Respreeza 4,000 mg powder and solvent for solution for infusion

4.1 Therapeutic indications Respreeza is indicated for maintenance treatment, to slow the progression of emphysema in adults with documented severe alpha1-proteinase inhibitor deficiency (*e.g.* genotypes PiZZ, PiZ(null), Pi(null,null), PiSZ). Patients are to be under optimal pharmacologic and non-pharmacologic treatment and show evidence of progressive lung disease (*e.g*. lower forced expiratory volume per second (FEV1) predicted, impaired walking capacity or increased number of exacerbations) as evaluated by a healthcare professional experienced in the treatment of alpha1-proteinase inhibitor deficiency.4.2 Posology and method of administration First infusions should be administered under the supervision of a healthcare professional experienced in the treatment of alpha1-proteinase inhibitor deficiency. Subsequent infusions can be administered by a caregiver or by the patient (see section 4.4). **Posology** The recommended dose of Respreeza is 60 mg / kg body weight (bw) administered once weekly. **Elderly population** The safety and efficacy of Respreeza in elderly patients (65 years of age or older) have not been established in specific clinical trials. **Patients with renal or hepatic impairment** No special investigations have been performed. No alternative dose regimen can be recommended in those patients. **Paediatric population** The safety and efficacy of Respreeza in the paediatric population (below 18 years) have not been established. No data are available. **Method of administration** Respreeza should only be administered intravenously by infusion after reconstitution. The powder must be reconstituted with water for injections (see instructions on reconstitution in section 6.6) and administered using an intravenous administration set (supplied with the 4,000 and 5,000 package). The reconstituted solution should be infused intravenously at an infusion rate of about 0.08 ml / kg bw/ min. This infusion rate may be adjusted, based upon patient tolerability. The recommended dose of 60 mg / kg bw will take approximately 15 minutes to infuse. One vial of Respreeza is for single use only. For detailed information regarding the administration of the reconstituted solution, see the instructions at the end of section 6.6.4.3 Contraindications • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see also section 4.4). • IgA deficient patients with known antibodies against IgA, due to the risk of severe hypersensitivity and anaphylactic reactions.4.4 Special warnings and precautions for use **Traceability** In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. The recommended infusion rate given under section 4.2 should be adhered to. During the first infusions, patient's clinical state, including vital signs, should be closely monitored throughout the infusion period. If any reaction takes place that might be related to the administration of Respreeza, the rate of infusion should be decreased or the administration should be stopped, as required by the clinical condition of the patient. If symptoms subside promptly after stopping, the infusion may be resumed at a lower rate that is comfortable for the patient. **Hypersensitivity** Hypersensitivity reactions may occur, including in patients who have tolerated previous treatment with human alpha1-proteinase inhibitor. Respreeza may contain trace amounts of IgA. Patients with selective or severe IgA deficiency can develop antibodies to IgA and, therefore, have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Suspected allergic or anaphylactic type reactions may require immediate discontinuation of the infusion, depending on the nature and severity of the reaction. In case of shock, emergency medical treatment should be administered. **Home-treatment / self-administration** There are limited data regarding the use of this medicinal product in home-treatment / self-administration. Potential risks associated with home-treatment / self-administration are related to the handling and administration of the medicinal product as well as to the handling of adverse reactions, particularly hypersensitivity. Patients should be informed of signs of hypersensitivity reactions. The decision of whether a patient is suitable for home-treatment / self-administration is made by the treating doctor, who should ensure appropriate training is provided (e.g. regarding reconstitution, use of Mix2Vial® set, assembly of intravenous tubing, infusion techniques, maintenance of a treatment diary, identification of adverse reactions and measures to be taken in case such reactions occur), and the use is reviewed at regular intervals. **Transmissible agents** Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation / removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens. The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) and for the non-enveloped hepatitis A (HAV) and parvovirus B19 virus. Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of human plasma-derived proteinase inhibitors. **Smoking** Tobacco smoke is an important risk factor for the development and progression of emphysema. Therefore, cessation of smoking and the avoidance of environmental tobacco smoke are strongly recommended. **Sodium content** **Respreeza 1,000 mg powder and solvent for solution for infusion** This medicine contains approximately 37 mg (1.6 mmol) sodium per 1,000 mg Respreeza vial. This is equivalent to 1.9% of the recommended maximum daily dietary intake of sodium for an adult. **Respreeza 4,000 mg powder and solvent for solution for infusion** This medicine contains approximately 149 mg (6.5 mmol) sodium per 4,000 mg Respreeza vial. This is equivalent to 7.4% of the recommended maximum daily dietary intake of sodium for an adult. **Respreeza 5,000 mg powder and solvent for solution for infusion** This medicine contains approximately 186 mg (8.1 mmol) sodium per 5,000 mg Respreeza vial. This is equivalent to 9.3% of the recommended maximum daily dietary intake of sodium for an adult. That should be taken into consideration for patients on a controlled sodium diet.4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed.4.6 Fertility, pregnancy and lactation **Pregnancy** No animal reproduction studies have been conducted with Respreeza and its safety for use in human pregnancy has not been established in controlled clinical trials. Since alpha1-proteinase inhibitor is an endogenous human protein, it is considered unlikely that Respreeza will cause harm to the foetus when given at recommended doses. However, Respreeza should be given with caution to pregnant women. **Breast-feeding** It is unknown whether Respreeza / metabolites are excreted in human milk. The excretion of human alpha1-proteinase inhibitor in milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Respreeza should be made, taking into account the benefit of breast-feeding to the child and the benefit of human alpha1-proteinase inhibitor therapy to the woman. **Fertility** No animal fertility studies have been conducted with Respreeza and its effect on human fertility has not been established in controlled clinical trials. Since human alpha1-proteinase inhibitor is an endogenous human protein, no adverse effects on fertility are expected when given at recommended doses.4.7 Effects on ability to drive and use machines Dizziness may occur following the administration of Respreeza (see section 4.8). Therefore, Respreeza may have a minor influence on the ability to drive and use machines.4.8 Undesirable effects **Summary of the safety profile** Hypersensitivity or allergic reactions have been observed during the treatment. In the most serious cases, allergic reactions may progress to severe anaphylactic reactions even when the patient has shown no hypersensitivity to previous administrations (see section 4.4). For safety information with respect to transmissible agents, see section 4.4. **Tabulated list of adverse reactions** The adverse reactions (ARs) collected from six clinical studies in 221 patients and post-marketing experience are presented in the table below according to the MedDRA system organ classification (SOC and Preferred Term (PT) Level). Frequency per patient (based on six months of exposure during clinical trials) has been evaluated according to the following convention: common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000). The frequency of ARs during post marketing only is considered as “not known (cannot be estimated from the available data)”. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. **Frequency of adverse reactions (ARs) in clinical studies and post-marketing experience** **with Respreeza** | | | | | | | --- | --- | --- | --- | --- | | **System organ class** **(SOC)** | **Frequency of ARs** | | | | | | Common (≥1/100 to <1/10) | Uncommon (≥1/1,000 to <1/100) | Very rare (<1/10,000) | Not known | | Blood and lymphatic system disorders | | | | Lymph node pain | | Immune system disorders | | Hypersensitivity reactions (including tachycardia, hypotension, confusion, syncope, oxygen consumption decreased and pharyngeal oedema) | Anaphylactic reactions | | | Nervous system disorders | Dizziness, headache | Paraesthesia | Hypoaesthesia | | | Eye disorders | | | | Eye swelling | | Vascular disorders | | Flushing | | | | Respiratory, thoracic and mediastinal disorders | Dyspnoea | | | | | Gastrointestinal disorders | Nausea | | | Lip swelling | | Skin and subcutaneous tissue disorders | | Urticaria, rash (including exfoliative and generalized) | Hyperhidrosis, pruritus | Face swelling | | General disorders and administration site conditions | | Asthenia, infusion-site reactions (including infusion site hematoma) | Chest pain, chills, pyrexia | | **Paediatric Population** Safety and effectiveness in the paediatric population have not been established. No data are available. **Geriatric population** The safety and efficacy of Respreeza in elderly patients (65 years of age or older) have not been established in clinical trials. **Reporting of suspected adverse reactions** Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose Consequences of overdose are unknown. In the event of overdose, the patient should be observed closely for the occurrence of adverse reactions and supportive measures should be available as necessary.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antihemorrhagics, proteinase inhibitor, ATC code: B02AB02 Human alpha1-proteinase inhibitor is a normal constituent of human blood. Human alpha1-proteinase inhibitor has a molecular weight of 51 kDa and belongs to the family of serine protease inhibitors. **Mechanism of action** Human alpha1-proteinase inhibitor is understood to be the primary anti-protease in the lower respiratory tract, where it inhibits neutrophil elastase (NE). Normal healthy individuals produce sufficient alpha1-proteinase inhibitor 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 deficient in endogenous alpha1-proteinase inhibitor are unable to maintain appropriate antiprotease defence and experience more rapid proteolysis of the alveolar walls starting prior to the development of clinically evident chronic obstructive lung disease in the third or fourth decade. **Pharmacodynamic effects** The administration of Respreeza increases and maintains serum levels and lung epithelial lining fluid (ELF) levels of alpha1-proteinase inhibitor leading to a slowdown of the progression of emphysema. **Clinical efficacy and safety** ***RAPID studies*** The safety and efficacy of Respreeza was evaluated in a randomized, double-blind, placebo-controlled, multi-center study (RAPID) followed by a 2-year open-label extension study (RAPID extension study). A total of 180 subjects with alpha1-proteinase inhibitor deficiency characterized by a serum alpha1-proteinase inhibitor level < 11 µM (*i.e.* < 50 mg/dL as determined by nephelometry) and clinical evidence of emphysema, were randomized to receive a weekly 60 mg / kg bw intravenous dose of either Respreeza (93 subjects) or placebo (87 subjects) for up to 24 months. The subjects ranged in age from 31 to 67 years (median age 54 years) with average baseline alpha1-proteinase inhibitor levels of approximately 6.15 µM, and average volume-adjusted CT lung density of 47 g/L / 50 g/L for Respreeza and placebo subjects, respectively. One-hundred forty subjects (76 Respreeza-treated subjects and 64 subjects treated with placebo in the RAPID Study) continued into the RAPID extension study and were treated with a weekly 60 mg/kg bw intravenous dose of Respreeza for up to 24 months. The studies investigated the effect of Respreeza on the progression of emphysema, assessed by the decline of lung density, measured by computer tomography (CT). Respreeza-treated subjects demonstrated a consistent pattern of slower lung density decline than those receiving placebo (see Figure 1). The annual rate of lung density decline, as measured by CT scan at total lung capacity (TLC) over 2 years was lower with Respreeza (-1.45 g/L) as compared with placebo (-2.19 g/L), reflecting a 34% reduction (p = 0.017, 1-sided). The RAPID extension study demonstrated that the reduced rate in lung density decline was maintained for subjects continuously treated with Respreeza for 4 years (see Figure 1). **Figure 1: Changes in Lung Density (TLC) from baseline in the RAPID and RAPID Extension studies** Single doses of 120 mg / kg bw have been administered to 137 subjects treated with Respreeza. **Paediatric population** The European Medicines Agency has waived the obligation to submit the results of studies with Respreeza in all subsets of the pediatric population in chronic obstructive pulmonary disease (COPD) due to alpha1-proteinase inhibitor deficiency (see section 4.2 for information on pediatric use).5.2 Pharmacokinetic properties Four clinical studies were conducted with Respreeza in 89 subjects (59 males and 30 females) to evaluate the effect of Respreeza on serum levels of alpha1-proteinase inhibitor. The subjects ranged in age from 29 to 68 years (median age 49 years). At screening, serum alpha1-proteinase inhibitor levels were between 3.2 and 10.1 µM (mean of 5.6 µM). A double-blind, randomized, active-controlled, crossover pharmacokinetic study was conducted in 13 males and 5 females with alpha1-proteinase inhibitor deficiency, ranging in age from 36 to 66 years. Nine subjects received a single 60 mg / kg bw dose of Respreeza followed by a comparator product, and 9 subjects received comparator product followed by a single 60 mg / kg bw dose of Respreeza, with a wash-out period of 35 days between doses. A total of 13 post-infusion serum samples were taken at various time points up to Day 21. Table 1 shows the mean results for the Respreeza pharmacokinetic parameters. **Table 1: Pharmacokinetic parameters for alpha1-proteinase inhibitor following a single 60 mg/kg bw dose of Respreeza** | | | | --- | --- | | **Pharmacokinetic Parameter** | **Mean (standard deviation)\** | | Area under the curve (AUC0-∞) | 144 (±27) µM x day | | Maximum concentration (Cmax) | 44.1 (±10.8) µM | | Terminal half-life (t1/2ß) | 5.1 (±2.4) days | | Total clearance | 603 (±129) mL/day | | Volume of distribution at steady state | 3.8 (±1.3) L | \ n=18 subjects. A population pharmacokinetic analysis was conducted using data from 90 Respreeza-treated subjects from the RAPID trial. The population estimate of mean half-life was 6.8 days. The model predicted mean steady-state concentration was 21.8 µM after a 60 mg /kg bw / week dose. The population pharmacokinetic analysis did not indicate that there were any significant effects of age, gender, weight, or baseline serum antigenic alpha1-proteinase inhibitor concentrations on the clearance of Respreeza. **Pharmacokinetic/pharmacodynamic relationship** In a double-blind, controlled clinical study to evaluate the safety and biochemical efficacy of Respreeza, 44 subjects were randomized to receive 60 mg / kg bw intravenous dose of Respreeza once weekly for 24 weeks. The mean trough serum alpha1-proteinase inhibitor levels at steady state (weeks 7-11) were maintained above 11 µM. The mean (standard deviation) of the steady state trough serum alpha1-proteinase inhibitor level for Respreeza-treated subjects was 17.7 µM (2.5). In a subgroup of subjects enrolled in this study (10 Respreeza-treated subjects) broncho-alveolar lavage was performed. Epithelial lining fluid measurements (ELF) of alpha1-proteinase inhibitor levels showed a consistent increase following treatment. ELF levels of antigenic alpha1-proteinase inhibitor and alpha1-proteinase inhibitor: NE complexes increased from baseline. Free elastase was immeasurably low in all samples. Following the completion of the RAPID study, an analysis of achieved median alpha1-proteinase inhibitor levels and lung density decline was conducted. This analysis revealed an inverse linear relationship between trough serum alpha1-proteinase inhibitor levels and the annual decline in lung density as measured by volume adjusted CT scans for subjects receiving 60 mg / kg bw intravenous dose of Respreeza.5.3 Preclinical safety data The safety of Respreeza has been assessed in several preclinical studies. Non-clinical data reveal no special risk for humans based on safety pharmacology and short-term toxicity studies. Repeat dose toxicity studies longer than 5 days, reproductive toxicity studies and carcinogenicity studies, have not been performed. Such studies are not considered meaningful due to the production of antibodies against the heterologous human protein in animals. Since human alpha1-proteinase inhibitor is a protein and a physiological constituent of human blood, it is not expected to present carcinogenic, genotoxic, or teratogenic effects.

6.1 List of excipients **Powder**: Sodium chloride Sodium dihydrogen phosphate monohydrate Mannitol **Solvent**: Water for injections6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products, except those mentioned in section 6.6.6.3 Shelf life 3 years From a microbiological point of view, the product should be used immediately after reconstitution. However chemical and physical in-use stability has been demonstrated for 3 h at room temperature (up to 25°C). Do not freeze the reconstituted solution.6.4 Special precautions for storage Do not store above 25°C. Do not freeze. For storage conditions after reconstitution of the medicinal product, see section 6.3.6.5 Nature and contents of container **Respreeza 1,000 mg powder and solvent for solution for infusion** Respreeza 1,000 mg of powder in a glass vial (type I), closed with a rubber (butyl) stopper and an aluminium seal with a plastic flip-off cap. 20 ml of water for injections in a glass vial (type I), closed with a rubber (butyl) stopper and an aluminium seal with a plastic flip-off cap. **Respreeza 4,000 mg powder and solvent for solution for infusion** Respreeza 4,000 mg of powder in a glass vial (type I), closed with a rubber (butyl) stopper and an aluminium seal with a plastic flip-off cap. 76 ml of water for injections in a glass vial (type I), closed with a rubber (butyl) stopper and an aluminium seal with a plastic flip-off cap. **Respreeza 5,000 mg powder and solvent for solution for infusion** Respreeza 5,000 mg of powder in a glass vial (type I), closed with a rubber (butyl) stopper and an aluminium seal with a plastic flip-off cap. 95 ml of water for injections in a glass vial (type I), closed with a rubber (butyl) stopper and an aluminium seal with a plastic flip-off cap. **Presentations** Each pack contains: **Respreeza 1,000 mg powder and solvent for solution for infusion:** One single-use powder vial One solvent vial of 20 ml water for injections One transfer set 20/20 (Mix2Vial set) for reconstitution **Respreeza 4,000 mg powder and solvent for solution for infusion:** One single-use powder vial One solvent vial of 76 ml water for injections One transfer set 20/20 (Mix2Vial set) for reconstitution Administration set (inner box): One IV infusion set One butterfly set Three alcohol swabs **Respreeza 5,000 mg powder and solvent for solution for infusion:** One single-use powder vial One solvent vial of 95 ml water for injections One transfer set 20/20 (Mix2Vial set) for reconstitution Administration set (inner box): One IV infusion set One butterfly set Three alcohol swabs Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling **General instructions** • The reconstitution should be performed according to the instructions provided below. • The product must be reconstituted, administered and handled with caution using aseptic technique to maintain product sterility. • Do not use provided sterile ancillaries for reconstitution and administration if their package is opened or if they are damaged. • The powder must be reconstituted with solvent (water for injections). • Total reconstitution of the powder should be obtained within 5 minutes (1,000 g presentation) or 10 minutes (4,000 g and 5,000 g presentation). • Inspect the reconstituted solution for particulate matter and discoloration prior to administration. • The reconstituted solution should be clear, colourless to slightly yellow, and free from visible particles. Follow the steps provided below for the preparation and reconstitution of Respreeza: | | | | --- | --- | | 1. Ensure that the Respreeza vial and water for injections vial are at room temperature (up to 25°C). | | | 2. Remove the plastic flip-off cap from the water for injections vial. | | | 3. Wipe the rubber stopper of the **water for injections** vial with an antiseptic like an alcohol swab and allow it to dry. | | | 4. Open the Mix2Vial set by peeling off the lid (Figure 1). Do not remove the Mix2Vial set from the blister package. | SMPC_30756_image2_11.jpg Figure 1 | | 5. Place the **water for injections** vial on an even, clean surface and hold the vial tight. Take the Mix2Vial set together with the blister package and vertically pierce the **water for injections** vial with the **blue** tip of the Mix2Vial set (Figure 2). | SMPC_30756_image3_11.jpg Figure 2 | | 6. Carefully remove the blister package from the Mix2Vial set by holding at the rim and pulling vertically upwards. Make sure that you only pull away the blister package and not the Mix2Vial set (Figure 3). | SMPC_30756_image4_11.jpg Figure 3 | | 7. Remove the plastic flip-off cap from the **Respreeza** vial. | | | 8. Wipe the rubber stopper of the **Respreeza** vial with an antiseptic like an alcohol swab and allow it to dry. | | | 9. Place the **Respreeza** vial on an even and firm surface. Invert the water for injections vial with the Mix2Vial set attached and vertically pierce the **Respreeza** vial with the **clear** tip of the Mix2Vial set (Figure 4). The water for injections will automatically flow into the Respreeza vial. NOTE: Ensure all water has transferred into the Respreeza vial. | SMPC_30756_image5_11.jpg Figure 4 | | 10. Follow steps below to remove entire Mix2Vial set from Respreeza vial: • With one hand tightly grasp the Respreeza vial as shown in Figure 5. • With the other hand tightly grasp the water for injections vial and the blue part of the Mix2Vial set. • Bend **the entire Mix2Vial set** to the side until it disconnects from the Respreeza vial (Figure 5). Discard the water for injections vial with the entire Mix2Vial set. | SMPC_30756_image6_11.jpg Figure 5 | | 11. Gently swirl the Respreeza vial until the powder is completely dissolved (Figure 6). DO NOT SHAKE. Take care not to touch the rubber vial stopper. | SMPC_30756_image7_11.jpg Figure 6 | | 12. Inspect visually the reconstituted solution. The solution should be clear, colourless to slightly yellow, and free from visible particles. Do not use solutions that are discoloured, cloudy or have particles. | | | 13. If more than 1 vial of Respreeza is needed to achieve the required dose, repeat instructions 1 to 12 above using an additional package containing an unused Mix2Vial set. **Use a separate, unused Mix2Vial set, and a water for injections vial for each Respreeza vial.** | | | 14. The reconstituted solutions can be sequentially administered directly from the vial, or the reconstituted solutions can alternatively be transferred into an infusion container (e.g. empty intravenous bag or glass bottle; (not supplied) via a commercially available intravenous fluid tubing transfer set (not supplied)) prior to administration. Use aseptic technique to transfer the reconstituted solution into an infusion container. | | **Administration** The reconstituted solution must be administered using an IV infusion set. | | | --- | | 1. Make sure that the air vent cap and the roller clamp of the IV infusion set are closed. VERTICALLY pierce the Respreeza vial with the IV infusion set spike **while twisting the IV infusion set spike gently** or connect it to an infusion container. | | 2. Elevate the Respreeza vial/infusion container or hang on an infusion stand. | | 3. Prime the drip chamber by squeezing it until the Respreeza solution has filled the chamber roughly half-way. | | 4. Open the air vent cap of the IV infusion set. | | 5. Slowly open the roller clamp of the IV infusion set and let the Respreeza solution flow until it reaches the end of the tubing with no air bubbles. | | 6. Close the roller clamp. | | 7. Disinfect the injection site with an antiseptic like an alcohol swab before carefully inserting the needle into the vein. Make sure that there is no more air in the butterfly tube left. | | 8. Connect the end of the IV infusion set to the butterfly set and open the roller clamp again. | | 9. Infuse the reconstituted solution into the vein. The solution should be infused at an infusion rate of about 0.08 ml per kg body weight each min, as determined by your response and your comfort. The recommended dose of 60 mg per kg of body weight will take approximately 15 minutes to infuse. | Any unused medicinal product or waste material should be disposed of in accordance with local requirements.