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  • CLASSES

    Agents used for Closure of a Patent Ductus Arteriosus

    DEA CLASS

    Rx

    DESCRIPTION

    IV propionic acid NSAID
    For pharmacological closure of patent ductus arteriosus (PDA) in preterm infants
    Similar efficacy to IV indomethacin; may have less adverse effects on cerebral, mesenteric, and renal circulation; long term effects not assessed.

    COMMON BRAND NAMES

    NeoProfen

    HOW SUPPLIED

    Ibuprofen Lysine/NeoProfen Intravenous Inj Sol: 1mL, 17.1mg

    DOSAGE & INDICATIONS

    For treatment of a clinically significant patent ductus arteriosus (PDA) in premature infants when usual medical management such as fluid restriction, diuretics, and respiratory support is ineffective.
    NOTE: Administration as a prophylactic is not recommended as a PDA may spontaneously close after birth.
    NOTE: Although the clinical trial was conducted among infants with an asymptomatic PDA, reserve treatment for infants with a clinically significant PDA, as the long-term consequences of treatment have not been evaluated.
    Intravenous dosage
    Premature neonates <= 32 weeks gestation who weigh 500—1500 g

    Initially, 10 mg/kg IV followed, if necessary, by 2 doses of 5 mg/kg IV at 24-hour intervals. Base all doses on birth weight. Dose should be held in cases of oliguria (< 0.6 ml/kg/hour) or anuria. If the ductus arteriosus fails to close or reopens, a second course of ibuprofen lysine, alternative pharmacological therapy, or surgical closure may be necessary.

    MAXIMUM DOSAGE

    Adults

    Safe and effective use has not been established.

    Elderly

    Safe and effective use has not been established.

    Children

    Safe and effective use has not been established.

    Infants

    Safe and effective use has not been established.

    Neonates

    Safe and effective use has not been established.
    Premature neonates (<= 32 weeks gestation): 10 mg/kg/day IV.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Use is contraindicated in patients with significant renal impairment; specific guidelines for dosage adjustments in renal impairment are not available.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Do NOT administer by IM injection or by IV bolus.
    Administration via an umbilical arterial line has not been evaluated.
     
    Reconstitution:
    Each ml has 17.1 mg of ibuprofen lysine, which is equivalent to 10 mg/mL of ibuprofen. The recommended dose is 10 mg/kg of ibuprofen. Dilute with dextrose or saline to an appropriate volume.
    Discard any remaining solution after the initial withdrawal from the vial, as this product is preservative free.
     
    Intravenous infusion:
    Administer within 30 minutes of preparation.
    Administer via the IV port that is nearest the insertion site.
    Infuse over 15 minutes.
    Avoid extravasation, as the drug may be irritating to extravascular tissue.
    Do not simultaneously administer in the same intravenous line with Total Parenteral Nutrition (TPN). TPN should be interrupted for a 15-minute period before and after drug administration. Maintain line patency by using dextrose or saline.

    STORAGE

    NeoProfen:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Infants, neonates

    Ibuprofen lysine is only indicated for use in premature neonates <= 32 weeks gestational age who weigh 500—1500 grams. This drug is not indicated for use in term neonates, older neonates, or infants.

    Anemia, bleeding, coagulopathy, GI bleeding, intracranial bleeding, surgery, thrombocytopenia

    Ibuprofen lysine, like other nonsteroidal anti-inflammatory agents, can inhibit platelet aggregation. This effect may be exaggerated in patients with underlying hemostatic defects. Use is contraindicated in patients with coagulopathy or thrombocytopenia and in patients who are actively bleeding, especially those with intracranial bleeding or GI bleeding. Preterm infants should be observed for signs of bleeding. Ibuprofen has been shown to prolong bleeding time (but within the normal range) in normal adult subjects. Use with caution in patients expected to undergo surgery. Anemia may be exacerbated with the use of NSAIDs. This may be due to fluid retention, GI blood loss, or an incompletely described effect upon erythrogenesis. Follow hemoglobin values in at risk patients.

    Aortic coarctation, congenital heart disease, heart failure, hypertension, hypotension

    Ibuprofen lysine is contraindicated in patients with congenital heart disease in whom patency of the PDA is necessary for satisfactory pulmonary or systemic blood flow (e.g., pulmonary atresia, severe tetralogy of Fallot, severe aortic coarctation). Typically, clinical trials involving ibuprofen lysine have excluded neonates with hypotension or hypertension. Conditions such as congestive heart failure or hypertension can be exacerbated with NSAID use.

    Infection

    Ibuprofen lysine is contraindicated in preterm neonates with an untreated suspected or proven infection. As NSAIDs may mask the signs of infection, neonates must be monitored closely during therapy. Caution should be exercised when this drug is used in patients with an active controlled infection or in neonates at risk of infection.

    Extravasation, intramuscular administration, subcutaneous administration

    Ibuprofen lysine should be administered via intravenous infusion only; avoid subcutaneous administration and intramuscular administration. Administer carefully to prevent extravasation, as the solution may be irritating to tissue.

    Anuria, electrolyte imbalance, oliguria, renal failure, renal impairment

    Due to the role of prostaglandins in renal function and hemodynamics, urine output should be closely monitored during therapy with ibuprofen lysine. Use is contraindicated in preterm neonates with severe renal impairment or renal failure. Use with caution in neonates with mild to moderate renal impairment; if anuria or marked oliguria (urinary output < 0.6 mL/kg/hour) is evident at the time of a scheduled dose of ibuprofen lysine, dosage should be held until laboratory studies indicate that renal function has returned to normal. The rate and extent of electrolyte and water elimination may be affected by NSAID induced changes in renal function. Correction of preexisting electrolyte imbalance and periodic determinations of serum electrolytes and renal function are prudent.

    GI perforation, necrotizing enterocolitis

    Ibuprofen lysine may alter mesenteric hemodynamics, use is therefore contraindicated in preterm neonates with, or who are suspected of having, necrotizing enterocolitis . A decrease in blood flow to the bowel in susceptible patients may result in intestinal tissue death and perforation. Patients with gastrointestinal malformations, GI perforation, or impaired intestinal circulation are not good candidates for pharmacologic closure of PDA. Severe gastrointestinal effects, due to alterations in prostaglandin synthesis and topical irritation, have been reported in adult patients treated with chronic oral NSAIDs; monitor for fecal occult blood as condition of neonate warrants.

    Jaundice

    Ibuprofen lysine has been shown to displace bilirubin from albumin binding-sites; therefore, use with caution in patients with elevated total bilirubin, as indicated by jaundice or laboratory result.

    Hepatic disease

    Because hepatotoxicities have been reported in adults treated chronically with oral NSAIDs such as ibuprofen lysine, and prospective studies of neonates with hepatic impairment have not been conducted, monitor for signs and symptoms of hepatic disease.

    Pregnancy

    Ibuprofen lysine is indicated for use in premature neonates only; it should not be used during pregnancy.

    Breast-feeding

    Ibuprofen lysine is indicated for use in premature neonates only; do not use in breast-feeding women. Acetaminophen and ibuprofen, products intended for use in adult patients, are both considered to be usually compatible with breast-feeding by the American Academy of Pediatrics (AAP) and may be appropriate alternatives.

    ADVERSE REACTIONS

    Severe

    intraventricular hemorrhage / Delayed / 29.0-29.0
    apnea / Delayed / 28.0-28.0
    enterocolitis / Delayed / 22.0-22.0
    renal failure (unspecified) / Delayed / 1.0-1.0
    seizures / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    GI perforation / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    pulmonary hypertension / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known

    Moderate

    anemia / Delayed / 32.0-32.0
    hyperuricemia / Delayed / 7.0-7.0
    edema / Delayed / 4.0-4.0
    hematuria / Delayed / 1.0-1.0
    sinus tachycardia / Rapid / Incidence not known
    hypotension / Rapid / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    prolonged bleeding time / Delayed / Incidence not known
    gastritis / Delayed / Incidence not known
    skin ulcer / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known

    Mild

    gastroesophageal reflux / Delayed / Incidence not known
    injection site reaction / Rapid / Incidence not known
    skin irritation / Early / Incidence not known
    infection / Delayed / Incidence not known

    DRUG INTERACTIONS

    Alprostadil: (Contraindicated) As ibuprofen lysine is used for the pharmacologic closure of patent ductus arteriosus (PDA), do not administer to patients who require alprostadil injection for dilation of the ductus arteriosus for oxygenation and perfusion. Alprostadil injection for pediatric use (Prostin VR) has been used with the standard therapy for neonates with restricted pulmonary or systemic blood flow which includes antibiotics (e.g., penicillin and gentamicin), vasopressors (e.g., dopamine, isoproterenol), cardiac glycosides, and diuretics (e.g., furosemide).
    Amikacin: (Moderate) Use caution in combining ibuprofen lysine with renally eliminated medications, like aminoglycosides, as ibuprofen lysine may reduce the clearance of aminoglycosides. Closely monitor renal function and adjust aminoglycoside doses based on renal function and serum aminoglycoside concentrations as clinically indicated.
    Aminoglycosides: (Moderate) Use caution in combining ibuprofen lysine with renally eliminated medications, like aminoglycosides, as ibuprofen lysine may reduce the clearance of aminoglycosides. Closely monitor renal function and adjust aminoglycoside doses based on renal function and serum aminoglycoside concentrations as clinically indicated.
    Gentamicin: (Moderate) Use caution in combining ibuprofen lysine with renally eliminated medications, like aminoglycosides, as ibuprofen lysine may reduce the clearance of aminoglycosides. Closely monitor renal function and adjust aminoglycoside doses based on renal function and serum aminoglycoside concentrations as clinically indicated.
    Kanamycin: (Moderate) Use caution in combining ibuprofen lysine with renally eliminated medications, like aminoglycosides, as ibuprofen lysine may reduce the clearance of aminoglycosides. Closely monitor renal function and adjust aminoglycoside doses based on renal function and serum aminoglycoside concentrations as clinically indicated.
    Loop diuretics: (Moderate) Ibuprofen lysine may reduce the effect of diuretics; diuretics can increase the risk of nephrotoxicity of NSAIDs in dehydrated patients. During coadministration of NSAIDs and diuretic therapy, patients should be monitored for changes in the effectiveness of their diuretic therapy and for signs and symptoms of renal impairment.
    Nonsteroidal antiinflammatory drugs: (Major) Because ibuprofen lysine exerts similar pharmacologic characteristics to other systemic NSAIDs, including COX-2 inhibitors, additive pharmacodynamic effects, including a potential increase for additive adverse GI effects, may be seen if ibuprofen lysine is used with other NSAIDs. In general, concurrent use of ibuprofen lysine and another NSAID should be avoided.
    Paromomycin: (Moderate) Use caution in combining ibuprofen lysine with renally eliminated medications, like aminoglycosides, as ibuprofen lysine may reduce the clearance of aminoglycosides. Closely monitor renal function and adjust aminoglycoside doses based on renal function and serum aminoglycoside concentrations as clinically indicated.
    Plazomicin: (Moderate) Use caution in combining ibuprofen lysine with renally eliminated medications, like aminoglycosides, as ibuprofen lysine may reduce the clearance of aminoglycosides. Closely monitor renal function and adjust aminoglycoside doses based on renal function and serum aminoglycoside concentrations as clinically indicated.
    Potassium-sparing diuretics: (Moderate) Ibuprofen lysine may reduce the effect of diuretics; diuretics can increase the risk of nephrotoxicity of NSAIDs in dehydrated patients. During coadministration of NSAIDs and diuretic therapy, patients should be monitored for changes in the effectiveness of their diuretic therapy and for signs and symptoms of renal impairment.
    Streptomycin: (Moderate) Use caution in combining ibuprofen lysine with renally eliminated medications, like aminoglycosides, as ibuprofen lysine may reduce the clearance of aminoglycosides. Closely monitor renal function and adjust aminoglycoside doses based on renal function and serum aminoglycoside concentrations as clinically indicated.
    Thiazide diuretics: (Moderate) Ibuprofen lysine may reduce the effect of diuretics; diuretics can increase the risk of nephrotoxicity of NSAIDs in dehydrated patients. During coadministration of NSAIDs and diuretic therapy, patients should be monitored for changes in the effectiveness of their diuretic therapy and for signs and symptoms of renal impairment.
    Tobramycin: (Moderate) Use caution in combining ibuprofen lysine with renally eliminated medications, like aminoglycosides, as ibuprofen lysine may reduce the clearance of aminoglycosides. Closely monitor renal function and adjust aminoglycoside doses based on renal function and serum aminoglycoside concentrations as clinically indicated.

    PREGNANCY AND LACTATION

    Pregnancy

    Ibuprofen lysine is indicated for use in premature neonates only; it should not be used during pregnancy.

    Ibuprofen lysine is indicated for use in premature neonates only; do not use in breast-feeding women. Acetaminophen and ibuprofen, products intended for use in adult patients, are both considered to be usually compatible with breast-feeding by the American Academy of Pediatrics (AAP) and may be appropriate alternatives.

    MECHANISM OF ACTION

    The exact mechanism by which ibuprofen lysine causes closure of a patent ductus arteriosus (PDA) in neonates is not known. However, it is thought that the inhibition of prostaglandin synthesis is relevant. Local release of prostaglandins results in the dilation of, and may delay the closure of, the ductus. Ibuprofen blocks arachidonate binding resulting in competitive inhibition of both cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, which in turn limits the COX-1 and COX-2 catalyzed conversion of arachidonic acid to prostaglandin G2 (PGG2) and subsequent prostaglandin and thromboxane synthesis. Based on in vitro information, ibuprofen has about equal inhibitory effects on COX-1 and COX-2.

    PHARMACOKINETICS

    Ibuprofen lysine is administered as an intravenous infusion. Pharmacokinetic data were obtained from 54 premature infants included in a double-blind, placebo-controlled, randomized, multicenter study. The infants were less than 30 weeks gestational age, weighed 500—1000 g, and exhibited asymptomatic PDA with echocardiographic documentation of ductal shunting. The study measured the average clearance and volume of distribution values of racemic ibuprofen at birth to be 3 mL/kg/hour and 320 mL/kg, respectively. Clearance increased rapidly with postnatal age (an average increase of approximately 0.5 mL/kg/hour per day). Inter-individual variability in clearance and volume of distribution were 55% and 14%, respectively. In general, the half-life in infants is estimated to be more than 10 times longer than in adults. Metabolism and excretion in premature infants have not been studied. In adults, ibuprofen is metabolized via hepatic oxidation by cytochrome P450 2C9 to two inactive metabolites then excreted in the urine; 50—60% as metabolites and approximately 10% as unchanged drug. Some biliary excretion may occur. Renal function and the enzymes associated with drug metabolism, in general, are underdeveloped at birth and substantially increase in the days after birth.
     
    Affected cytochrome P450 isoenzymes: CYP2C9