INOmax Therapy with INOmax DSIR. Linde: Living healthcare

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1 INOmax Therapy with INOmax DSIR are INOmax Therapy

2 02 We are INOmax Therapy 03 Contents. 4 We are INOmax Therapy 6 INOmax Therapy Mode of action The benefits of INOmax Therapy 18 Efficacy and safety of INOmax Therapy 24 INOmax DSIR: ino delivery system

3 04 We are INOmax Therapy 0 We are INOmax Therapy. We are INOmax Therapy INOmax Therapy it s more than a pharmaceutical drug. It is the unique combination of science, technology and the people of Linde Healthcare. To save lives, together with you. We are there when you need us to support you, through our passionate commitment. 24 hours, every day. It s the We that counts. With more than years of practical experience in neonatal intensive care, INOmax Therapy has been your partner in the treatment of hypoxic respiratory failure in term and near-term infants ( 34 weeks). Since 11 INOmax is also indicated for the use in cardiac surgery, as a treatment for peri- and post-operative pulmonary hypertension in adults and children of all ages.* We aim for the highest standards when it comes to the way We work and the quality of our products and services. are INOmax Therapy The people Our passion and commitment is the key driving force. We stand by you around the clock taking care of maintenance and full service of the device, emergency deliveries including additional devices and ongoing in-house training. The product INOmax it s more than a gas. It is the first nitric oxide approved by the EMA and FDA as a pharmaceutical drug.** The science Since its introduction, INOmax Therapy, has proven to be an effective and safe ino therapy you can rely on. 1-3,13-18 The technology We are particularly aware of the fact that precision of dosage is vital to delivering nitric oxide reliably and safely. The INOmax DSIR ensures precise control and safe delivery of INOmax along with easy operation. 4 * See also **EMA: European Medicines Agency; FDA: US Food and Drug Administration

4 06 INOmax Therapy Mode of action 07 INOmax. Selective pulmonary vasodilation. Signalling molecule Endothelium- derived relaxing factor (EDRF) Mode of action The first FDA- and EMA-approved inhaled nitric oxide. Smooth muscle cell relaxation with nitric oxide. Nitric oxide has shown to be a signalling molecule in the cardiovascular system which accounts for the biologic activities of the EDRF:,9 Endothelium-derived relaxing factor which acts as local vasodilator restricted to pulmonary circulation Significantly improves oxygenation as measured by partial pressure of arterial oxygen (PaO₂) and oxygenation index (OI)6 Decreases pulmonary vascular pressure, thereby reducing right heart cardiac load7 Alleviates ventilation/perfusion mismatch associated with hypoxaemia8 Smooth muscle cell NO + O2 NO Guanylate cyclase L-arginine NO + citrulline (NOS) Endothelial cell Nobel Prize for nitric oxide. In 1998, the three researchers Robert F. Furchgott, Louis Ignarro and Ferid Murad were awarded the Nobel Prize in Physiology or Medicine for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system. A fourth researcher, Salvador Moncada, showed that nitric oxide is produced by endothelial cells, thus explaining the actions of EDRF. These discoveries opened new avenues in patient treatment and the diagnosis of various diseases. INOmax significantly improves oxygenation dilating the pulmonary vessels, thus selectively reducing pulmonary artery pressure and resistance without affecting systemic circulation.1-3,13- INOmax acts through the same physiological pathway as endogenous nitric oxide and promotes calcium dependent smooth muscle cell relaxation by entering vascular smooth muscle cells. It activates the guanylate cyclase and increases intracellular levels of cyclic guanosine mono-phosphate (cgmp) which then leads to vasodilation.⁹ Effective vasodilation

5 08 8 INOmax Therapy Mode of action 09 Effective vasodilator Beneficial effects of INOmax. Proven to be a selective pulmonary vasodilator Significantly reduces pulmonary vascular resistance and lowers increased pulmonary artery pressure Mode of action Improves oxygenation and blood circulation, thus improving right ventricular ejection fraction 7 No systemic effect Has shown to be well tolerated with a low rate of adverse events 1-3,13 Less need for ECMO Does not trigger systemic hypotension due to rapid haemoglobin-mediated inactivation 3,,9 Improves right ventricular function and oxygenation reducing the need for ECMO 1,2, Indications of INOmax. INOmax, in conjunction with ventilator support and other appropriate active substances, is indicated: For the treatment of newborn infants 34 weeks gestation with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, in order to improve oxygenation and to reduce the need for extracorporeal membrane oxygenation. As part of the treatment of periand post-operative pulmonary hypertension in adults and newborn infants, infants, toddlers, children and adolescents, age 0 17 years in conjunction to heart surgery, in order to selectively decrease pulmonary arterial pressure and improve right ventricular function and oxygenation.

6 The benefits of INOmax Therapy 11 You can rely on. Evidence with confidence. INOmax DSIR. Developed for reliable and precise control. 4 Efficacy and safety are equally critically dependent on the delivery device. The unique injector module of the INOmax DSIR identifies individual ventilator waveforms and flow and delivers a synchronised and proportional exact dose of nitric oxide independent of ventilator flow pattern or breath rate. Reliable and precise control More than years of clinical practice in intensive critical care The INOmax Therapy is more than a pharmaceutical drug. It is the history of more than years of practical and personal experience of Linde Healthcare in the field of inhaled nitric oxide therapy to make INOmax Therapy effective and safe. Since the beginning the INOmax Therapy competence team aims for optimal technological and operational solutions to maximise efficacy and patient safety in intensive critical care. INOmax Therapy was first approved for the treatment of term and nearterm neonates ( 34 weeks) with respiratory heart failure in 01. Since 11, INOmax Therapy is also indicated for the use in cardiac surgery for the treatment of peri- and post-operative pulmonary hypertension in adults, children of all ages in conjunction to heart surgery in the European Union. A number of researchers found that INOmax selectively decreases pulmonary arterial pressure and improves right ventricular function and oxygenation without toxic effects. -7 Constant concentration, no risk of overdosing* by avoiding spikes. INOmax DSIR: synchronous and proportional volume delivered to maintain constant desired dose Ventilator flow Delivered nitric oxide (NO) concentration using INOmax DSIR delivery system NO concentration ppm INOmax DSIR NO concentration delivered to patient Fixed nitric oxide delivery dose leads to varying concentration delivered to patient Synchronous and proportional volume The benefits Nitric oxide (NO) concentration delivered to patient Ventilator flow Nitric oxide (NO) flow/injection More than 600,000 patients treated worldwide* 11 Proven to selectively improve oxygenation with no systemic effect,9 Reduces right ventricular workload 7 Well tolerated and low rate of adverse effects 1-3,13 Flow/ NO concentration ppm Time State-of-the-art ino delivery system INOmax DSIR 24h/7d technological and therapy support The INOmax DSIR provides a constant concentration of NO throughout the inspired breath thanks to the specially designed injector module. * All indications *Overdosing related to various NO concentration delivered to patients.

7 12 The benefits of INOmax Therapy 13 Operational risk management. Avoidance of rebound effects The delivery system INOmax DSIR is equipped with two unique back-up systems to bridge an acute device delivery failure until a back-up administration device is available and running. This could prevent an abrupt withdrawal from the therapy. The INOmax DSIR transport solution allows safe patient transfer without interruption of the ino therapy. Methods of handling adverse effects Risk management of ino. In general, inhaled nitric oxide can be associated with some risks which, however, occur infrequently.* 4, Risks associated with inhaled nitric oxide: Rebound effects associated with abrupt interruption of ino therapy NO₂ formation Increased methaemoglobin levels Secure control of NO₂ concentration Using INOmax DSIR NO₂ concentration will be monitored automatically. Excess increase of NO₂ will be detected immediately and trigger alarm. Prevention of elevated methaemoglobin (MetHB) levels The risk for the formation of MetHB is related to the applied nitric oxide concentration. 12 INOmax DSIR ensures an exact dosage of INOmax: peaks can be avoided due to delivery of constant concentration and an automatic shutdown of the system if the measured NO is over 0 ppm. Methaemoglobin levels should be measured within one hour after initiation of If you have questions about this therapy, read the SmPC carefully as well as the instruction manual for INOmax DSIR, or contact your local Linde Healthcare representative. The benefits Service you can rely on. The delivery system INOmax DSIR from Linde Healthcare meets all requirements for a safe administration and effective control of inhaled nitric oxide. If assistance is needed, your local INOmax Therapy specialist is at your disposal on the phone round the clock to provide direct support 24 hours a day, 7 days per week. *

8 14 The benefits of INOmax Therapy In your caring hands. Safe performance with INOmax DSIR.⁴ Automatic adaption to changes in the ventilator flow Monitoring of NO, NO₂ and O₂ Different low and high visual and audible alarm signals according to priority No interruption of therapy during transport Integrated back-up system ensures continuation of therapy in case of unplanned termination The benefits Specially developed injector module provides precise and constant dosing into the inspiratory limb with no risk of overdose and concentration spikes or generation of excessive inhaled NO₂ Documentation of the complete INOmax Therapy available Easy operations with INOmax DSIR.⁴ Simple to use direct and precise dosage of INOmax in ppm No calculation of dose needed Easy to use, safe delivery of INOmax Validated and easy to connect with almost all ventilators Suitable for all patients regardless of age (neonates, paediatrics and adults) Stand-by-mode ready for use for up to 12 hours after set-up Easy to handle patient transportation Long operating time without cylinder change* *Depending on dosage and ventilator

9 16 The benefits of INOmax Therapy 17 INOmax quality management. Manufacturing and quality control of the active substance nitric oxide (NO) and final pharmaceutical drug (INOmax) is conducted in accordance with current Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) standards for 0% batch traceability on the market. These international regulations are required for the safe use of drugs for human use and are laid down by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). High quality of products taken for granted It s the We that counts. All production sites are authorised and regularly GMP inspected by competent authorities. Each final drug product batch is individually tested and released by a qualified person (QP) in the EU to meet its defined quality specification. Manufacturing and test methods must be verified and all staff trained in GMP and GDP standards before handling the product. Additionally, supply and use of INOmax in the EU market is monitored by a QP who is available 24 hours a day, 7 days per week for any medical and/or technical follow-up questions from the agency. INOmax: pharmaceutical drug The benefits Passionate commitment The INOmax Therapy from Linde Healthcare is a full-service package to give you the support you need. We take care of maintenance and full service of the device, emergency deliveries including additional devices and ongoing in-house training 24 hours a day, 7 days per week. As any other drug for human use, INOmax has been licensed as a pharmaceutical drug in the US, EU and other markets in the world. Linde AG Linde Healthcare, Seitnerstrasse Pullach, Germany

10 18 Efficacy and safety of INOmax Therapy 19 Proven clinical benefits. INOmax. Clinical evidence. In two pivotal double-blind, randomised, placebo-controlled multicentre trials CINRGI and NINOS, INOmax clearly demonstrates that it significantly improves oxygenation in term and near-term neonates with hypoxic respiratory failure. 1,2 Significant reduction of extracorporeal membrane oxygenation (ECMO). Change in Pa0₂ following initiation of INOmax ± Standard Error 1 Incidence of death or need for ECMO¹ First FDA- and EMAapproved ino In babies with hypoxic respiratory failure, blood vessels in the lung constrict, preventing the heart from pumping blood through the lungs for oxygenation. This, in turn, reduces oxygen delivery to the body tissue. INOmax was the first pharmaceutically approved inhaled nitric oxide for the treatment of term and near-term neonates with hypoxic respiratory failure associated with clinical echographic evidence of pulmonary hypertension. Change in Pa0 2 (mm Hg) p< (n=121) 8.2 (n=114) Placebo INOmax control At 30 minutes Percentage of patients dead by 1 days of age or initiation of ECMO 64% (n=77) p<0.006 Placebo control 46% (n=2) INOmax Reduction in the incidence of death or need for ECMO NINOS (The Neonatal Nitric Oxide Study Group): INO therapy significantly reduces the need for ECMO and the occurrence of chronic lung disease. 1 INOmax significantly improves pulmonary blood flow through pulmonary vasodilation, thus reducing the incidence of death and the need of invasive ECMO in term and near-term neonates with hypoxic respiratory failure (HRF). 1,2 Receipt of ECMO 2 Percentage of patients receiving ECMO p= % (n=78) Placebo control 38% (n=48) INOmax Efficacy and safety CINRGI (Clinical Inhaled Nitric Oxide Research Group): The incidence of the combined primary outcome (death by 1 days of age or the initiation of ECMO) was significantly lower in the NO group than in the control group. 2

11 Efficacy and safety of INOmax Therapy 21 INOmax. Reduced risk of complications. INOmax. Proven clinical benefits. The clinical benefit of inhaled nitric oxide compared to intravenous vasodilation. Rapid and effective improvement of oxygenation. Low rate of adverse events: rapid on- and offset The non-invasive INOmax Therapy effectively reduces elevated pulmonary artery pressure (PAP) without affecting systemic haemodynamics.,9 The rapid on- and offset-effect of inhaled nitric oxide helps reduce the risk of complications. 1-3 Patients undergoing cardiac surgery are often at risk of developing pulmonary hypertension due to pulmonary vasoconstriction. Conventional treatment, such as nitrates, calcium antagonists or prostaglandins, supplemented with pulmonary vasodilators or inotropic vasodilators in the early post-operative period effectively reduce pulmonary vascular resistance yet are often associated with systemic hypotension. 13 INOmax has shown: Selective pulmonary vasodilator (EDRF) without any effect on systemic circulation,9 Intravenous vasodilator INO is rapidly inactivated as it is scavenged by haemoglobin upon diffusing into the blood. Thus, the vasodilator effect of ino is limited to pulmonary vasodilation effects without systemic effects. This is in contrast to intravenously infused vasodilators that can cause systemic vasodilation and severe systemic arterial hypotension. INO Rapid effect to significantly reduce increased pulmonary artery pressure 3 Significantly reduces pulmonary vascular resistance 6 Improves right ventricular function and oxygenation reducing the need for ECMO 7 Helps to speed up postoperative patient recovery 13,17 Patients undergoing cardiac surgery may benefit from less adverse effects and a more rapid recovery through the selective vasodilator effects of INOmax on pulmonary circulation. 13,14 Efficacy and safety

12 22 Efficacy and safety of INOmax Therapy 23 Evidence-based nitric oxide for patients undergoing cardiac surgery. Study Proven safety and efficacy. % Δ MPAP (±sd) NO Time (min.) NO ** ** ** ** P <0.01 Post bypass, pulmonary hypertension Solina et al. J Clin Anesth 01 Placebo NO Selectively reduces MPAP in paediatric patients who developed pulmonary hypertension (p=0.008) immediately after CPB and surgical repair 30% lower frequency of PHTC (p=0.04) Shorter time to meeting weaning criteria Shorter time on mechanical ventilation and extubation (p=0.019) Shorter postoperative course No toxic effects Prospective, randomised, non-blinded study 62 consecutive cardiac surgery patients with pulmonary hypertension immediately prior to induction of anaesthesia Subjects randomly received one of five doses ( ppm 40 ppm) of ino on termination of CPB Time (min.) % Δ MPAP (±sd) INOmax Therapy: examples of clinical indications Placebo Children undergoing corrective surgery Time NO for congenital heart disease (CHD)(min.) Adults undergoing cardiac surgery Heart transplants and valve replacement Post bypass, normal pulmonary pressure. Nitric oxide demonstrates reductions in PVR in all groups augmenting right ventricular performance Doses higher than ppm were not associated with greater reductions in pulmonary vascular tone There were no significant differences found in demographic and clinical data Heart transplants & valve replacement Rajek et al. Anesth Analg Post bypass, normal pulmonary pressure. Prostaglandin E1 vs ino min. before weaning and just before weaning from CPB, respectively Patients undergoing orthotopic heart transplantation for congestive heart failure Gas off Adults undergoing cardiac surgery Controlled, randomised, double-blind study 40 patients with preoperative evidence of pulmonary hypertension after surgical repair of congenital heart disease (MPAP >0% MSAP) Prospective, randomised, double-blind placebo-controlled study 124 infants median age 3 months: 76% with large ventricular or atrioventricular septal defects, who had high pulmonary flow, pressure, or both, and were undergoing corrective surgery for congenital heart disease Wagner et al. SCRIPTA MEDICA 0319 Retrospective study with a total of 0 patients randomly allocated to two groups. One had NO added to the inhalation mixture at the time of weaning (NO group) and the other was administered nitroglycerine (NTG group) INO selectively reduces PVR and PAP immediately after heart transplantation facilitating weaning from CPB PVR nearly halved in the NO group, but reduced by only approx. % in the PGE1 group PAP was approx. decreased 30% during NO inhalation, but only approx. 16% during the PGE1 infusion Pulmonary-to-systemic vascular resistance ratio was significantly less with NO, whereas increased approx. 30% in the PGE1 group NO is more effective in reducing vascular resistance than nitroglycerine (p<0.0) NO allows for a better function of the right ventricle (p<0.0) and easier weaning from ECC after mitral valve repair PHTC: pulmonary hypertensive crisis; PVR: pulmonary vascular resistance, PAP: pulmonary arterial pressure, MPAP: mean pulmonary arterial pressure, MSAP mean systemic arterial pressure, CPB: cardiopulmonary bypass, ECC: extracorporeal circulation Efficacy and safety ** % Δ MPAP (±sd) % Δ MPAP (±sd) Gas off Placebo Miller et al. Lancet 0013 ** Gas off Time (min.) ** P <0.01 Positive effect of NO on postoperative pulmonary hypertension in Post bypass, pulmonary hypertension. 3 infants and children undergoing surgical repair Positive effect of NO in CHD Russell et al. Anesth Analg ** Efficacy and safety results of INOmax Children undergoing corrective surgery for congenital heart disease (CHD) With more than years of practical experience of inhaled nitric oxide therapy, INOmax has demonstrated to be effective and safe in numerous researches for cardiac surgery.3,13,16,17 Subsequently, INOmax Therapy is Gas off indicated as part of the treatment of peri- and3post-operative pulmonary hypertension in adults and children of all ages30 in conjunction to heart 2 surgery, in order to selectively decrease pulmonary arterial pressure and Placebo improve right ventricular function and oxygenation with low incidence 0 of adverse effects. - Study design

13 24 INOmax DSIR: ino delivery system INOmax DSIR. State-of-the-art technology.⁴ 3 INOmax DSIR: state-of-the-art technology Exclusive innovations to Linde Healthcare. From the very beginning, advanced technology has been at the very heart of the We are particularly aware of the fact that dosage precision is key to reliable and safe delivery of nitric oxide. The next generation ino delivery system INOmax DSIR presents the combined technological know-how of INOmax Therapy in a smart format. This delivery system stands for precise control, reliable monitoring along with easy set-up, connections and operations. Exclusive service to Linde Healthcare. We make sure that everything is available at your hospital so that you can carry out the ino therapy at any time. Your local specialist is at your disposal on the phone round-the-clock to provide direct assistance 24 hours a day, 7 days per week Simple and intuitive colour touch screen. Immediate view of monitoring, alarm messaging and dosing Lightweight head for easy interand intra-hospital transportation and integrated back-up system (up to 6 hrs of battery life) INOblender (manual bagging) ensures even more precise dosage. Primary back-up device in case of system failure Small cart safely secures two litre cylinders, easy moveable and space-saving 4 Please see also INOmax DSIR brochure. INOmax DSIR

14 26 INOmax DSIR: ino delivery system 27 Ready, when you are. Unique personal service The INOmax DSIR delivery system is part of the INOmax Therapy package from Linde Healthcare. The INOmax Therapy includes the complete device system, a 24-hour customer support as well as technical and operational training for you and your team. The full-service package includes: INOmax DSIR (device for administering INOmax) INOmax litre cylinder and 2 litre cylinder for transportation* INOcal (NO/NO₂ calibration gas for high range calibration of INOmax DSIR) Disposables (to allow use with wide range of ventilators) Maintenance and full service of the device 24h/7d technical and therapy support Emergency INOmax deliveries Ongoing in-house training INOmax DSIR safety footprint.⁴ INOmax DSIR utilises state-of-the-art technology that combines the latest navigation, calibration and monitoring features into an easy-to-use interface: Dual channel design to ensure safe delivery independent of monitoring Validated and easy to connect with almost all ventilators Dual back-up system to ensure precise continuation of therapy Up to 6 hrs of battery life Easy to change cylinders without interruption of therapy Suitable for inter- and intra-hospital transport Infrared signal communication to enhance patient safety and intuitive graphic display with colour touch screen *Nitric oxide 400 ppm or 800 ppm concentration INOmax DSIR

15 References 1. Neonatal inhaled nitric oxide study group. Inhaled nitric oxide in fullterm and nearly full-term infants with hypoxic respiratory failure, N Engl J Med 1997;336(9): Clark RH et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn, N Engl J Med 00;342(7): Russell IA et al. The effects of inhaled nitric oxide on postoperative pulmonary hypertension in infants and children undergoing surgical repair of congenital heart disease. Anesth Analg 1998;87(1): INOmax DSIR Operation and Maintenance Manual 13.. Frostell C et al. Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991;83(6): Chock VY et al. Inhaled nitric oxide for preterm premature rupture of membranes, oligohydramnios, and pulmonary hypoplasia. Am J Perinatol 09;26(4): Rossaint R et al. Inhaled nitric oxide: its effects on pulmonary circulation and airway smooth muscle cells. Eur Heart J 1993;14 Suppl I: Lohbrunner H et al. Inhaled nitric oxide for the treatment of ARDS. Anaesthesist 04;3(8): Griffiths MJ, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med 0;33(2): INOmax Summary of Product Characteristics. index.jsp?curl=pages/medicines/ human/medicines/000337/ human_med_ jsp&mid=wc0b01ac08001d Data on File Davidson D et al. Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, doublemasked, placebo-controlled, doseresponse, multicenter study. Pediatrics 1998;1: Miller OI et al. Inhaled nitric oxide and prevention of pulmonary hypertension after congenital heart surgery: a randomised double-blind study. Lancet 00;36(9240): Goldman AP et al. Nitric oxide is superior to prostacyclin for pulmonary hypertension after cardiac operations. Ann Thorac Surg 199;60(2):300-;discussion Solina AR et al. Dose response to nitric oxide in adult cardiac surgery patients. J Clin Anesth 01;13(4): Girard C et al. Inhaled nitric oxide after mitral valve replacement in patients with chronic pulmonary artery hypertension. Anesthesiology 1992;77(): Rajek A et al. Inhaled nitric oxide reduces pulmonary vascular resistance more than prostaglandin E(1) during heart transplantation. Anesth Analg 00;90(3): Radovancevic B et al. Nitric oxide versus prostaglandin E1 for reduction of pulmonary hypertension in heart transplant candidates. J Heart Lung Transplant 0;24(6): Wagner R et al. Effect of nitric oxide on early myocardial function in valvular surgery. SCRIPTA MEDICA (BRNO) 03;76(6): INOmax. Active substance: Nitric oxide (Stickstoffmonoxid) Presentations: 2 and litre cylinder with 400 ppm or 800 ppm NO diluted in N₂. Indications: To treat the Persistent Pulmonary Hypertension in the Newborn (PPHN) of newborn infants 34 weeks gestation with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, in order to improve oxygenation and to reduce the need for extracorporeal membrane oxygenation; or/and as part of the treatment of peri- and post-operative Pulmonary Hypertension Associated with Heart Surgery from newborn infants to adults, in order to selectively decrease pulmonary arterial pressure and improve right ventricular function and oxygenation. Contraindications: Hypersensitivity to the active substance (NO) or to the excipient (N₂). Neonates known to be dependent on right-to-left, or significant left-to-right, shunting of blood. Adverse Events: Thrombocytopenia ( 1/); Hypotension, atelectasis ( 1/0 to <1/); Methaemoglobinaemia ( 1/1,000 to <1/0); Bradycardia (following abrupt discontinuation of therapy), hypoxia, dyspnoea, chest discomfort, dry throat, headache, dizziness (not known). Rebound reaction when therapy is abruptly disconnected. Warnings: The INOmax dose should not be discontinued abruptly as it may result in an increase in pulmonary artery pressure (PAP) and/or worsening of blood oxygenation (PaO₂) (rebound reaction). Deterioration in oxygenation and elevation in PAP may also occur in neonates with no apparent response to INOmax. Weaning from inhaled nitric oxide should be performed with caution. For patients transported to other facilities for additional treatment, who need to continue with inhaled nitric oxide, arrangements should be made to ensure the continuous supply of inhaled nitric oxide during transportation. The physician should have access at the bedside to a reserve nitric oxide delivery system. During the treatment control and monitor the inspired INOmax, NO₂, FiO₂, methaemoglobin concentrations. A regular monitoring of haemostasis and measurement of bleeding time is recommended. When INOmax is used combined with other vasodilators (e.g. sildenafil), or with other nitric oxide donor substances including sodium nitroprusside and nitroglycerine, or substances known to cause increased methaemoglobin (e.g. alkyl nitrates and sulphonamides. Prilocaine) care must be taken. INOmax should not be used during pregnancy or breastfeeding. No efficacy has been demonstrated with the use of inhaled nitric oxide in patients with congenital diaphragmatic hernia. For prescription. Linde Healthcare AB, SE Lidingö, Sweden. April 14. For detailed information please read full SmPC. Linde AG Linde Healthcare, Seitnerstrasse 70, 849 Pullach, Germany Phone , INOmax, INOblender and INOcal are registered trademarks of The Linde Group.