Palivizumab (Systemic)


VA CLASSIFICATION
Primary: IM402

Commonly used brand name(s): Synagis.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Immunizing agent (passive)—

Indications

Accepted

Respiratory syncytial virus infection (prophylaxis)—Palivizumab is indicated for the prevention of serious lower respiratory tract infection caused by respiratory syncytial virus (RSV) in infants and children with bronchopulmonary dysplasia (BPD) and infants with a history of premature birth (gestation £ 35 weeks).

Note: The safety and efficacy of palivizumab have not been demonstrated for treatment of established RSV disease. {01}



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Palivizumab is a humanized monoclonal antibody (IgG1k) produced by recombinant DNA technology, directed to an epitope in the A antigenic site of the F protein of respiratory syncytial virus (RSV). It is a composite of 95% human and 5% murine antibody sequences. Palivizumab is supplied as a sterile lyophilized product. {01}
Molecular weight—
    Approximately 148,000 Daltons

Mechanism of action/Effect:

Palivizumab exhibits neutralizing and fusion-inhibitory activity against RSV. These activities inhibit RSV replication in laboratory experiments. Although resistant RSV strains may be isolated in laboratory studies, a panel of 57 clinical RSV isolates were all neutralized by palivizumab.

Palivizumab serum concentrations of ³ 40 mcg/mL have been shown to reduce pulmonary RSV replication in the cotton rat model of RSV infection by 100-fold.

The in vivo neutralizing activity of palivizumab was assessed in a randomized, placebo-controlled study of 35 pediatric patients tracheally intubated because of RSV disease. In these patients, palivizumab significantly reduced the quantity of RSV in the lower respiratory tract compared with that in control patients. {01}


Protective effect

The safety and efficacy of palivizumab were assessed in a randomized, double blind, placebo controlled trial (IMpact-RSV Trial) of RSV disease prophylaxis among high-risk pediatric patients. This trial, conducted at 139 centers in the U.S., Canada, and the United Kingdom (U.K.), studied patients £ 24 months of age with bronchopulmonary dysplasia (BPD) and patients with premature birth (gestation £ 35 weeks) who were £ 6 months of age at study entry. Patients with uncorrected congenital heart disease were excluded from enrollment. In this trial, 500 patients were randomized to receive five monthly placebo injections and 1002 patients were randomized to receive five monthly injections of 15 mg per kg (mg/kg) of palivizumab. Subjects were randomized into the study for 28 days, and were followed for safety and efficacy for 150 days. Ninety-nine percent of all subjects completed the study and 93% received all five injections. The primary end point was the incidence of RSV hospitalization.

RSV hospitalization occurred among 53 of 500 (10.6%) patients in the placebo group and 48 of 1002 (4.8%) patients in the palivizumab group, a difference of 55%. The lower rate of RSV hospitalization was observed both in patients enrolled with a diagnosis of BPD and in patients enrolled with a diagnosis of prematurity without BPD. The lower rate of RSV hospitalization was observed throughout the course of the RSV season.

Among secondary end points, the incidence of intensive care unit (ICU) admission during hospitalization for RSV infection was lower among subjects receiving palivizumab (1.3%) than among those receiving placebo (3%), but there was no difference in the mean duration of ICU care. Overall, the data do not suggest that RSV illness was less severe among patients who received palivizumab and who required hospitalization due to RSV infection. Palivizumab did not alter the incidence and mean duration of hospitalization from non-RSV respiratory illness or the incidence of otitis media.

Half-life:

Adults—18 days.

Children younger than 24 months of age—20 days.


Precautions to Consider

Carcinogenicity

Carcinogenicity studies have not been performed with palivizumab.

Tumorigenicity

Tumorigenicity studies have not been performed with palivizumab.

Pregnancy/Reproduction
Fertility—
Reproductive toxicity studies have not been performed with palivizumab.

Pregnancy—
Studies have not been done in humans. However, palivizumab is not indicated for adult usage.

Studies have not been done in animals.

FDA Pregnancy Category C.

Breast-feeding

Problems in humans have not been documented.

Pediatrics

Safety and efficacy have been established in infants with bronchopulmonary dysplasia (BPD) and infants with a history of premature birth (gestation £ 35 weeks).


Geriatrics


No information is available on the relationship of age to the effects of palivizumab in geriatric patients. However, palivizumab is not indicated for adult usage.

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to palivizumab    (palivizumab should not be used in pediatric patients with a history of severe prior reaction to palivizumab or other components of the product)



Side/Adverse Effects

Note: In the combined pediatric prophylaxis studies of pediatric patients with BPD or prematurity involving 420 subjects receiving placebo and 1168 subjects receiving palivizumab, the proportions of subjects in the placebo and palivizumab groups who experienced any adverse effect or any serious adverse effect were similar.
Most of the safety information was derived from the IMpact-RSV Trial. In this study, palivizumab was discontinued in five patients: two because of vomiting and diarrhea, one because of erythema and moderate induration at the site of the fourth injection, and two because of pre-existing medical conditions that required management (one with congenital anemia and one with pulmonary venous stenosis requiring cardiac surgery). Deaths in study patients occurred in 5 of 500 placebo recipients and 4 of 1002 palivizumab recipients. Sudden infant death syndrome (SIDS) was responsible for two of these deaths in the placebo group and one death in the palivizumab group.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Otitis media (ringing or buzzing in the ears)
    
rhinitis (runny nose)
    
skin rash
    
upper respiratory tract infection (difficulty in breathing)





Overdose
No data from clinical studies are available on overdosage. No toxicity was observed in rabbits administered a single intramuscular or subcutaneous injection of palivizumab at a dose of 50 mg/kg. No data are available from human subjects who have received more than five monthly palivizumab doses during a single RSV season.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Palivizumab (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Other medical problems, especially hypersensitivity to palivizumab

Proper use of this medication

» Proper dosing


Side/adverse effects
Signs of potential side effects, especially otitis media, rhinitis, skin rash, and upper respiratory tract infection


General Dosing Information
Although anaphylactoid reactions following the administration of palivizumab have not been observed, these reactions can occur following the administration of proteins. Therefore appropriate precautions should be taken prior to palivizumab injection to prevent allergic or other unwanted reactions. These precautions should include the ready availability of epinephrine 1:1000 and other appropriate agents used to control immediate allergic reactions.

The recommended dose of palivizumab is 15 mg/kg of body weight. Palivizumab should be administered intramuscularly, preferably in the anterolateral aspect of the thigh. Injection volumes over 1 mL should be given as a divided dose.

Patients, including those who develop a respiratory syncytial virus (RSV) infection, should receive monthly doses throughout the RSV season. The first dose should be administered prior to commencement of the RSV season. In the northern hemisphere, the RSV season typically commences in November and lasts through April, but it may begin earlier or persist later in certain communities.

For treatment of adverse effects
Recommended treatment consists of the following:    • For severe hypersensitivity or anaphylactic reaction—Administering epinephrine and providing supportive care as required.



Parenteral Dosage Forms

PALIVIZUMAB INJECTION

Usual adult and adolescent dose
Use is not recommended.

Usual pediatric dose
Respiratory syncytial virus infection (prophylaxis)
Intramuscular, 15 mg per kg of body weight.


Strength(s) usually available
U.S.—


100 mg palivizumab per vial (Rx) [Synagis (47 mM histidine) (3 mM glycine) (5.6% mannitol)]

Packaging and storage:
Store between 2 and 8 ºC (36 and 46 ºF), in its original container, unless otherwise specified by manufacturer.

Preparation of dosage form:
To reconstitute, remove the tab portion of the vial cap and clean the rubber stopper with 70% ethanol or equivalent.

Slowly add 1 mL of sterile water for injection to a 100 mg vial. The vial should be gently swirled for 30 seconds to avoid foaming. Do not shake vial.

Reconstituted palivizumab should stand at room temperature for a minimum of 20 minutes until the solution clarifies.

Reconstituted palivizumab does not contain preservative and should be administered within 6 hours of reconstitution.

Auxiliary labeling:
   • Do not freeze.



Developed: 08/11/1998



References
  1. Synagis package insert (MedImmune—US), Rev 6/98, Rec 7/98.
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