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| Product NDC Code | 82605-006 | ||||||
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| Drug Name | Ulspira |
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| Type | Generic | ||||||
| Pharm Class | Vasodilation [PE], Vasodilator [EPC] |
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| Active Ingredients |
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| Route | RESPIRATORY (INHALATION) | ||||||
| Dosage Form | GAS | ||||||
| RxCUI drug identifier | 582608 | ||||||
| Application Number | ANDA203144 | ||||||
| Labeler Name | Airgas Therapeutics, LLC | ||||||
| Packages |
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Overdosage of Ulspira
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE Overdosage with nitric oxide is manifest by elevations in methemoglobin and pulmonary toxicities associated with inspired NO2. Elevated NO2 may cause acute lung injury. Elevations in methemoglobin reduce the oxygen delivery capacity of the circulation. In clinical studies, NO2 levels >3 ppm or methemoglobin levels >7% were treated by reducing the dose of, or discontinuing, nitric oxide. Methemoglobinemia that does not resolve after reduction or discontinuation of therapy can be treated with intravenous vitamin C, intravenous methylene blue, or blood transfusion, based upon the clinical situation.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the label; Hypoxemia [see Warnings and Precautions (5.2)] Worsening Heart Failure [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from the clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Controlled studies have included 325 patients on nitric oxide doses of 5 to 80 ppm and 251 patients on placebo. Total mortality in the pooled trials was 11% on placebo and 9% on nitric oxide, a result adequate to exclude nitric oxide mortality being more than 40% worse than placebo. In both the NINOS and CINRGI studies, the duration of hospitalization was similar in nitric oxide and placebo-treated groups. From all controlled studies, at least 6 months of follow-up is available for 278 patients who received nitric oxide and 212 patients who received placebo. Among these patients, there was no evidence of an adverse effect of treatment on the need for rehospitalization, special medical services, pulmonary disease, or neurological sequelae. In the NINOS study, treatment groups were similar with respect to the incidence and severity of intracranial hemorrhage, Grade IV hemorrhage, periventricular leukomalacia, cerebral infarction, seizures requiring anticonvulsant therapy, pulmonary hemorrhage, or gastrointestinal hemorrhage. In CINRGI, the only adverse reaction (>2% higher incidence on nitric oxide than on placebo) was hypotension (14% vs. 11%). 6.2 Post-Marketing Experience Post marketing reports of accidental exposure to nitric oxide for inhalation in hospital staff has been associated with chest discomfort, dizziness, dry throat, dyspnea, and headache. The most common adverse reaction is hypotension. (6). To report SUSPECTED ADVERSE REACTIONS, contact Airgas Therapeutics at 1-833-ULSPIRA (857-7472) and http://www.ulspira.com/ or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Ulspira Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS 7.1 Nitric Oxide Donor Agents Nitric oxide donor agents such as prilocaine, sodium nitroprusside and nitroglycerine may increase the risk of developing methemoglobinemia. Nitric oxide donor compounds may increase the risk of developing methemoglobinemia (7).
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Nitric oxide relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate, which then leads to vasodilation. When inhaled, nitric oxide selectively dilates the pulmonary vasculature, and because of efficient scavenging by hemoglobin, has minimal effect on the systemic vasculature. Nitric oxide appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios. 12.2 Pharmacodynamics Effects on Pulmonary Vascular Tone in PPHN Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defect or as a condition secondary to other diseases such as meconium aspiration syndrome (MAS), pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH), and pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale. In neonates with PPHN, nitric oxide improves oxygenation (as indicated by significant increases in PaO2). 12.3 Pharmacokinetics The pharmacokinetics of nitric oxide has been studied in adults. Absorption and Distribution Nitric oxide is absorbed systemically after inhalation. Most of it traverses the pulmonary capillary bed where it combines with hemoglobin that is 60% to 100% oxygen-saturated. At this level of oxygen saturation, nitric oxide combines predominantly with oxyhemoglobin to produce methemoglobin and nitrate. At low oxygen saturation, nitric oxide can combine with deoxyhemoglobin to transiently form nitrosylhemoglobin, which is converted to nitrogen oxides and methemoglobin upon exposure to oxygen. Within the pulmonary system, nitric oxide can combine with oxygen and water to produce nitrogen dioxide and nitrite, respectively, which interact with oxyhemoglobin to produce methemoglobin and nitrate. Thus, the end products of nitric oxide that enter the systemic circulation are predominantly methemoglobin and nitrate. Metabolism Methemoglobin disposition has been investigated as a function of time and nitric oxide exposure concentration in neonates with respiratory failure. The methemoglobin (MetHb) concentration- time profiles during the first 12 hours of exposure to 0, 5, 20, and 80 ppm nitric oxide are shown in Figure 1. Figure 1: Methemoglobin Concentration-Time Profiles Neonates Inhaling 0, 5, 20 or 80 ppm Nitric Oxide Methemoglobin concentrations increased during the first 8 hours of nitric oxide exposure. The mean methemoglobin level remained below 1% in the placebo group and in the 5 ppm and 20 ppm nitric oxide groups, but reached approximately 5% in the 80 ppm nitric oxide group. Methemoglobin levels >7% were attained only in patients receiving 80 ppm, where they comprised 35% of the group. The average time to reach peak methemoglobin was 10 ± 9 (SD) hours (median, 8 hours) in these 13 patients, but one patient did not exceed 7% until 40 hours. Elimination Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accounting for >70% of the nitric oxide dose inhaled. Nitrate is cleared from the plasma by the kidney at rates approaching the rate of glomerular filtration. figure1
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS ULSPIRA is contraindicated in neonates dependent on right-to-left shunting of blood. Neonates dependent on right-to-left shunting of blood (4).
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION ULSPIRA (nitric oxide gas) is a drug administered by inhalation. Nitric oxide, the active substance in ULSPIRA, is a pulmonary vasodilator. ULSPIRA is a gaseous blend of nitric oxide and nitrogen (0.08% and 99.92%, respectively for 800 ppm). ULSPIRA is supplied in aluminum cylinders as a compressed gas under high pressure (2000 pounds per square inch gauge [psig]). The structural formula of nitric oxide (NO) is shown below: NO pic
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION 2.1 Dosage Term and near-term neonates with hypoxic respiratory failure The recommended dose of ULSPIRA is 20 ppm. Maintain treatment up to 14 days or until the underlying oxygen desaturation has resolved and the neonate is ready to be weaned from ULSPIRA therapy. Doses greater than 20 ppm are not recommended [see Warnings and Precautions (5.2)] . 2.2 Administration Nitric Oxide Delivery Systems ULSPIRA must be administered using a calibrated FDA-cleared Nitric Oxide Delivery System (NODS). There are various FDA-cleared NODS; refer to the NODS labeling to determine which NODS to use with this drug product and for needed information on training and technical support for users of this drug product with the NODS. Do not use ULSPIRA with Inomax DSIR Plus and DSIR Plus MRI NODS. Do not use ULSPIRA in the MRI suite. Keep available a backup battery power supply and an independent reserve nitric oxide delivery system to address power and system failures . Monitoring Measure methemoglobin within 4-8 hours after initiation of treatment with ULSPIRA and periodically throughout treatment [see Warnings and Precautions (5.2)]. Monitor for PaO2 and inspired NO2 during ULSPIRA administration [see Warnings and Precautions 5.3)] . Weaning and Discontinuation Avoid abrupt discontinuation of ULSPIRA [see Warnings and Precautions (5.1)]. To wean ULSPIRA, downtitrate in several steps, pausing several hours at each step to monitor for hypoxemia. The recommended dose is 20 ppm, maintained for up to 14 days or until the underlying oxygen desaturation has resolved (2.1). Doses greater than 20 ppm are not recommended (2.1, 5.2) Administration: Avoid abrupt discontinuation (2.2, 5.1).
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS ULSPIRA (nitric oxide) gas is available in a 800 ppm concentration. ULSPIRA (nitric oxide) is a gas available in a 800 ppm concentration (3).
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE ULSPIRA™ is indicated to improve oxygenation and reduce the need for extracorporeal membrane oxygenation in term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension in conjunction with ventilatory support and other appropriate agents. ULSPIRA is a vasodilator indicated to improve oxygenation and reduce the need for extracorporeal membrane oxygenation in term and near- term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension in conjunction with ventilatory support and other appropriate agents.
Spl product data elements
Usually a list of ingredients in a drug product.Ulspira Ulspira NITROGEN NITRIC OXIDE NITRIC OXIDE
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of a carcinogenic effect was apparent, at inhalation exposures up to the recommended dose (20 ppm), in rats for 20 hr/day for up to two years. Higher exposures have not been investigated. Nitric oxide has demonstrated genotoxicity in Salmonella (Ames Test), human lymphocytes, and after in vivo exposure in rats. There are no animal or human studies to evaluate nitric oxide for effects on fertility.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.Ulspira TM (nitric oxide for inhalation) 800 PPM Rx Only CAUTION: HIGH PRESSURE GAS. CAN CAUSE RAPID SUFFOCATION WITHOUT WARNING. Use equipment rated for cylinder pressure. Store and use with adequate ventilation. Secure cylinder in use and storage. Close valve after each use and when empty. USE IN ACCORDANCE WITH APPROPRIATE SDS. WARNING: Administration of this gas mixture may be hazardous or contraindicated. For use only by or under the supervision of a licensed practitioner who is experienced in the use and administration of gas mixtures, and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications, and side effects and the precautions to be taken. FIRST AID: IF INHALED, remove person to fresh air. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical help. RETURN WITH 25 PSIG. TO BE REFILLED ONLY BY A PHARMACEUTICAL FACILITY AUTHORIZED BY AIRGAS THERAPEUTICS, LLC Manufactured Under Pharmaceutical Current Good Manufacturing Practices (cGmps). DO NOT REMOVE THIS PRODUCT LABEL Store at 25 C (77 F) with excursions permitted between 15 – 30 C (59 – 86 F). Volume 2138 Liters Airgas Therapeutics An Air Liquide company Manufactured by: AIRGAS THERAPEUTICS, LLC 6141 Easton Road Plumsteadville, PA 18949-0310 For Product Inquiry 1-833-ULSPIRA (857-7472) UN1956 COMPRESSED GAS, N.O.S. (NITRIC OXIDE, NITROGEN) 2.2 Net Weight: 2.5 kg LOT: EXP: NDC 82605-005-01 nitric oxide two
Ulspira TM (nitric oxide for inhalation) 800 PPM Rx Only CAUTION: HIGH PRESSURE GAS. CAN CAUSE RAPID SUFFOCATION WITHOUT WARNING. Use equipment rated for cylinder pressure. Store and use with adequate ventilation. Secure cylinder in use and storage. Close valve after each use and when empty. USE IN ACCORDANCE WITH APPROPRIATE SDS. WARNING: Administration of this gas mixture may be hazardous or contraindicated. For use only by or under the supervision of a licensed practitioner who is experienced in the use and administration of gas mixtures, and if familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications and side effects and the precautions to be taken. FIRST AID: IF INHALED, remove person to fresh air. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical help. RETURN WITH 25 PSIG. TO BE REFILLED ONLY BY A PHARMACEUTICAL FACILITY AUTHORIZED BY AIRGAS THERAPEUTICS, LLC Manufactured Under Pharmaceutical Current Good Manufacturing Practices (cGMPs). DO NOT REMOVE THIS PRODUCT LABELS Store at 25 C (77 F) with excursions permitted between 15 - 30 C (59 – 86 F). Volume 362 Liters Airgas Therapeutics An Air Liquide company Manufactured by: AIRGAS THERAPEUTICS, LLC 6141 Easton Road Plumsteadville, PA 18949-0310 For Product Inquiry 1-833-ULSPIRA (857-7472) UN 1956 COMPRESSED GAS, N.O.S. (NITRIC OXIDE, NITROGEN) 2.2 Net Weight: 0.4 kg LOT: EXP: NDC 82605-005-02 Label No. ULSMD15 Rev. 00 800PPM MD15 nitric oxide one
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES 14.1 Treatment of Hypoxic Respiratory Failure (HRF) The efficacy of nitric oxide has been investigated in term and near-term newborns with hypoxic respiratory failure resulting from a variety of etiologies. Inhalation of nitric oxide reduces the oxygenation index (OI= mean airway pressure in cm H2O × fraction of inspired oxygen concentration [FiO2]× 100 divided by systemic arterial concentration in mm Hg [PaO2]) and increases PaO2 [see Clinical Pharmacology (12.1)]. Control (n=121) NO (n=114) P value Death or ECMO*,† 77 (64%) 52 (46%) 0.006 Death 20 (17%) 16 (14%) 0.60 ECMO 66 (55%) 44 (39%) 0.014 Placebo Nitric Oxide P value ECMO*,† 51/89 (57%) 30/97 (31%) <0.001 Death 5/89 (6%) 3/97 (3%) 0.48 14.3 Ineffective in Prevention of Bronchopulmonary Dysplasia (BPD) The safety and efficacy of nitric oxide for the prevention of chronic lung disease [bronchopulmonary dysplasia, (BPD)] in neonates ≤ 34 weeks gestational age requiring respiratory support has been studied in four large, multi-center, double-blind, placebo-controlled clinical trials in a total of 2,600 preterm infants. Of these, 1,290 received placebo, and 1,310 received inhaled nitric oxide at doses ranging from 5-20 ppm, for treatment periods of 7-24 days duration. The primary endpoint for these studies was alive and without BPD at 36 weeks postmenstrual age (PMA). The need for supplemental oxygen at 36 weeks PMA served as a surrogate endpoint for the presence of BPD. Overall, efficacy for the prevention of bronchopulmonary dysplasia in preterm infants was not established. There were no meaningful differences between treatment groups with regard to overall deaths, methemoglobin levels, or adverse events commonly observed in premature infants, including intraventricular hemorrhage, patent ductus arteriosus, pulmonary hemorrhage, and retinopathy of prematurity. The use of nitric oxide for prevention of BPD in preterm neonates ≤ 34 weeks gestational age is not recommended.
| Death or ECMO*,† | 77 (64%) | 52 (46%) | 0.006 |
| Death | 20 (17%) | 16 (14%) | 0.60 |
| ECMO | 66 (55%) | 44 (39%) | 0.014 |
| ECMO*,† | 51/89 (57%) | 30/97 (31%) | <0.001 |
| Death | 5/89 (6%) | 3/97 (3%) | 0.48 |
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS 8.4 Pediatric Use The safety and efficacy of nitric oxide for inhalation has been demonstrated in term and near- term neonates with hypoxic respiratory failure associated with evidence of pulmonary hypertension [see Clinical Studies (14.1)]. Additional studies conducted in premature neonates for the prevention of bronchopulmonary dysplasia have not demonstrated substantial evidence of efficacy [see Clinical Studies (14.3)]. No information about its effectiveness in other age populations is available. 8.5 Geriatric Use Nitric oxide is not indicated for use in the adult population.
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING Size D Portable aluminum cylinders containing 362 liters at STP of nitric oxide gas in 800 ppm concentration in nitrogen (delivered volume 350 liters) (NDC 82605-006-02) Size 88 Aluminum cylinders containing 2138 liters at STP of nitric oxide gas in 800 ppm concentration in nitrogen (delivered volume 2083 liters) (NDC 82605-006-01) Distributed by Airgas Therapeutics LLC Radnor, PA 19087 USA AirGas Therapeutics an Air Liquide company © 2023 Airgas ULSPI 01
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API