weight. Your doctor will determine your weekly Hizentra dose (for adults, children and adolescents). The weekly maintenance doses may be divided into smaller doses and administered by desired number of times per week. For dosing every two weeks, your doctor will double the determined weekly Hizentra dose. Your healthcare professional may adjust the dose based on your response to the treatment.

Method and route of administration

In case of home treatment, this will be initiated and initially monitored by a healthcare professional experienced in the treatment of immunodeficiency/CIDP and in the guidance of patients for home treatment.

You will be instructed in:

Ø  aseptic infusion techniques

Ø  the keeping of a treatment diary, and

Ø  measures to be taken in case of severe side effects. Only after such guidance should you follow the instructions below.

Infusion site(s)

Ø  Administer Hizentra under the skin only.

Ø  You may infuse Hizentra into sites such as abdomen, thigh, upper arm, and lateral hip (see Figure 1). If large doses are given (> 50 ml), try to administer them at multiple sites.

Ø  There is no limit to the number of infusion sites used at the same time.

Ø  In the case, you will use a device-assisted infusion technique (e.g. pump-assisted infusion), more than one infusion device can be used simultaneously.

Ø  In the case, you will use the manual push infusion technique with a syringe, you may use only one infusion site per syringe. If you need to administer an additional Hizentra syringe, you must use a new sterile injection needle and change the infusion site.

Ø  The volume of product infused into a particular site may vary.

Ø  Infusion sites should be at least 5 cm apart.

Figure 1: Possible infusion sites for Hizentra

Infusion rate(s)

Your doctor will determine the appropriate infusion technique and the infusion rate for you taking into account your individual dose, dosing frequency and product tolerability.

Device-assisted infusion:

The recommended initial infusion rate is up to 20 ml/ hour/ site. If well-tolerated, you may gradually increase the infusion rate to 100 ml/ hour/ site for the following two infusions.

If you are a patient at a risk, as described in section 2 (see section 2), administer Hizentra at the minimum dose and infusion rate practicable.

Manual push infusion:

The recommended initial infusion rate is up to 0.5 ml / min / site (30 ml / hour / site). If well-tolerated, you may increase the infusion rate up to 2.0 ml / min / site (120 ml / hour / site).

Other instructions for use

Ø  Hizentra is a ready-to-use solution (see section 5 and section 6)

Ø  Do not use solutions that are cloudy or contain particles.

Ø  Do not use solutions that have been frozen.

Ø  Administer solution which is at room temperature (25 °C).

Ø  Once a vial has been opened, use the solution immediately.

Ø  Use aseptic technique when preparing and administering Hizentra.

Ø  Record the following data in your treatment diary:

·                the date of administration,

·                the batch number of the medicine, and

·                the infused volume, flow rate, the number and location of infusion sites.

If you have any further questions on the use of this medicine, please ask your doctor or healthcare professional.

If you use more Hizentra than you should

If you think you have had too much Hizentra, speak to your doctor as soon as possible.

If you forget to use Hizentra

If you think you have missed a dose, speak to your doctor as soon as possible.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Side effects observed in controlled clinical studies are presented in order of decreasing frequency. Side effects observed in post-marketing are of unknown frequency:

The following side effects are very common (affects more than 1 patient in 10):

Ø  Nasopharyngitis

Ø  Headache

Ø  Rash

Ø  Reactions at the infusion site

The following side effects are common (affects 1 to 10 patients in 100):

Ø  Dizziness

Ø  Migraine

Ø  Increased blood pressure (hypertension)

Ø  Cough

Ø  Diarrhea

Ø  Abdominal pain

Ø  Feeling sick (nausea)

Ø  Vomiting

Ø  Itching (pruritus)

Ø  Skin reaction such as blistering (urticaria)

Ø  Contact dermatitis

Ø  Pain related to the musculature and bones (musculoskeletal pain)

Ø  Joint pain (arthralgia)

Ø  Tiredness (fatigue), including generally feeling unwell (malaise)

Ø  Fever

Ø  Chest pain

Ø  Flu-like symptoms

Ø  Pain

The following side effects are uncommon (affects 1 to 10 patients in 1.000):

Ø  Hypersensitivity

Ø  Aseptic meningitis syndrome (AMS, a temporary and reversible non-infectious inflammation of the protective membranes surrounding the brain and spinal cord)

Ø  Tremor, including psychomotor hyperactivity

Ø  Fast heartbeat (tachycardia)

Ø  Flushing

Ø  Joint inflammation (arthritis)

Ø  Muscle spasms

Ø  Muscular weakness

Ø  Chills, including low body temperature

Ø  Weight loss

Ø  Results of blood tests suggesting impaired e.g. liver and kidney function

In isolated cases (post-marketing experience) hypersensitivity and anaphylactic reactions of the immune system, burning sensation, sleepiness, formation of blood clots which may be carried off in the blood circulation and which may result in blockage of a blood vessel (embolic and thrombotic events), and infusion-site ulcer have been observed in treatment with Hizentra.

In isolated cases (post-marketing experience with other immunoglobulins; not observed with Hizentra) haemolytic anaemia, acute renal failure, acute tubular necrosis, proximal tubulopathy and osmotic nephrosis.

ETell your doctor immediately if you have any of the following signs or symptoms during or following an infusion of Hizentra:

Ø  You may be allergic (hypersensitive) to immunoglobulins and allergic reactions such as a sudden fall in blood pressure or shock may occur (e.g. you may feel light-headed, dizzy, faint

on standing, cold in the hands and feet, sense an abnormal heart beat or chest pain, or have blurred vision).

If you notice such signs during the infusion of Hizentra, tell your doctor immediately. Please see also section 2 of this leaflet about the risk of allergic reactions.

You may reduce or even avoid possible side effects if you slowly infuse Hizentra.

Ø  Pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body, sudden confusion, or trouble speaking or understanding could be signs of a blood clot.

Ø  Bad headache with nausea, vomiting, stiff neck, fever, and sensitivity to light could be signs of AMS.

Side effects such as these may occur even when you have previously received human immunoglobulins and tolerated them well.

Please also refer to section 2 for additional details on circumstances which increase the risk of side effect.

Reporting of side effects

If you get any side effects, talk to your doctor or healthcare professional. This includes any possible side effects not listed in this leaflet. By reporting side effects you can help provide more information on the safety of this medicine.

Ø  Do not use this medicine after the expiry date (EXP) which is stated on the outer carton and the vial label after EXP.

Ø  Hizentra should be administered as soon as possible after opening the vial as the solution contains no preservative.

Ø  Do not store above 25°C.

Ø  Do not freeze.

Ø  Do not use if Hizentra has been frozen.

Ø  Keep this medicine out of the sight and reach of children.

Ø  Keep the vial in the outer carton in order to protect from light.

Ø  Do not throw away any medicines via wastewater or household waste. Ask your doctor or healthcare professional how to throw away medicines you no longer use. These

measures will help protect the environment.