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Palivizumab

A Review of its Use as Prophylaxis for Serious Respiratory Syncytial Virus Infection

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Summary

Abstract

In two double-blind, placebo-controlled trials, intramuscular palivizumab 15 mg/kg every 30 days for 5 months significantly reduced RSV-related hospitalizations by 55% in 1502 infants with prematurity and/or bronchopulmonary dysplasia/chronic lung disease (BPD/CLD) and by 45% in 1287 infants with hemodynamically significant congenital heart disease (HSCHD). Reductions were statistically significant versus placebo in infants with BPD/CLD, with all degrees of prematurity, and with acyanotic/other heart disease.

Palivizumab was generally well tolerated, with ≤1.9% of recipients discontinuing treatment for tolerability reasons. In placebo-controlled trials, the most common potentially drug-related adverse events were fever, nervousness, injection-site reactions, and diarrhea. Drug-related events occurred in 7.2–11% of palivizumab recipients in controlled trials (vs 6.9–10% with placebo) and 0–7.9% in open-label trials.

Very few serious potentially drug-related adverse events occurred in clinical trials; four occurred in 2 of 285 patients in one open-label trial.

No significant anti-palivizumab antibodies developed during palivizumab use. Palivizumab trough serum concentrations were below the recommended 40 μg/mL in about 33% and up to 14% of children prior to their second and third palivizumab injections.

In pharmacoeconomic studies, the cost of palivizumab per hospitalization averted was generally lowest in the highest-risk infants. Drug cost was generally the most influential factor in sensitivity analyses.

In conclusion, prophylaxis with palivizumab significantly reduces the incidence of RSV-related hospitalization relative to placebo and is generally well tolerated in high-risk infants aged <2 years, including those with prematurity and BPD/CLD or HSCHD, which are risk factors for early or serious RSV infection. Palivizumab is approved for use in these patients. Other high-risk infants in whom palivizumab has not been formally assessed, such as those with immunodeficiency, cystic fibrosis, or location-specific risk factors (including extended hospital stays) might potentially benefit from palivizumab. The use of palivizumab in these other high-risk populations is likely to be determined as much by pharmacoeconomic considerations as by efficacy outcomes.

Pharmacodynamic Properties

In in vitro studies, palivizumab bound to and neutralized all respiratory syncytial virus (RSV) isolates tested and was more active against RSV than RSV intravenous immune globulin (RSV-IGIV). In vivo, a 99% reduction in RSV types A and B titers occurred in cotton rats at palivizumab serum concentrations of ≤30 μg/mL. Capsaicin-induced airway extravasation, potentiated by RSV infection, was significantly reduced in cotton rats treated with palivizumab either before or after intranasal RSV infection and before endotracheal infection. RSV-IGIV was effective before, but not after, intranasal RSV infection.

Mean nasal RSV loads in infants aged <2 years hospitalized with RSV infections were significantly lower in those who had received palivizumab prophylaxis at any time in the RSV season than in those who had not, despite the former having significantly lower mean gestational age and birth weight. Palivizumab serum concentrations ≈10 times those which reduced lung RSV loads were required to reduce nasal RSV loads.

In mechanically ventilated infants who received palivizumab 15 mg/kg, mean tracheal aspirate RSV concentrations, but not nasal wash concentrations, were reduced to a significantly greater extent over 24 and 48 hours than in placebo recipients. RANTES, but not other chemokines, increased significantly from baseline in palivizumab recipients, but decreased in placebo recipients; the clinical significance of this was unclear.

Infants receiving palivizumab, even for their second season, seldom developed anti-palivizumab antibodies. Where low-level titers occurred, antibodies were generally nonspecific and transient.

Pharmacokinetic Properties

Palivizumab reaches a maximum serum concentration 5 days after intramuscular injection. In premature infants aged ≤2 years, palivizumab 15 mg/kg reached serum concentrations of 91.1 and 150.3 μg/mL 2 days after the first and second intramuscular injections. In this age group, cardiac bypass was shown to reduce palivizumab serum concentrations by 58%. Palivizumab has a mean volume of distribution of 57 mL/kg.

Although palivizumab serum concentrations of ≤30 μg/mL in cotton rats reduced RSV titers 100-fold, higher concentrations were required to reduce nasal loads in infants, and a dose of 15 mg/kg, resulting in a serum concentration of ≥40 μg/mL is recommended. About 33% of infants in the target population for palivizumab had a serum trough concentration (Cmin) of <40 μg/mL on day 30 after their first 15 mg/kg injection (mean Cmin 49.2–50.54 μg/mL), and up to 14% after their second (mean Cmin 69.4–76.8 μg/mL). In very premature neonates, 68% had a Cmin of <40 μg/mL on day 28 after their first injection (mean Cmin 32.2 μg/mL). Cmin values were similar in infants’first and second palivizumab seasons. Mean Cmin in infants aged ≤24 months with hemodynamically significant congenital heart disease (HSCHD) was 55.5 μg/mL after the first injection of palivizumab 15 mg/kg, with 7.9% of infants having a Cmin <30 μg/mL.

The mean serum elimination half-life of palivizumab is 20 days in infants.

Therapeutic Efficacy

Intramuscular palivizumab 15 mg/kg at 30-day intervals over 5 months during peak RSV season reduced the incidence of RSV-related hospitalization by 55%, from 10.6% to 4.8%, in a randomized, double-blind, placebo-controlled trial in 1502 high-risk, premature infants (the IMpact-RSV study). Infants were born at a gestational age of ≤35 weeks and aged ≤6 months or aged ≤24 months with active bronchopulmonary dysplasia/chronic lung disease (BPD/CLD). Reductions were significant in infants with gestational ages of <32 and 32–35 weeks and in those with BPD/CLD, but palivizumab was most effective (relative reduction in RSV-related hospitalizations of 82%) in infants without BPD/CLD born at a gestational age of 32–35 weeks (significance not stated).

In prospective, postmarketing surveillance studies in high-risk infants, including those over several RSV seasons, the incidence of RSV-related hospitalization in palivizumab recipients was mostly lower than the 4.8% reported in the IMpact-RSV trial (although results should be interpreted in the light of the open-label nature of these trials). RSV-related hospitalization rates were generally highest (5.5–9.5%) among infants with BPD/CLD, particularly those born at a gestational age of ≤30 weeks. In a large trial in Spain, rates were reduced by 70% in palivizumab recipients (gestational age 29–32 weeks) compared with infants who did not receive prophylaxis.

Palivizumab significantly reduced RSV-related hospitalizations (by 45%) in a randomized, double-blind, placebo-controlled trial in 1287 infants aged ≤24 months with HSCHD. The reduction in palivizumab recipients was significant relative to placebo in infants with acyanotic/other (58%), but not cyanotic (29%) heart disease. Total days of RSV-related hospitalization and on increased supplemental oxygen were also significantly lower in palivizumab than placebo recipients, but not the incidences or days of either intensive-care-unit admission or mechanical ventilation.

Tolerability

Prophylactic treatment with palivizumab was generally well tolerated in infants aged ≤2 years born prematurely and/or with BPD/CLD and/or HSCHD. In two randomized, placebo-controlled trials and three nonblind trials, ≤1.9% of infants discontinued palivizumab for tolerability reasons.

Adverse events considered possibly or probably drug-related occurred in 7.2–11% of palivizumab recipients and 6.9–10% of placebo recipients in controlled trials (n = 1287 and 1502) and 0–7.9% of infants in open-label trials (n = 134–565). Four serious adverse events potentially related to palivizumab (RSV-related hospitalization with severe bronchiolitis and bacterial pneumonia plus conjunctivitis) occurred in one open-label study (n = 285). All other potentially drug-related adverse events were mild or moderate, or not regarded as significant toxicities.

In placebo-controlled trials, adverse events occurred in a similar number of palivizumab and placebo recipients, including those with HSCHD. The most commonly reported all-cause events were fever, upper respiratory tract infections, cough or increased cough, diarrhea, and injection-site reactions.

In infants with HSCHD, serious adverse events were significantly less common in palivizumab than placebo recipients in the overall study group (55.4% vs 63.1%) and infants with acyanotic/other congenital heart disease (50.3% vs 58.7%), but not in infants with cyanotic heart disease (59.9% vs 67.1%).

Pharmacoeconomics

Numerous pharmacoeconomic studies that assessed palivizumab prophylaxis in high-risk infants found cost effectiveness was best in a subset of infants at the highest risk of RSV-related hospitalization (number needed to treat four to nine). One study calculated costs per life-year saved, assuming 1.2% mortality in hospitalized infants and no long-term detriment from RSV infection, at $US33 000–1 200 000 with palivizumab and $US70 000–1 900 000 (all 1995 values, discounted at 3%) with RSV-IGIV. In another study which assumed a 30% chance of developing asthma by age 4 years because of RSV infection, incremental palivizumab costs per discounted quality-adjusted life-year saved were $US341 917–852 202 (2000 values, discounted at 3%).

In sensitivity analyses, drug cost (affected by acquisition cost, infant size, doses per season, and drug wastage) had the most influence on cost-effectiveness outcomes.

Several healthcare providers implemented successful cost-reduction strategies, including active follow-up of high-risk infants, restrictive palivizumab allocation for infants with a gestational age >32 weeks, and bulk purchasing or lot preparation and dispensing of palivizumab.

Dosage and Administration

Palivizumab is indicated in the US for the prevention of serious lower respiratory tract infections in infants at high risk of RSV disease. In the EU it is indicated in infants aged <6 months at the start of the RSV season who were born at ≤35 weeks gestation and infants aged <2 years who have required treatment for BPD/CLD within 6 months of the RSV season, or have hemodynamically significant congenital heart disease.

The recommended palivizumab dosage is 15 mg/kg administered intramuscularly each month from just before onset, through to the completion of, the RSV season, with the course continuing even if infants develop an RSV infection. The response to vaccines is not affected by palivizumab, and the need for supplemental doses of routine childhood vaccinations is not supported by data. No studies on the use of palivizumab in the treatment of established RSV disease have been undertaken.

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Notes

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  1. Adis International Inc., 770 Township Line Road, Suite 300, Yardley, Pennsylvania, 19067, USA

    Caroline Fenton, Lesley J. Scott & Greg L. Plosker

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Correspondence to Caroline Fenton.

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Various sections of the manuscript reviewed by: L.F. Avendaño, Programa de Virologia, Facultad de Medicina, Universidad de Chile, Santiago, Chile; R. Berner, University Children’s Hospital, Freiburg, Germany; A. Duppenthaler, Pediatric Infectious Disease Department, University Hospital, Bern, Switzerland; K. Fairman, Express Scripts, Inc., St Louis, Missouri, USA; M. Giovannini, Clinica Pediatrica Ospedale San Paolo, Università degli Studi di Milano, Milan, Italy; A. Greenough, King’s College Hospital, London, England; E. Rietveld, Department of Pediatric Medicine, Erasmus University, Rotterdam, The Netherlands; L.G. Stensballe, Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut, Copenhagen, Denmark; D. Willson, Division of Pediatric Critical Care, University of Virginia Healthcare System, Charlottesville, Virginia, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on palivizumab, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company which developed the drug.

Search strategy: Medline search terms were ‘palivizumab’ or ‘medi-493’. EMBASE search terms were ‘palivizumab’. AdisBase search terms were ‘palivizumab’ or ‘medi-493’. Searches were last updated 5 May 2004.

Selection: Studies in patients aged ≤2 years who received palivizumab. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Palivizumab, respiratory syncytial virus, RSV, pharmacodynamics, pharmacokinetics, therapeutic use.

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Fenton, C., Scott, L.J. & Plosker, G.L. Palivizumab. Pediatr-Drugs 6, 177–197 (2004). https://doi.org/10.2165/00148581-200406030-00004

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