Drug Criteria & Outcomes: NeoProfen Formulary Evaluation
Drug Criteria & Outcomes
NeoProfen Formulary Evaluation
By Reena Patel, PharmD Candidate, Huntsville (AL) Hospital
• NeoProfen® (ibuprofen lysine injection), manufactured and distributed by Ovation Pharmaceuticals
• Indocin IV (indomethacin sodium trihydrate injection) manufactured and distributed by Ovation Pharmaceuticals
Mechanism of Action: The mechanism of action is unknown for both drugs, but is hypothesized to involve prostaglandin inhibition, leading to constriction of ductus arteriosus. Indomethacin is predicted to have additional or more extensive actions that increase the chances of cerebral, renal, and gastrointestinal (GI) adverse reactions.
Indication: Ibuprofen is indicated for closing patent ductus arteriosus (PDA) in premature infants weighing 500-1,500 g, and who are no more than 32 weeks gestational age. Ibuprofen is indicated when usual medical management, such as fluid restrictions, respiratory support, and diuretics, is ineffective.
Indomethacin has the same PDA indication, though for infants weighing 500-1,750 g and no gestational age is mentioned. Indomethacin also has been used for prophylaxis of PDA in high-risk infants (not FDA-approved).
Strength/Dosage Forms: Ibuprofen is available in a carton of three single-use vials, each containing 10 mg/mL ibuprofen for injection.
Indomethacin is supplied in one single-dose vial containing powder equal to 1 mg indomethacin.
Storage/Stability: Ibuprofen is stored at 20-25° C. It should be protected from light and stored in cartons until used.
Indomethacin is an injectable product available as a powder for reconstitution with a preservative-free diluent. It should be protected from light and stored at temperatures below 30° C and in cartons until used. It is not stable in alkaline solutions and must be reconstituted immediately prior to administration. Any unused amount should be discarded.
Pharmacokinetics
Pharmacokinetic information can be found in Table 1.
Dosing
The initial dose of ibuprofen is 10 mg/kg, followed by 5 mg/kg at 24- and 48-hour intervals. Doses are based on birth weight and available as single-use vials containing 2 mL of 10 mg/mL sterile solution (preservative-free). Infuse each dose continuously over 15 minutes via IV port that is nearest to the insertion site.
Dosing information for indomethacin is presented in Table 2.
Special Dosing
Renal: Stop doses of ibuprofen and perform renal function tests if patient is anuric or oliguric (< 0.6 mL/kg/hr) at the 24- and 48-hour intervals. Monitor BUN, electrolytes, I/O, and creatinine.
Indomethacin is not recommended in advanced renal disease.
Administration
Ibuprofen
• Administer medication as a three-dose regimen.
• Infuse over at least 15 minutes.
• Doses are based on birth weight and appropriately diluted with dextrose or saline.
• Administer the medication within 30 minutes of preparation and discard medication left in the vial after dose is given.
• Avoid extravascular leakage because this can cause irritation.
Indomethacin
• Administer medication as a three-dose regimen.
• Doses for indomethacin are 12-24 hours apart:
— If urine output is > 1 mL/kg/hr after prior dose, give doses at 12-hour intervals.
— If urine output is between 1 and 0.6 mL/kg/hr, give doses at 24-hour intervals.
— If urine output is < 0.6 mL/kg/hr, hold doses.
• Infuse over 20-30 minutes.
• Dilute with 1-2 mL of preservative-free 0.9% sodium chloride or preservative-free sterile water for injection.
• Concentration of solution diluted with 1 mL will be 0.1 mg/0.1 mL and 0.05 mg/0.1 mL if diluted with 2 mL.
• Avoid extravascular leakage because this can cause irritation.
• Doses are based on birth weight.
Precautions/Warning
Pregnancy/Lactation: Category C; Category D in third trimester for both drugs.
Ibuprofen
• Do not administer in the same line as TPN. Stop TPN 15 minutes prior to and following administration of ibuprofen.
• Ibuprofen has not been evaluated beyond 36 weeks post-gestational age.
• May inhibit platelet aggregation so monitor for bleeding.
• Signs/symptoms of infection may be masked when using this drug.
• Use with caution in patients with high total bilirubin.
• Drug interactions have not been evaluated.
Indomethacin
• Use caution in patients with decreased hepatic or renal function, and concurrent use with aspirin.
• Use for shortest duration with lowest effective dose to prevent cardiovascular or GI effects.
• May inhibit platelet aggregation, so watch for bleeding.
• May suppress water excretion, leading to electrolyte disturbances, such as hyponatremia.
• Documented drug interactions include aminoglycosides, digitalis, and furosemide.
Contraindications (for both ibuprofen and indomethacin)
• Preterm infants with proven or suspected infection that is untreated
• Preterm infants with congenital heart disease in whom patency of the PDA is necessary for satisfactory pulmonary or systemic blood flow (i.e., pulmonary atresia, severe coarctation of the aorta)
• Preterm infants who are bleeding, especially those with active intracranial hemorrhage or GI bleeding
• Preterm infants with thrombocytopenia
• Preterm infants with or who are suspected of having necrotizing entercolitis
• Preterm infants with significant renal function impairment
Adverse Effects
Potential adverse effects of ibuprofen include: bleeding, anemia, and hemorrhage; sepsis, respiratory infection, and apnea; hypoglycemia, hypocalcemia, hypernatremia, and other alterations in renal function; UTI; edema and atelectasis; skin lesion/irritation; adrenal insufficiency; and GI disturbances.
Indomethacin has similar adverse effects, but possibly to a greater extent. Indomethacin is more COX-1 selective and also has a greater volume of distribution, lower plasma protein binding, longer half-life, and increased bioavailability as compared to ibuprofen. These characteristics make indome-thacin a more potent anti-inflammatory in terms of negative effects on renal and GI hemodynamics.
Cost
The cost of three doses of ibuprofen lysine IV is $1450. Indomethacin sodium trihydrate IV costs $1,500 per three-dose regimen.
Clinical Trials
Trial 1: Su PH, Chen JY, Su CM, et al. Comparison of ibuprofen and indomethacin therapy for patent ductus ateriosus in preterm infants. Pediatr Int 2003;45:665-670.
Objective: To evaluate the efficacy of ibuprofen lysine vs. indomethacin sodium trihydrate as second-line treatment of PDA.
Study Design: Randomized, comparative trial.
Study Population: Sixty-three preterm infants.
Inclusion Criteria
• Birth weight ≤ 1,500 g; gestational age ≤ 32 weeks
• Platelet count ≥ 100,000/µL, SCr ≥ 1.5 mg/dL; absence of clinical manifestations of abnormal clotting
• Aged 2-7 days with color Doppler echocardiographic evidence of significant PDA
• Absence of 3-4 grades IVH according to the classification of Papile et al
• Treatment with continuous positive airway pressure with additional oxygen supply > 30% in inspired air or with mechanical ventilation
Exclusion Criteria
• Major congenital anomalies
• Life-threatening infection
• Hydrops fetalis
• Intraventricular hemorrhage within the previous 24 hours
• Urine output < 1 mL/kg of body weight per hour during the preceding eight hours
Interventions: Sixty-three patients were randomly assigned to receive ibuprofen or indomethacin. Doppler echocardiography was conducted daily for seven days, then every three days until four weeks of age. SCr, BUN, urine output, glucose, and CrCl were evaluated before treatment and 24, 48, 72, 96, and 120 hours after completing the three-dose regimen.
Study Endpoints: Closure of PDA or changes in renal hemodynamics
Statistical Analysis: Student's T-test and the X2 test
Results: Closure of PDA was similar in the ibuprofen (84.4%) and indomethacin treatment groups (80.6%). Statistically significant differences in renal changes indicated that ibuprofen had a more favorable safety profile. Renal function values were better with the use of ibuprofen:
• SCr was lower with the greatest differences being 1.48 mg/dL vs. 2.03 mg/dL at 48 hours (P < 0.01 at 24, 48, 72 hours post-dose)
• BUN of 22.5 vs. 31.9 mg/dL at 48 hours (P < 0.01 at 24 and 72 hours)
• CrCl of 6.8 vs. 4 mL/min/1.73 m2 at 48 hours (P < 0.01 at 48, 72, 96, and 120 hours)
• Urine output of 3.6 vs. 2.8 mL/kg/hr at 24 hours (P < 0.02 at 24 hours)
Strengths
• Study was a randomized, comparative trial
• Detailed inclusion/exclusion criteria
• Reasonable inclusion/exclusion allowed for external application of data
• Similar baseline population characteristics
Weaknesses
• Small study population and conducted at one site.
• Endpoints not directly specified
• Lack of data regarding effects of each drug on cerebral perfusion and intestinal hemodynamics
• Lack of P values regarding percentage of PDA closure
• Clinical significance of renal changes not discussed
Authors' Conclusion: Ibuprofen and indomethacin appear to be equally efficacious in inducing closure of PDA in premature infants. Ibuprofen also is less likely to cause renal impairment.
Trial 2: Fanos V, Benini D, Verlato G, et al. Efficacy and renal tolerability of ibuprofen vs. indomethacin in preterm infants with patent ductus arteriosus. Fundam Clin Pharmacol 2004;19:187-193.
Objective: To compare the efficacy and safety of ibuprofen vs. indomethacin for PDA.
Study Design: Retrospective data analysis
Study Population: Sixty premature infants from one institution between 1995 and 2001
Intervention: Twenty premature infants who were treated with indomethacin, 20 patients treated with ibuprofen, 20 patients were not treated due to lack of symptomatic PDA, and 20 patients with no clinically evident PDA. Patients received the recommended doses of each medication.
Study Endpoint: Echocardiography and daily assessments of renal values such as BUN, SCr, and urine output
Strengths and Weaknesses: The small study population had similar baseline characteristics, but no P values comparing indomethacin and ibuprofen were provided and there was a lack of analysis regarding the effects of concomitant drug use with aminoglycosides, surfactant, furosemide, and dopamine.
Authors' Conclusion: Use of ibuprofen for the treatment of PDA is promising, but more clinical studies are needed to clarify the renal effects of each drug.
Trial 3: Pezzati M, Vangi V, Biagiotti R, et al. Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus. J Pediatr 1999;135:733-738.
Objective: To investigate the effects of ibuprofen vs. indomethacin on renal and mesenteric blood flow velocity.
Study Design: Randomized, comparative trial
Study Population: Seventeen preterm infants younger than 33 weeks old
Intervention: Patients were randomized into two groups and renal and mesenteric artery blood flow were measured 10, 30, 60, and 120 minutes after administration of each drug using a computed ultrasound scanner. Renal function was evaluated by calculating urine flow rates and SCr on a daily basis.
Results: Significant reductions were found in peak systolic velocity, end diastolic velocity, and mean velocity at 30 minutes, and renal and mesenteric blood flow was significantly reduced up until 120 minutes of measurement in the indomethacin group. Patients on ibuprofen had increased renal and mesenteric blood flow. Lastly, urine output and SCr were significantly affected by indomethacin and no change was observed in the ibuprofen group.
Strengths
• Randomized, comparative study
• Similar baseline fetal and maternal characteristics
Weaknesses
• Small sample size
• Lack of evaluation of clinical significance
• Lack of long-term evaluation
Authors' Conclusions: The proposed mechanism of indomethacin is thought to be due to direct vasoconstriction on the primary arteries and arterioles that are involved in the regulation of arterial blood pressure as well as blood flow within organs. Ibuprofen does not significantly reduce mesenteric and renal blood flow velocity.
Conclusion
Indomethacin and ibuprofen have similar hypothesized mechanisms of action and are equally efficacious for the treatment of PDA. However, researchers also believe that indomethacin has an additional mechanism of action, which leads to more severe adverse effects on newborns.
Indomethacin has been shown to have the greatest transient effect on renal function, along with cerebral perfusion and GI hemodynamics as compared to ibuprofen. There is more experience using indomethacin and more defined pharmacokinetic and drug interaction information is available.
The primary difference between these drugs appears to be the adverse effects profiles. Based on available data and similar cost, ibuprofen should be placed on the formulary to treat PDA.
Mechanism of Action: The mechanism of action is unknown for both drugs, but is hypothesized to involve prostaglandin inhibition, leading to constriction of ductus arteriosus. Indomethacin is predicted to have additional or more extensive actions that increase the chances of cerebral, renal, and gastrointestinal (GI) adverse reactions.Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.