Zemaira

Dosage Forms And Strengths

Zemaira is supplied in a single-use vial containing approximately 1000 mg of functionally active A1-PI as a lyophilized powder for reconstitution with 20 mL of Sterile Water for Injection, USP. The amount of functional A1-PI is printed on the vial label and carton.

Storage And Handling

Zemaira is supplied in a single use vial containing the amount of functionally active A1-PI printed on the label.

The product presentation includes a package insert and the following components:

When stored up to 25°C (77°F), Zemaira is stable for the period indicated by the expiration date on its label. Avoid freezing, which may damage the diluent vial.

Manufactured by: CSL Behring LLC, Kankakee, IL 60901 USA.

It is very important that your doctor check you closely while you are receiving this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to use it.

This medicine may cause serious allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash, itching, hoarseness, lightheadedness, dizziness, or fainting, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth after you receive this medicine.

Alpha 1-PI is made from donated human blood. Some human blood products have transmitted certain viruses to people who have received them. The risk of getting a virus from alpha 1-PI is very low and has been greatly reduced in recent years. This is the result of required testing of human donors for certain viruses, and testing during the manufacture of these medicines. Although the risk is low, talk with your doctor if you have concerns. Your doctor may give you a hepatitis B vaccine before receiving this medicine.

Alpha1-proteinase inhibitor (A1-PI) deficiency is a chronic, hereditary, autosomal, co-dominant disorder that is usually fatal in its severe form. Low blood levels of A1-PI (i.e., below 11 µM) are most commonly associated with progressive, severe emphysema that becomes clinically apparent by the third to fourth decade of life. In addition, PiSZ individuals, whose serum A1-PI levels range from approximately 9 to 23 µM are considered to have moderately increased risk for developing emphysema, regardless of whether their serum A1-PI levels are above or below 11 µM.1 Not all individuals with severe genetic variants of A1-PI deficiency have emphysema. Augmentation therapy with Alpha1-Proteinase Inhibitor (Human) is indicated only in patients with severe congenital A1-PI deficiency who have clinically evident emphysema. A recent registry study showed 54% of A1-PI deficient subjects had emphysema.2 Another registry study showed 72% of A1-PI deficient subjects had pulmonary symptoms.3 Smoking is an important risk factor for the development of emphysema in patients with A1-PI deficiency.

Approximately 100 genetic variants of A1-PI deficiency can be identified electrophoretically, only some of which are associated with the clinical disease.4,5 Ninety-five percent of A1-PI deficient individuals are of the severe PiZZ phenotype. Up to 39% of A1-PI deficient patients may have an asthmatic component to their lung disease, as evidenced by symptoms and/or bronchial hyperreactivity.2 Pulmonary infections, including pneumonia and acute bronchitis, are common in A1-PI deficient patients and contribute significantly to the morbidity of the disease.

Augmenting the levels of functional protease inhibitor by intravenous infusion is an approach to therapy for patients with A1-PI deficiency. However, the efficacy of augmentation therapy in affecting the progression of emphysema has not been demonstrated in randomized, controlled clinical trials. The intended theoretical goal is to provide protection to the lower respiratory tract by correcting the imbalance between neutrophil elastase and protease inhibitors. Whether augmentation therapy with Zemaira® or any A1-PI product actually protects the lower respiratory tract from progressive emphysematous changes has not been evaluated. Individuals with endogenous levels of A1-PI below 11 µM, in general, manifest a significantly increased risk for development of emphysema above the general population background risk.5,6,7,8 Although the maintenance of blood serum levels of A1-PI (antigenically measured) above 11 µM has been historically postulated to provide therapeutically relevant anti-neutrophil elastase protection9, this has not been proven. Individuals with severe A1-PI deficiency have been shown to have increased neutrophil and neutrophil elastase concentrations in lung epithelial lining fluid compared to normal PiMM individuals, and some PiSZ individuals with A1-PI above 11 µM have emphysema attributed to A1-PI deficiency.1 These observations underscore the uncertainty regarding the appropriate therapeutic target serum level of A1-PI during augmentation therapy.

Mechanism of Action

Pulmonary disease, particularly emphysema, is the most frequent manifestation of A1-PI deficiency.5 The pathogenesis of emphysema is understood to evolve as described in the "protease-antiprotease imbalance" model. A1-PI is now understood to be the primary antiprotease in the lower respiratory tract, where it inhibits neutrophil elastase (NE).10 Normal healthy individuals produce sufficient A1-PI to control the NE produced by activated neutrophils and are thus able to prevent inappropriate proteolysis of lung tissue by NE. Conditions that increase neutrophil accumulation and activation in the lung, such as respiratory infection and smoking, will in turn increase levels of NE. However, individuals who are severely deficient in endogenous A1-PI are unable to maintain an appropriate antiprotease defense and are thereby subject to more rapid proteolysis of the alveolar walls leading to chronic lung disease. Zemaira® serves as A1-PI augmentation therapy in this patient population, acting to increase and maintain serum levels and lung epithelial lining fluid (ELF) levels of A1-PI.

In 18 subjects treated with a single dose (60 mg/kg) of Zemaira®, the mean area under the curve (AUC) and standard deviation (SD) were 144 µM × day (SD 27), maximum serum concentration was 44.1 µM (SD 10.8), clearance was 603 mL per day (SD 129), and terminal half-life was 5.1 days (SD 2.4).

Weekly repeated infusions of A1-PI at a dose of 60 mg/kg lead to serum A1-PI levels above the historical target threshold of 11 µM.

The clinical benefit of the increased blood levels of A1-PI at the recommended dose for any A1-PI product has not been established.

Zemaira® is contraindicated in individuals with a known hypersensitivity to any of its components. Zemaira® is also contraindicated in individuals with a history of anaphylaxis or severe systemic response to A1-PI products.

Zemaira® is contraindicated in IgA deficient patients with antibodies against IgA, due to the risk of severe hypersensitivity.

Zemaira® may contain trace amounts of IgA. Patients with known antibodies to IgA, which can be present in patients with selective or severe IgA deficiency, have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Zemaira® is contraindicated in patients with antibodies against IgA due to risk of severe hypersensitivity.

Zemaira® is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. Because Zemaira® is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically the Creutzfeldt-Jakob disease (CJD) agent. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses during manufacture. (See DESCRIPTION section for viral reduction measures.) The manufacturing procedure for Zemaira® includes processing steps designed to reduce further the risk of viral transmission. Stringent procedures utilized at plasma collection centers, plasma testing laboratories, and fractionation facilities are designed to reduce the risk of viral transmission. The primary viral reduction steps of the Zemaira® manufacturing process are pasteurization (60°C for 10 hours) and nanofiltration. Additional purification procedures used in the manufacture of Zemaira® also potentially provide viral reduction. Despite these measures, such products may still potentially contain human pathogenic agents, including those not yet known or identified. Thus, the risk of transmission of infectious agents can not be totally eliminated. Any infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to CSL Behring at 1-866-915-6958. The physician should discuss the risks and benefits of this product with the patient.

Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections (see Information For Patients).

During clinical studies, no cases of hepatitis A, B, C, or HIV viral infections were reported with the use of Zemaira®.

You should not use Zemaira if you have ever had an allergic reaction to alpha 1-proteinase inhibitor, or if you have an IgA (immunoglobulin A) deficiency or antibody against IgA.

Zemaira must be mixed with a liquid (diluent) before given as an injection. If you are using the injections at home, be sure you understand how to properly prepare and store your medicine.

Call your doctor at once if you have a serious side effect such as fever, chills, body aches, flu symptoms, mouth sores, pain or burning when you urinate, wheezing, chest pain or tightness, trouble breathing, or vision changes. Zemaira is made from human plasma (part of the blood) which may contain viruses and other infectious agents. Donated plasma is tested and treated to reduce the risk of it containing infectious agents, but there is still a small possibility it could transmit disease. Talk with your doctor about the risks and benefits of using this medication.

You should not use Zemaira if you have ever had an allergic reaction to alpha 1-proteinase inhibitor, or if you have an IgA (immunoglobulin A) deficiency or antibody against IgA.

To make sure you can safely use Zemaira, tell your doctor if you have any of these other conditions:

• liver disease; or

• asthma, chronic obstructive pulmonary disease (COPD), or other breathing disorder.

FDA pregnancy category C. It is not known whether Zemaira will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether alpha 1-proteinase inhibitor passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Alpha 1-proteinase inhibitor is made from human plasma (part of the blood) which may contain viruses and other infectious agents. Donated plasma is tested and treated to reduce the risk of it containing infectious agents, but there is still a small possibility it could transmit disease. Talk with your doctor about the risks and benefits of using Zemaira.

Zemaira is injected into a vein through an IV. You may be shown how to use an IV at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.

Zemaira is usually given once per week. Follow your doctor's dosing instructions very carefully.

You will most likely receive your first few doses of this medication in a hospital or clinic setting where your vital signs can be watched closely in case the medication causes serious side effects.

Zemaira is a powder form of alpha 1-proteinase inhibitor. Zemaira must be mixed with a liquid (diluent) before preparing your dose.

Do not shake the mixture or you may ruin the medicine. Prepare your dose in a syringe only when you are ready to give yourself an injection. Do not use the medication if it has changed colors or has particles in it. Call your doctor for a new prescription.

If you are using the injections at home, be sure you understand how to properly mix and store the medicine.

This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.

Each single use vial (bottle) of this medicine is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.

Store Zemaira at cool room temperature, away from moisture and heat. Do not freeze. The diluent bottle can break if it becomes frozen.

After mixing Zemaira powder with a diluent, you must use the mixture within 3 hours.

Do not use Zemaira after the expiration date on the medicine label has passed.

Call your doctor for instructions if you miss a dose of Zemaira.

Get emergency medical help if you have any of these signs of an allergic reaction to Zemaira: hives; wheezing, difficulty breathing; feeling like you might pass out; swelling of your face, lips, tongue, or throat.

Stop using Zemaira and call your doctor at once if you have a serious side effect such as:

• fever, chills, body aches, flu symptoms, sores in your mouth and throat;

• pain or burning when you urinate;

• wheezing, chest pain or tightness, trouble breathing; or

• vision changes.

Less serious Zemaira side effects may include:

• nausea, bloating;

• headache, dizziness, drowsiness;

• feeling tired;

• back pain, joint or muscle pain;

• swelling in your hands or feet;

• flushing (warmth, redness, or tingly feeling);

• cold symptoms such as stuffy nose, sneezing, sore throat, cough; or

• mild itching.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.
• This medicine will be given to you by a doctor.

What do I do if I miss a dose?

• Call your doctor to find out what to do.