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  • CLASSES

    Emphysema Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Parenteral preparation of purified human alpha1-proteinase inhibitor (A1-PI) from plasma of healthy donors, also known as alpha-1-antitrypsin (AAT)
    Used to treat adults with emphysema due to severe hereditary alpha1-antitrypsin deficiency (AATD)
    A1-PI treatment may delay the time to death, lung transplantation, or crippling respiratory complaints

    COMMON BRAND NAMES

    Aralast NP, Glassia, Prolastin C, Zemaira

    HOW SUPPLIED

    Aralast NP/Prolastin C/Zemaira Intravenous Inj Pwd F/Sol
    Glassia/Prolastin C Intravenous Inj Sol

    DOSAGE & INDICATIONS

    For chronic augmentation and maintenance therapy in adults with emphysema due to alpha-1 proteinase inhibitor (A1PI) deficiency.
    Intravenous dosage
    Adults

    60 mg/kg IV infusion once weekly. Different brands are infused at different rates. Infuse at a rate of approximately 0.08 mL/kg/minute for Zemaira, Aralast NP, Prolastin, and Prolastin-C. For Glassia, infuse at a rate not to exceed 0.2 mL/kg/minute IV. If needed for patient comfort or adverse reactions, reduce the infusion rate. Alpha-1-proteinase inhibitor is indicated for patients in whom severe congenital alpha-1-proteinase inhibitor deficiency has been established. The impact of therapy on pulmonary exacerbations in patients with severe deficiency has not been determined. Findings from the RAPID/RAPID Extension program have confirmed the benefits of A1-PI therapy in slowing disease progression and provided evidence of a disease-modifying effect in patients with AATD; the study suggests that the early introduction of treatment may delay the time to death, lung transplantation, or crippling respiratory complaints in patients with emphysema related to severe AATD.

    MAXIMUM DOSAGE

    Adults

    60 mg/kg IV once weekly.

    Geriatric

    60 mg/kg IV once weekly.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Have epinephrine and other appropriate supportive therapy available for the treatment of any acute anaphylactic or anaphylactoid reactions.

    Intravenous Administration

    Aralast NP
    Reconstitution
    Have lyophilized drug vial and diluent at room temperature before reconstitution.
    The unreconstituted, lyophilized cake should be white or off-white to slightly yellow-green or yellow in color.
    Remove the cover from one end of the transfer needle, and insert the needle into the diluent vial. Remove the cover at the other end of the transfer needle. Invert the diluent vial, and insert the attached needle into the product vial at an angle, so that the diluent will be directed against the wall of the product to minimize foaming. The vacuum in the product vial will draw the diluent into it. Remove the diluent vial and the transfer needle.
    Let the vial stand until most of the content is in solution, then gently swirl the vial until the powder is completely dissolved. Do not shake the vial or invert it until ready to withdraw content. Reconstitution requires no more than 5 minutes for a 0.5 gram vial and no more than 10 minutes for a 1 gram vial. The reconstituted solution should be colorless to slightly yellow to yellowish-green. A few small, visible particles may remain and will be removed by the microaggregate filter.
    Each single-use vial contains approximately 500 mg or 1,000 mg of functionally active alpha-1-proteinase inhibitor. If needed, the reconstituted solution from several vials may be pooled into an empty, sterile IV solution container; aseptic technique is needed.
    Keep reconstituted solution at room temperature, and administer reconstituted solution within 3 hours.
    Intravenous infusion
    Do not mix Aralast NP with any other agent or solution.
    Use a sterile 20 micron in-line filter when administering the product.
    Infuse intravenously at a rate not exceeding 0.08 mL/kg/minute. Continuously monitor vital signs, and carefully observe the patient throughout the infusion. Immediately discontinue the infusion if anaphylactic or severe anaphylactoid reactions occur. If other adverse events occur, reduce the rate or interrupt the infusion until symptoms subside. The infusion may resume at a rate tolerated by the patient.
     
    Glassia
    Intravenous infusion
    Glassia should be administered by a healthcare professional or self-administered by the patient or caregiver after appropriate training. For self-administration, provide the patient/caregiver with detailed instructions and adequate training for infusion in the home or other appropriate setting.
    Glassia is supplied in a ready-to-use solution that should be clear and colorless to yellow-green and may contain a few protein particles; do not use if cloudy.
    Each single-use vial contains approximately 1,000 mg of functionally active alpha-1-proteinase inhibitor.
    Infusion can be made directly from the vial using a vented spike adapter and a 5-micron in-line filter. Alternatively, vial contents may be pooled in an empty, sterile intravenous container. Attach an appropriate intravenous administration set to the intravenous container, and use a vent filter to withdraw the material from the vial. Use the supplied 5-micron filter needle to transfer the product into the infusion container.
    Administer Glassia within 3 hours of entering a vial.
    Do not mix Glassia with any other agent or solution.
    Using an appropriate intravenous administration set, administer Glassia at a rate not greater than 0.2 mL/kg/minute; the infusion will take approximately 15 minutes. 
    A 5-micron in-line filter is recommended during the infusion.
    Continuously monitor the patient's vital signs throughout the infusion. If infusion-related reactions occur, reduce the rate or interrupt the infusion until the symptoms subside. The infusion may resume at a rate tolerated by the patient.
     
    Prolastin
    Reconstitution
    Have lyophilized drug vial and diluent at room temperature before reconstitution.
    Remove the plastic cover from the short end of the transfer needle and insert the needle into the diluent vial. Remove the cover at the other end of the transfer needle. Invert the diluent vial, and insert the attached needle into the product vial at a 45 degree angle, so that the diluent will be directed against the wall of the product to minimize foaming. The vacuum in the product vial will draw the diluent into it. Remove the diluent vial and the transfer needle.
    Gently swirl the vial until the powder is completely dissolved.
    Clean the top of the drug vial with alcohol and let it dry. Attach the supplied filter needle to a sterile syringe. Withdraw the Prolastin solution into the syringe through the filter needle. Replace the filter needle with an appropriate injection needle.
    Each single-use vial contains approximately 500 mg or 1,000 mg of functionally active alpha-1-proteinase inhibitor. If needed, the reconstituted solution from several vials may be pooled into an empty, sterile IV solution container; aseptic technique is needed. Avoid pushing an IV administration spike set into the product container stopper, as this action may force the stopper into the vial with a resulting sterility loss.
    Keep reconstituted solution at room temperature, and administer reconstituted solution within 3 hours.
    Intravenous infusion
    Do not mix Prolastin with any other agent or solution.
    Infuse intravenously at a rate of 0.08 mL/kg/minute or greater.
     
    Prolastin-C
    Reconstitution of lyophilized powder vials
    Have lyophilized drug vial and diluent at room temperature before reconstitution.
    Remove the plastic cover from the short end of the transfer needle and insert the needle into the diluent vial. Remove the cover at the other end of the transfer needle. Invert the diluent vial, and insert the attached needle into the product vial at a 45 degree angle, so that the diluent will be directed against the wall of the product to minimize foaming. The vacuum in the product vial will draw the diluent into it. Remove the diluent vial and the transfer needle.
    Immediately after adding the diluent, vigorously swirl the vial for 10 to 15 seconds to thoroughly break up the cake; continuously swirl the vial until the powder is completely dissolved. Some foaming will occur and does not affect the product quality. A few small particles may remain after reconstitution and should be removed by passage through a sterile 15 micron filter, which is not supplied.
    Each single-use vial contains approximately 1,000 mg of functionally active alpha-1-proteinase inhibitor. If needed, the reconstituted solution from several vials may be pooled into an empty, sterile IV solution container; aseptic technique is needed, and a sterile filter needle is provided for this purpose.
    Keep reconstituted solution at room temperature, and administer reconstituted solution within 3 hours.
    Intravenous infusion
    Do not mix the prepared Prolastin-C infusion with any other agent or solution.
    Use a sterile 15 micron in-line filter when administering the product.
    Infuse intravenously at a rate of approximately 0.08 mL/kg/minute, as determined by patient comfort and response. The recommended dosage of 60 mg/kg takes approximately 15 minutes to infuse.
     
    Prolastin-C Liquid
    Allow unopened vial of liquid to warm up to room temperature before administration.
    Remove the plastic flip top from the vial.
    Swab the exposed stopper surface with alcohol and allow to dry.
    Prolastin-C Liquid is supplied in a ready-to-use solution. Inspect the liquid prior to pooling. The product may contain a few protein particles. The solution is clear, colorless or pale yellow or pale green. Do not use if the product is discolored or cloudy.
    Each single-use vial contains approximately 1,000 mg of functionally active alpha-1-proteinase inhibitor.
    Pool the liquid from several vials to achieve the intended mg/kg body weight dose into an empty, sterile intravenous solution container using aseptic technique.
    Keep pooled solution at room temperature for administration within 3 hours.
    Do not mix Prolastin-C Liquid with any other agent or solution.
    Use a sterile 15 micron in-line filter when administering the product.
    Infuse intravenously at a rate of approximately 0.08 mL/kg/minute, as determined by patient comfort and response. The recommended dosage of 60 mg/kg takes approximately 15 minutes to infuse.
     
    Zemaira
    Reconstitution
    Have lyophilized drug vial and diluent at room temperature before reconstitution.
    The transfer device is sterile: do not touch the exposed ends of the spike after removing the protective covers. Remove the protective cover from the white end of the transfer device, and insert the needle into the diluent vial. Remove the protective cover from the green end of the transfer device. Invert the diluent vial, and using minimum force, insert the green end of the transfer device into the drug vial. The flange of the transfer device should rest on the surface of the stopper, so that the diluent flows into the drug vial. The vacuum in the product vial will draw the diluent into it. Do not allow the air inlet filter to face downward. Remove the diluent vial and the transfer device. During diluent transfer, gently tilt the drug vial to wet the lyophilized cake.
    Gently swirl the vial until the powder is completely dissolved. Do not shake the vial.
    Each single-use vial contains approximately 1,000 mg of functionally active alpha-1-proteinase inhibitor. If needed, the reconstituted solution from several vials may be pooled into an empty, sterile IV solution container; aseptic technique is needed.
    Keep reconstituted solution at room temperature, and administer reconstituted solution within 3 hours of reconstitution.
    Intravenous infusion
    Do not mix Zemaira with any other agent or solution.
    Use an intravenous administration set with a suitable 5-micron in-line infusion filter.
    Infuse intravenously at a rate of approximately 0.08 mL/kg/minute, as determined by patient comfort and response. Closely monitor the infusion rate and the patient's clinical state during the infusion. Watch for signs of infusion-related reactions.

    STORAGE

    Aralast:
    - Do not freeze
    - May be stored at temperatures up to 77 degrees F if used within 1 month
    - Refrigerate (between 36 and 46 degrees F)
    Aralast NP:
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Reconstituted product should be used within 3 hours
    - Store in carton until time of use
    - Store unreconstituted product at or below 77 degrees F
    Glassia:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - May be stored at temperatures up to 77 degrees F if used within 1 month
    - Product stored at controlled room temperature should not be returned to a refrigerator
    - Refrigerate (between 36 and 46 degrees F)
    - Store in carton until contents are used
    Prolastin:
    - Protect from freezing
    - Store at 77 degrees F
    Prolastin C:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard product that has been stored at room temperature for over 30 days
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Reconstituted product should be used within 3 hours
    - Refrigerate (between 36 and 46 degrees F)
    Zemaira:
    - Protect from freezing
    - Store at or below 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Alpha-1-proteinase inhibitor (A1-PI) products are contraindicated for use by patients with alpha-1-proteinase inhibitor hypersensitivity such as a history of severe, immediate hypersensitivity reactions including anaphylaxis to alpha-1-proteinase inhibitor products or any of the product components. Hypersensitivity reactions, including anaphylaxis, may occur during use. Monitor vital signs and observe the patient carefully throughout the infusion. Early signs and symptoms of hypersensitivity reactions may include pruritus; generalized urticaria; flushing; swollen lips, tongue, or uvula; wheezing; tightness of the chest; dyspnea; hypotension; and syncope. If hypersensitivity symptoms occur, promptly stop the A1-PI infusion and begin appropriate therapy. Have epinephrine and other appropriate therapy available for the treatment of any acute anaphylactic or anaphylactoid reaction.

    IgA deficiency

    All parenteral alpha-1-proteinase inhibitor products are made from pooled human plasma. These alpha-1-proteinase inhibitor products are contraindicated for use by patients with IgA deficiency with antibodies against IgA, as the risk of severe hypersensitivity exists.

    Viral infection

    Alpha-1-proteinase inhibitor products are derived from human plasma and thus may carry a risk of transmitting infectious agents (e.g., viruses) and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The process for manufacturer of these drugs incorporates additional plasma safety and virus reduction measures that minimize the residual risk of virus transmission. Screening plasma donors for prior exposure to certain viruses, testing for the presence of viruses, and inactivating and/or reducing viruses has reduced the risk of transmission of infectious agents. The manufacturing processes are designed to reduce the risk of transmitting viral infection; however, none of the processes are completely effective. There is also the possibility that unknown infectious agents may be present in this product. Some viruses, such as parvovirus B19, are particularly difficult to remove or inactivate. The health care provider should discuss the risks and benefits of this product with the patient, before prescribing or administering it to a patient. Any viral infection or other infection thought by a physician possibly to have been transmitted by a given product should be reported to the manufacturer of the product chosen.

    Pregnancy

    Alpha-1-proteinase inhibitor products should be given during pregnancy only if clearly needed. There are no data with alpha-1-proteinase inhibitor product use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted. It is also not known whether alpha-1-proteinase inhibitor products can cause fetal harm when administered to pregnant women or can affect reproductive capacity.

    Breast-feeding

    Caution is advised if alpha-1-proteinase inhibitor is administered to a woman who is breast-feeding her infant because many drugs are excreted in human milk. Excretion of alpha-1-proteinase inhibitor into human milk is unknown. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    Safety and efficacy of alpha-1-proteinase inhibitor in neonates, infants, and children and adolescents under the age of 18 years have not been established.

    ADVERSE REACTIONS

    Severe

    bronchospasm / Rapid / 0.2-0.4
    anaphylactoid reactions / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 0-11.1
    dyspnea / Early / 0.2-0.5
    chest pain (unspecified) / Early / 0-0.5
    migraine / Early / 0-0.4
    hot flashes / Early / 0.2-0.4
    candidiasis / Delayed / Incidence not known
    peripheral edema / Delayed / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    hypotension / Rapid / Incidence not known
    peripheral vasodilation / Rapid / Incidence not known
    wheezing / Rapid / Incidence not known
    hypertension / Early / Incidence not known
    cholangitis / Delayed / Incidence not known

    Mild

    infection / Delayed / 0.4-15.8
    nausea / Early / 0.2-10.5
    sinusitis / Delayed / 1.5-10.0
    headache / Early / 0.2-9.0
    dizziness / Early / 0.2-6.0
    fatigue / Early / 0-6.0
    diarrhea / Early / 0.2-6.0
    cough / Delayed / 0.4-5.3
    chills / Rapid / 0-5.3
    pharyngitis / Delayed / 0.5-5.0
    rhinitis / Early / 4.0-5.0
    rhinorrhea / Early / 4.0-5.0
    arthralgia / Delayed / 0.2-3.2
    malaise / Early / 0.2-1.6
    asthenia / Delayed / 0.2-1.2
    pruritus / Rapid / 0-1.1
    injection site reaction / Rapid / 0-1.1
    musculoskeletal pain / Early / 0.2-0.7
    fever / Early / 0.5-0.7
    drowsiness / Early / 0.2-0.5
    rash / Early / 0.2-0.5
    myalgia / Early / 0.2-0.4
    back pain / Delayed / 0.2-0.4
    ecchymosis / Delayed / 0.2-0.4
    paresthesias / Delayed / 0.2-0.4
    abdominal pain / Early / 0.2-0.4
    dyspepsia / Early / 0.2-0.4
    flushing / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    syncope / Early / Incidence not known
    vomiting / Early / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Alpha-1-proteinase Inhibitor products.

    PREGNANCY AND LACTATION

    Pregnancy

    Alpha-1-proteinase inhibitor products should be given during pregnancy only if clearly needed. There are no data with alpha-1-proteinase inhibitor product use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted. It is also not known whether alpha-1-proteinase inhibitor products can cause fetal harm when administered to pregnant women or can affect reproductive capacity.

    Caution is advised if alpha-1-proteinase inhibitor is administered to a woman who is breast-feeding her infant because many drugs are excreted in human milk. Excretion of alpha-1-proteinase inhibitor into human milk is unknown. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Alpha-1-proteinase inhibitor (A1-PI), or alpha-1-antitrypsin (ATA) inhibits serine proteases such as neutrophil elastase. Neutrophil elastase is always present in the lungs and is capable of degrading protein components of the alveolar walls. Normally, ATA provides most of the anti-neutrophil elastase protection in the lower respiratory tract. Patients with ATA deficiency have an imbalance in the anti-neutrophil elastase protection. This imbalance allows unopposed destruction of the connective tissue framework of the lung parenchyma. Receipt of exogenous A1-PI increases the concentration of ATA and functional anti-neutrophil elastase capacity in the epithelial lining fluid of the lower respiratory tract of the lung.
     
    Alpha-1-antitrypsin deficiency (AATD) is an autosomal, co-dominant, hereditary disorder that is characterized by low serum and lung concentrations of alpha-1-proteinase inhibitor (alpha-1-antitrypsin or ATA). In severe forms, AATD is frequently associated with slowly progressive, moderate-to-severe panacinar emphysema. However, some patients with severe AATD may never develop clinically-evident emphysema. Of note, augmentation therapy with alpha-1-proteinase inhibitor (A1-PI) is indicated only in patients with congenital AATD who have clinically evident emphysema. The effect of alpha-1-proteinase inhibitor receipt on the frequency, duration, or severity of pulmonary exacerbations has not been demonstrated in randomized, controlled clinical trials. Findings from the RAPID/RAPID Extension program have confirmed the benefits of A1-PI therapy in slowing disease progression and provided evidence of a disease-modifying effect in patients with AATD; the study suggests that the early introduction of treatment may delay the time to death, lung transplantation, or crippling respiratory complaints in patients with emphysema related to severe AATD.

    PHARMACOKINETICS

    Alpha-1-proteinase inhibitor (A1-PI) products are administered intravenously, doses of 60 mg/kg weekly have been shown to increase plasma levels above the postulated protective threshold level (more than 11 micromolar). The maintenance of blood serum concentrations of antigenically measured alpha-1 antitrypsin (AAT) above 11 microMolar is hypothesized to provide therapeutically relevant anti-neutrophil elastase protection. Individuals with severe AAT-deficiency have been shown to have increased neutrophil and neutrophil elastase concentrations in lung epithelial lining fluid as compared to patients without this deficiency. Uncertainty exists regarding the appropriate therapeutic target serum concentration of AAT during augmentation therapy, as some emphysema patients with AAT-deficiency have baseline AAT concentrations above 11 microMolar. Patients with normal AAT levels (non-ATT deficient) typically have concentrations of AAT greater than 22 microMolar. After several weeks, the alpha-1-proteinase inhibitor concentrations and the alpha-1-proteinase; neutrophil elastase complexes in the epithelial lining fluid of the lower respiratory tract of the lung increase in AAT-deficient patients as compared with findings before drug receipt.
     
    Affected Cytochrome P450 (P450) isoenzymes and drug transporters: None

    Intravenous Route

    Prolastin: Receipt of Prolastin 60 mg/kg IV once weekly led to alpha-1-proteinase inhibitor concentrations above 80 mg/dL (11 microMolar) that were maintained during the average drug receipt duration of 24 weeks. As measured by an antigenic content assay, the mean trough Prolastin concentration was 16.7 +/- 2.7 microMolar. The mean trough steady-state serum antigenic alpha-1-proteinase inhibitor concentration was 19.1 microMolar (range, 14.7 to 23.1).
     
    Prolastin-C: After weekly IV doses of 60 mg/kg of Prolastin-C, the mean maximum serum concentration was 1.79 mg/mL, and the half-life was 146.3 hours. Similar values were obtained for Prolastin: the mean maximum serum concentration was 1.84 mg/mL, and the half-life was 139.3 hours. As measured by an antigenic content assay, the mean trough Prolastin-C concentration was 16.9 +/- 2.3 microMolar. Bioequivalence has been established between Prolastin-C to Prolastin-C liquid in a pharmacokinetic study.
     
    Aralast NP: After a single intravenous infusion of 60 mg/kg of Aralast NP, the maximum serum concentration was 1.6 +/- 0.3 mg/mL, and the half-life was 4.7 +/- 2.7 days. Receipt of weekly Aralast led to a gradual increase in peak and trough serum alpha-1-proteinase inhibitor concentrations; stabilization occurred after several weeks. Serum trough concentrations rose substantially in all patients; by week 3, most patients had trough concentrations that exceeded 11 micromolar. Concentrations remained above this threshold through 24 weeks with a few exceptions. NOTE: Aralast is no longer available, but the pharmacokinetic parameters of Aralast and Aralast NP are comparable.
     
    Zemaira: After a single 60 mg/kg IV dose of Zemaira, the mean maximum serum concentration was 44.1 +/- 10.8 microMolar, and the terminal half-life was 5.1 +/- 2.4 days. Weekly repeated infusions led to serum alpha-1-proteinase inhibitor concentrations above 11 microMolar. The mean trough steady-state serum antigenic alpha-1-proteinase inhibitor concentration was 17.7 microMolar (range, 13.9 to 23.2)..
     
    Glassia: After a single 60 mg/kg dose of Glassia, the terminal half-life was 111 +/- 33 hours. Serum alpha-1-proteinase inhibitor trough concentrations rose substantially in all patients by week 2 and were comparatively stable during weeks 7 to 12. The median trough alpha-1-proteinase inhibitor concentrations for weeks 7 to 12 were 14.5 microMolar (range, 11.6 to 18.5 microMolar) for antigenic and 11.8 microMolar (range, 8.2 to 16.9 microMolar) for functional alpha-1-proteinase inhibitor. Eleven of 33 patients had mean steady-state functional alpha-1 proteinase inhibitor concentrations below 11 microMolar.