1 HIGHLIGHTS OF PRESCRIBING INFORMATION 2 These highlights do not include all the information needed to use PROLASTIN®-C 3 LIQUID safely and effectively. See full prescribing information for PROLASTIN-C 4 LIQUID. 5 PROLASTIN®-C LIQUID (Alpha -Proteinase Inhibitor [Human]) 1 6 Solution for Intravenous Injection 7 Initial U.S. Approval: 1987 8 9 INDICATIONS AND USAGE 10 PROLASTIN-C LIQUID is an Alpha -Proteinase Inhibitor (Human) (Alpha -PI) indicated 1 1 11 for chronic augmentation and maintenance therapy in adults with clinical evidence of 12 emphysema due to severe hereditary deficiency of Alpha -PI (alpha -antitrypsin deficiency). 1 1 13 (1) 14 Limitations of Use: 15 • The effect of augmentation therapy with any Alpha -PI, including PROLASTIN-C 1 16 LIQUID, on pulmonary exacerbations and on the progression of emphysema in Alpha -PI 1 17 deficiency has not been conclusively demonstrated in randomized, controlled clinical 18 trials. 19 • Clinical data demonstrating the long-term effects of chronic augmentation or 20 maintenance therapy with PROLASTIN-C LIQUID are not available. 21 • PROLASTIN-C LIQUID is not indicated as therapy for lung disease in patients in whom 22 severe Alpha -PI deficiency has not been established. 1 23 24 DOSAGE AND ADMINISTRATION 25 For intravenous use only. (2) 26 • Dose: 60 mg/kg body weight intravenously once per week. (2.1) 27 • Dose ranging studies using efficacy endpoints have not been performed with any Alpha - 1 28 PI product, including PROLASTIN-C LIQUID. (2.1) 29 • Use a sterile 15 micron in-line filter when administering the product (not supplied). (2.2) 30 • Administration: 0.08 mL/kg/min as determined by patient response and comfort. (2.3) 31 DOSAGE FORMS AND STRENGTHS 32 For injection: approximately 1,000 mg in a single-use vial containing 20 mL of solution for 33 injection. (3) CONFIDENTIAL Page 1 of 22 34 CONTRAINDICATIONS 35 • Immunoglobulin A (IgA) deficient patients with antibodies against IgA. (4) 36 • History of anaphylaxis or other severe systemic reaction to Alpha -PI. (4) 1 37 38 WARNINGS AND PRECAUTIONS 39 • Severe hypersensitivity and anaphylactic reactions may occur in IgA deficient patients 40 with antibodies against IgA. Discontinue administration of the product and initiate 41 appropriate emergency treatment if hypersensitivity reactions occur. (5.1) 42 • Because PROLASTIN-C LIQUID is made from human plasma, it may carry a risk of 43 transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) 44 agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. (5.2) 45 46 ADVERSE REACTIONS 47 The most common adverse reactions during PROLASTIN-C LIQUID clinical trials in > 5% 48 of subjects were diarrhea and fatigue, each of which occurred in 2 subjects (6%). (6.1) 49 To report SUSPECTED ADVERSE REACTIONS, contact Grifols Therapeutics Inc. at 50 1-800-520-2807 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 51 See 17 for PATIENT COUNSELING INFORMATION. Revised: 9/2017 CONFIDENTIAL Page 2 of 22 52 FULL PRESCRIBING INFORMATION: CONTENTS* 53 1 INDICATIONS AND USAGE 54 2 DOSAGE AND ADMINISTRATION 55 2.1 Dose 56 2.2 Preparation and Handling 57 2.3 Administration 58 3 DOSAGE FORMS AND STRENGTHS 59 4 CONTRAINDICATIONS 60 5 WARNINGS AND PRECAUTIONS 61 5.1 Hypersensitivity Reactions 62 5.2 Transmissible Infectious Agents 63 6 ADVERSE REACTIONS 64 6.1 Clinical Trials Experience 65 6.2 Postmarketing Experience 66 8 USE IN SPECIFIC POPULATIONS 67 8.1 Pregnancy 68 8.2 Lactation 69 8.4 Pediatric Use 70 8.5 Geriatric Use 71 11 DESCRIPTION 72 12 CLINICAL PHARMACOLOGY 73 12.1 Mechanism of Action 74 12.2 Pharmacodynamics 75 12.3 Pharmacokinetics CONFIDENTIAL Page 3 of 22 76 13 NON-CLINICAL TOXICOLOGY 77 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 78 13.2 Animal Toxicology and/ or Pharmacology 79 14 CLINICAL STUDIES 80 15 REFERENCES 81 16 HOW SUPPLIED/STORAGE AND HANDLING 82 17 PATIENT COUNSELING INFORMATION 83 * Sections or subsections omitted from the full prescribing information are not listed. CONFIDENTIAL Page 4 of 22 84 FULL PRESCRIBING INFORMATION 85 1 INDICATIONS AND USAGE 86 PROLASTIN-C LIQUID is an Alpha -Proteinase Inhibitor (Human) (Alpha -PI) indicated 1 1 87 for chronic augmentation and maintenance therapy in adults with clinical evidence of 88 emphysema due to severe hereditary deficiency of Alpha -PI (alpha -antitrypsin deficiency). 1 1 89 Limitations of Use 90 • The effect of augmentation therapy with any Alpha -PI, including PROLASTIN-C 1 91 LIQUID, on pulmonary exacerbations and on the progression of emphysema in Alpha -PI 1 92 deficiency has not been conclusively demonstrated in randomized, controlled clinical 93 trials. 94 • Clinical data demonstrating the long-term effects of chronic augmentation or 95 maintenance therapy with PROLASTIN-C LIQUID are not available. 96 • PROLASTIN-C LIQUID is not indicated as therapy for lung disease in patients in whom 97 severe Alpha -PI deficiency has not been established. 1 98 99 2 DOSAGE AND ADMINISTRATION 100 For intravenous use only. 101 2.1 Dose 102 • The recommended dose of PROLASTIN-C LIQUID is 60 mg/kg body weight 103 administered intravenously once weekly. 104 • Dose ranging studies using efficacy endpoints have not been performed with any Alpha - 1 105 PI product. 106 • The carton and the label on each vial of PROLASTIN-C LIQUID show the actual amount 107 of functionally active Alpha -PI in milligrams (as determined by the capacity to 1 108 neutralize porcine pancreatic elastase). 109 110 2.2 Preparation and Handling 111 1. Allow unopened PROLASTIN-C LIQUID to warm up to room temperature before 112 administration. 113 2. Remove the plastic flip top from the vial. 114 3. Swab the exposed stopper surface with alcohol and allow to dry. 115 4. Inspect the PROLASTIN-C LIQUID visually for particulate matter and discoloration 116 prior to pooling. The product may contain a few protein particles. The solution is clear, 117 colorless or pale yellow or pale green. Do not use if the product is discolored or cloudy. CONFIDENTIAL Page 5 of 22 118 5. Pool PROLASTIN-C LIQUID from several vials to achieve the intended mg/kg body 119 weight dose into an empty, sterile intravenous solution container using aseptic technique. 120 6. Keep pooled solution at room temperature for administration within three hours. 121 122 2.3 Administration 123 • Visually inspect parenteral drug products for particulate matter and discoloration prior to 124 administration, whenever solution and container permit. The product may contain a few 125 protein particles. Do not use if discolored or cloudy. 126 • Use a sterile 15 micron in-line filter when administering the product. 127 • Infuse PROLASTIN-C LIQUID separately, without mixing with other agents or diluting 128 solutions. 129 • Infuse PROLASTIN-C LIQUID intravenously at 0.08 mL/kg/min as determined by 130 patient response and comfort. The recommended dosage of 60 mg/kg takes 131 approximately 15 minutes to infuse. 132 133 3 DOSAGE FORMS AND STRENGTHS 134 PROLASTIN-C LIQUID is supplied in a 1,000 mg (approximate) single-use vial containing 135 20 mL of solution for injection. The actual amount of functionally active Alpha -PI in 1 136 milligrams is printed on the vial label and carton. 137 4 CONTRAINDICATIONS 138 PROLASTIN-C LIQUID is contraindicated in: 139 • IgA deficient patients with antibodies against IgA, due to the risk of severe 140 hypersensitivity. 141 • Patients with a history of anaphylaxis or other severe systemic reaction to Alpha -PI. 1 142 143 5 WARNINGS AND PRECAUTIONS 144 5.1 Hypersensitivity Reactions 145 Hypersensitivity reactions, including anaphylaxis, may occur. Monitor vital signs and 146 observe the patient carefully throughout the infusion. Early signs and symptoms of 147 hypersensitivity reactions may include pruritus; generalized urticarial; flushing; swollen lips, 148 tongue, or uvula; wheezing; tightness of the chest; dyspnea; hypotension; and syncope. If 149 hypersensitivity symptoms occur, promptly stop PROLASTIN-C LIQUID infusion and begin 150 appropriate therapy. Have epinephrine and other appropriate therapy available for the 151 treatment of any acute anaphylactic or anaphylactoid reaction. [see Patient Counseling 152 Information (17)] CONFIDENTIAL Page 6 of 22 153 PROLASTIN-C LIQUID may contain trace amounts of IgA. Patients with known antibodies 154 to IgA, which can be present in patients with selective or severe IgA deficiency, have a 155 greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. 156 5.2 Transmissible Infectious Agents 157 Because PROLASTIN-C LIQUID is made from human plasma, it may carry a risk of 158 transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) 159 agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. This also applies to 160 unknown or emerging viruses and other pathogens. The risk of transmission of infectious 161 agents has been reduced by screening plasma donors for prior exposure to certain infectious 162 agents, by testing for the presence of certain virus infections, and by including steps in the 163 manufacturing process with the demonstrated capacity to inactivate and /or remove certain 164 infectious agents. Despite these measures, this product may still potentially transmit disease. 165 Report all infections thought by a physician possibly to have been transmitted by this product 166 to Grifols Therapeutics Inc. (1-800-520-2807). 167 6 ADVERSE REACTIONS 168 The most serious adverse reaction observed during clinical trials with PROLASTIN-C was 169 an abdominal and extremity rash in one subject. [see Warnings and Precautions (5.1)] The 170 most common adverse reactions observed at a rate of > 5% in subjects receiving 171 PROLASTIN-C LIQUID were diarrhea and fatigue, each of which occurred at a rate of 6% 172 (two subjects each). 173 6.1 Clinical Trials Experience 174 Because clinical studies are conducted under widely varying conditions, adverse reaction 175 rates observed cannot be directly compared to rates in other clinical trials and may not reflect 176 the rates observed in practice. 177 One clinical trial was conducted with PROLASTIN-C LIQUID: a 16 week, multicenter, 178 randomized, double-blind crossover study to assess the safety, immunogenicity, and 179 pharmacokinetic comparability of PROLASTIN-C LIQUID to PROLASTIN-C in 32 180 subjects. 181 Adverse reactions (as defined in the footnote to Table 1) occurring in >5% of subjects during 182 the 16 week double-blind crossover treatment period are shown in Table 1. CONFIDENTIAL Page 7 of 22 Table 1: Adverse Reactions Occurring in >5% of Subjects during the Double- Blinded Crossover Treatment PROLASTIN-C LIQUID PROLASTIN-C (N=32) (N=31) No. of Subjects with Adverse No. of Subjects with Adverse Reaction Reaction Adverse Reaction*,† (percentage of all subjects) (percentage of all subjects) Diarrhea 2 (6) 0 Fatigue 2 (6) 0 * An adverse reaction is defined as any adverse event that occurred where either a) the event was not considered “unrelated” to administration of the product, or b) the occurrence was during or within 72 hours of the end of the previous infusion of the product, or c) the investigator's causality assessment of the event was missing or indeterminate, or d) the incidence during treatment with 1 investigational product was 130% or more of the incidence during treatment with the other investigational product. † Source: the randomized double-blinded comparator trial of PROLASTIN-C LIQUID vs PROLASTIN-C. 183 184 Table 2 below displays the adverse reaction (defined as per Table 1) rate as a percentage of 185 infusions received during the 16 week double-blinded treatment period. Table 2: Adverse Reaction Frequency as a Percent of All Infusions and Occurring More than Once in the PROLASTIN-C LIQUID Group during the 16 Week Double Blinded Treatment Period PROLASTIN-C LIQUID PROLASTIN-C No. of infusions: 252 No. of infusions: 245 No. of Adverse Reactions No. of Adverse Reactions Adverse Reaction* (percentage of all infusions) (percentage of all infusions) Diarrhea 3 (1.2) 0 Fatigue 2 (0.8) 0 * Source: the randomized double-blinded comparator trial of PROLASTIN-C LIQUID vs PROLASTIN-C. 186 187 A total of 23 COPD exacerbations were reported for a total of 18 individual subjects. Twelve 188 subjects (12/32, 38%) during PROLASTIN-C LIQUID treatment experienced 13 COPD 189 exacerbations, and 9 subjects (9/31, 29%) during PROLASTIN-C treatment had 10 COPD 190 exacerbations. Three COPD exacerbations occurred during the Follow-Up Period after 191 PROLASTIN-C LIQUID treatment and 1 COPD exacerbation occurred in the Follow-up CONFIDENTIAL Page 8 of 22 192 period after PROLASTIN-C treatment. The overall rate of pulmonary exacerbations during 193 treatment with either product was 1.9 exacerbations per subject-year. No exacerbation was 194 considered to be serious, except for one event after PROLASTIN-C treatment during the 195 Follow-Up period (due to hospitalization). 196 Two separate prior clinical trials were conducted with PROLASTIN-C: 1.) a 20 week, open- 197 label, single arm safety study in 38 subjects (single-arm open-label trial), and 2.) a 16 week, 198 randomized, double-blind, crossover pharmacokinetic comparability study vs. PROLASTIN 199 in 24 subjects, followed by an 8 week open-label treatment with PROLASTIN-C 200 (randomized double-blinded comparator trial). Thus, a total of 93 subjects were exposed to 201 PROLASTIN-C in clinical trials. 202 The most serious adverse reaction observed during clinical trials with PROLASTIN-C was 203 an abdominal and extremity rash in one subject. The rash resolved subsequent to outpatient 204 treatment with antihistamines and steroids. Two instances of a less severe, pruritic abdominal 205 rash were observed upon rechallenge despite continued antihistamine and steroid treatment, 206 which led to withdrawal of the subject from the trial. 207 Grifols assessed the randomized double-blinded comparator trial of PROLASTIN and 208 PROLASTIN-C for adverse reactions (as defined in the footnote to Table 3) occurring during 209 each 8 week double-blind crossover treatment period, as shown in Table 3. CONFIDENTIAL Page 9 of 22 Table 3: Adverse Reactions Occurring during the First 8 Weeks of Each Double-Blinded Treatment PROLASTIN®-C PROLASTIN® No. of subjects: 24 No. of subjects: 24 No. of Subjects with Adverse No. of Subjects with Adverse Reaction Reaction Adverse Reaction*,† (percentage of all subjects) (percentage of all subjects) Upper respiratory tract infection 3 (12.5%) 1 (4.2%) Headache 1 (4.2%) 2 (8.3%) Pruritus 1 (4.2%) 0 Urticaria 1 (4.2%) 0 Nausea 1 (4.2%) 0 Peripheral edema 1 (4.2%) 0 Pyrexia 1 (4.2%) 0 * An adverse reaction is defined as any adverse event where either a) the incidence with PROLASTIN-C was greater than with PROLASTIN, or b) the occurrence was within 72 hours of treatment, or c) the event was otherwise considered related or possibly related to the drug. † Source: the randomized double-blinded comparator trial. 210 211 Table 4 below displays the adverse reaction (defined as per Table 3) rate as a percentage of 212 infusions received during the 8 weeks of each double-blinded treatment. CONFIDENTIAL Page 10 of 22