PROLASTIN-C

• The recommended dose of PROLASTIN-C is 60 mg/kg body weight administered intravenously once weekly.
• Dose ranging studies using efficacy endpoints have not been performed with any Alpha₁-PI  product.
• The carton and the label on each vial of PROLASTIN-C show the actual amount of functionally active Alpha₁-PI in milligrams (as determined by the capacity to neutralize porcine pancreatic elastase).

1. Allow unopened PROLASTIN-C and diluent vials to warm up to room temperature before reconstitution.
2. Remove the plastic flip tops from each vial.
3. Swab the exposed stopper surfaces with alcohol and allow to dry.
4. Remove the plastic cover from the short end of the transfer needle. Insert the exposed end of the needle through the center of the stopper in the diluent vial.
5. Remove the cover at the other end of the transfer needle by twisting it carefully.
6. Invert the diluent vial and insert the attached needle into the PROLASTIN-C vial at a 45° angle (Figure A below). This will direct the stream of diluent against the wall of the product vial and minimize foaming. The vacuum will draw the diluent into the PROLASTIN-C vial.
7. Remove the diluent vial and transfer needle.
8. Immediately after adding the diluent, swirl vigorously for 10-15 seconds to thoroughly break up cake, then swirl continuously until the powder is completely dissolved (Figure B below). Some foaming will occur, but does not affect the quality of the product.
9. Inspect the reconstituted PROLASTIN-C visually for particulate matter and discoloration prior to pooling. A few small particles may remain after reconstitution. If particles are visible, remove by passage through a sterile filter, such as a 15 micron filter used for administering blood products (not supplied).
10. Pool reconstituted PROLASTIN-C from several vials into an empty, sterile intravenous solution container using aseptic technique. Use the sterile filter needle provided for this purpose.
11. Keep reconstituted solution at room temperature for administration within three hours.

• Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit.
• Infuse PROLASTIN-C separately, without mixing with other agents or diluting solutions.
• Infuse PROLASTIN-C intravenously at 0.08 mL/kg/min as determined by patient response and comfort.  The recommended dosage of 60 mg/kg takes approximately 15 minutes to infuse.

Hypersensitivity reactions, including anaphylaxis, may occur. 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 PROLASTIN-C infusion and begin appropriate therapy. Have epinephrine and other appropriate therapy available for the treatment of any acute anaphylactic or anaphylactoid reaction. [see Patient Counseling Information (17)]

PROLASTIN-C 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.

Because PROLASTIN-C is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. This also applies to unknown or emerging viruses and other pathogens. The risk of transmission of infectious agents has been reduced by screening plasma donors for prior exposure to certain infectious agents, by testing for the presence of certain virus infections, and by including steps in the manufacturing process with the demonstrated capacity to inactivate and/or remove certain infectious agents.  Despite these measures, this product may still potentially transmit disease.

Report all infections thought by a physician possibly to have been transmitted by this product to Grifols Therapeutics LLC (1-800-520-2807).

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice.

Two separate clinical trials were conducted with PROLASTIN-C: 1.) a 20 week, open-label, single arm safety study in 38 subjects (single-arm open-label trial), and 2.) a 16 week, randomized, double-blind, crossover pharmacokinetic comparability study vs. PROLASTIN in 24 subjects, followed by an 8 week open-label treatment with PROLASTIN-C (randomized double-blinded comparator trial). Thus, 62 subjects were exposed to PROLASTIN-C in clinical trials.

The most serious adverse reaction observed during clinical trials with PROLASTIN-C was an abdominal and extremity rash in one subject. The rash resolved subsequent to outpatient treatment with antihistamines and steroids. Two instances of a less severe, pruritic abdominal rash were observed upon rechallenge despite continued antihistamine and steroid treatment, which led to withdrawal of the subject from the trial.

Grifols assessed the randomized double-blinded comparator trial for adverse reactions (as defined in the footnote to Table 1) occurring during each 8 week double-blind crossover treatment period, as shown in Table 1.

Table 2 below displays the adverse reaction (defined as per Table 1) rate as a percentage of infusions received during the 8 weeks of each double-blinded treatment.

Table 3 below displays the adverse reactions occurring in two or more subjects during the single-arm open-label trial.

Ten exacerbations of chronic obstructive pulmonary disease were reported by 8 subjects in the 24 week crossover pharmacokinetic study. During the 16 week double-blind crossover phase, 4 subjects (17%) had a total of 4 exacerbations during PROLASTIN-C treatment and 4 subjects (17%) had a total of 4 exacerbations during PROLASTIN treatment. Two additional exacerbations in 2 subjects (8%) occurred during the 8 week open-label treatment period with PROLASTIN-C. The overall rate of pulmonary exacerbations during treatment with either product was 0.9 exacerbations per subject-year.

Immunogenicity

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.  For these reasons, comparison of the incidence of antibodies to PROLASTIN-C with the incidence of antibodies to other products may be misleading.

In the single-arm, open-label safety clinical trial, three treatment naïve subjects out of 36 subjects evaluated developed antibody to Alpha₁-PI at week 24 after receiving PROLASTIN-C. A fourth subject (non-naïve) was positive prior to and after receiving PROLASTIN-C, but levels were unchanged during the study. None of the four antibody specimens was able to neutralize the protease inhibitor capacity of PROLASTIN-C. In the randomized, crossover pharmacokinetic clinical trial, none of 24 subjects developed antibodies to PROLASTIN-C.

Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.

The reactions which have been chosen for inclusion due to their seriousness, frequency of reporting, possible causal connection to PROLASTIN^®–C, or a combination of these factors, are:

• General/ Body as a Whole:               Fatigue, malaise, influenza-like illness, pain, asthenia
• Immune system:                                Hypersensitivity including anaphylactoid/anaphylactic reactions
• Cardiovascular:                                 Tachycardia
• Musculoskeletal:                                Arthralgia, myalgia
• Gastrointestinal:                                Vomiting, diarrhea 
• Investigation:                                     Blood pressure increased

Risk Summary

There are no data with PROLASTIN-C use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with PROLASTIN-C. It is not known whether PROLASTIN-C can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. PROLASTIN-C should be given to a pregnant woman only if clearly needed. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Risk Summary

There is no information regarding the presence of PROLASTIN-C in human milk, the effect on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PROLASTIN-C and any potential adverse effects on the breastfed infant from PROLASTIN-C.

Safety and effectiveness in the pediatric population have not been established.

Clinical studies of PROLASTIN-C did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. As for all patients, dosing for geriatric patients should be appropriate to their overall situation.

Alpha₁-PI deficiency is an autosomal, co-dominant, hereditary disorder characterized by low serum and lung levels of Alpha₁-PI. Smoking is an important risk factor for the development of emphysema in patients with Alpha₁-PI deficiency.(1,2) Because emphysema affects many, but not all individuals with the more severe genetic variants of Alpha₁-PI deficiency, augmentation therapy with Alpha₁-PI is indicated only in patients with severe Alpha₁-PI deficiency who have clinically evident emphysema.

Only some Alpha₁-PI alleles are associated with clinically apparent Alpha₁-PI deficiency.(3,4) Approximately 95% of all severely deficient patients are homozygous for the PiZ allele.(4) Individuals with the PiZZ variant typically have serum Alpha₁-PI levels less than 35% of the average normal level. Individuals with the Pi(null)(null) variant have undetectable Alpha₁-PI protein in their serum. Individuals with these low serum Alpha₁-PI levels, i.e., less than 11 µM, have a markedly increased risk for developing emphysema over their lifetimes. In addition, PiSZ individuals, whose serum Alpha₁-PI levels range from approximately 9 to 23 µM,(5) are considered to have moderately increased risk for developing emphysema, regardless of whether their serum Alpha₁-PI levels are above or below 11 µM.

Augmenting the levels of functional protease inhibitor by intravenous infusion is an approach to therapy for patients with Alpha₁-PI deficiency. 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 any Alpha₁-PI product actually protects the lower respiratory tract from progressive emphysematous changes has not been demonstrated in adequately powered, randomized controlled, clinical trials. Although the maintenance of blood serum levels of Alpha₁-PI (antigenically measured) above 11 µM has been historically postulated to provide therapeutically relevant anti-neutrophil elastase protection,(6) this has not been proven. Individuals with severe Alpha₁-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 Alpha₁-PI above 11 µM have emphysema attributed to Alpha₁-PI deficiency. These observations underscore the uncertainty regarding the appropriate therapeutic target serum level of Alpha₁-PI during augmentation therapy.

The pathogenesis of emphysema is understood as described in the “protease-antiprotease imbalance” model. Alpha₁-PI is understood to be the primary antiprotease in the lower respiratory tract, where it inhibits neutrophil elastase (NE). Normal healthy individuals produce sufficient Alpha₁-PI to control the NE produced by activated neutrophils and are thus able to prevent inappropriate proteolysis of the 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 Alpha₁-PI are unable to maintain an appropriate antiprotease defense, and, in addition, they have been shown to have increased lung epithelial lining fluid neutrophil and NE concentrations. Because of these factors, many (but not all) individuals who are severely deficient in endogenous Alpha₁-PI are subject to more rapid proteolysis of the alveolar walls leading to chronic lung disease. PROLASTIN^®-C (Alpha₁-Proteinase Inhibitor [Human]) serves as Alpha₁-PI augmentation therapy in the patient population with severe Alpha₁-PI deficiency and emphysema, acting to increase and maintain serum and lung epithelial lining fluid levels of Alpha₁-PI.

Chronic augmentation therapy with the predecessor product, PROLASTIN^® (Alpha₁-Proteinase Inhibitor [Human]), administered weekly at a dose of 60 mg/kg body weight, results in statistically significant increased levels of Alpha₁-PI and functional anti-neutrophil elastase capacity in the epithelial lining fluid of the lower respiratory tract of the lung, as compared to levels prior to commencing therapy with PROLASTIN.(7) However, the clinical benefit of the increased levels at the recommended dose has not been demonstrated in adequately powered, randomized, controlled clinical trials for any Alpha₁-PI product.

The crossover pharmacokinetic (PK) study was a randomized, double-blind trial comparing PROLASTIN-C to PROLASTIN conducted in 24 adult subjects age 40 to 72 with severe Alpha₁-PI deficiency. Ten subjects were male and 14 subjects were female. Twelve subjects were randomized to each treatment sequence. All but one subject had the PiZZ genotype and the remaining subject had PiSZ. All subjects had received prior Alpha₁-PI therapy with PROLASTIN for at least 1 month.

Study subjects were randomly assigned to receive either 60 mg/kg body weight of functional PROLASTIN-C or PROLASTIN weekly by intravenous infusion during the first 8-week treatment period. Following the last dose in the first 8-week treatment period, subjects underwent serial blood sampling for PK analysis and then crossed over to the alternate treatment for the second 8-week treatment period. Following the last treatment in the second 8-week treatment period, subjects underwent serial blood sampling for PK analysis. In addition, blood samples were drawn for trough levels before infusion at Weeks 6, 7, and 8, as well as before infusion at Weeks 14, 15, and 16.

In the 8-week open-label treatment phase that followed the crossover period, all subjects received 60 mg/kg body weight of functional PROLASTIN-C.

The pharmacokinetic parameters of Alpha₁-PI in plasma, based on functional activity assays, showed comparability between PROLASTIN-C treatment and PROLASTIN treatment, as shown in Table 5.

The key pharmacokinetic parameter was the area under the plasma concentration-time curve (AUC_0-7days) following 8 weeks of treatment with PROLASTIN-C or PROLASTIN. The 90% confidence interval (0.97-1.09) for the ratio of AUC_0-7days for PROLASTIN-C and PROLASTIN indicated that the 2 products are pharmacokinetically equivalent. Figure 1 shows the concentration (functional activity) vs. time curves of Alpha₁-PI after intravenous administration of PROLASTIN-C and PROLASTIN.

Trough levels measured during the crossover PK study via an antigenic content assay showed PROLASTIN-C treatment resulted in a mean trough of 16.9 ± 2.3 µM and PROLASTIN resulted in a mean trough of 16.7 ± 2.7 µM. Using the functional activity assay, PROLASTIN-C resulted in a mean trough of 11.8 ± 2.2 µM and PROLASTIN resulted in a mean trough of 11.0 ± 2.2 µM.