Synagis: Indications, Dosage, Precautions, Adverse Effects
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Synagis - Product Information

Manufacture: AbbVie
Country: Canada
Condition: Respiratory Syncytial Virus
Class: Immune globulins
Form: Liquid solution, Intramuscular (IM), Powder
Ingredients: palivizumab, glycine, histidine, mannitol

SYNAGIS

palivizumab

Summary Product Information

Route of
Administration
Dosage Form/Strength Clinically Relevant Non-medicinal
Ingredients
intramuscular injection lyophilized powder / 50 mg
& 100 mg
glycine, histidine and mannitol
solution for injection /
50 mg/0.5 mL &
100 mg/1 mL
chloride, glycine and histidine
For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING section.

Description

SYNAGIS (palivizumab) is a humanized monoclonal antibody (IgG1κ) produced by recombinant DNA technology, directed to an epitope in the A antigenic site of the F protein of respiratory syncytial virus (RSV). Palivizumab is a composite of (95%) human and (5%) murine amino acid sequences. The human heavy chain sequence was derived from the constant domains of human IgG1 and the variable framework regions of the VH genes Cor and Cess. The human light chain sequence was derived from the constant domain of Cκ and the variable framework regions of the VL gene K104 with Jκ-4.The murine sequences were derived from a murine monoclonal antibody, Mab 1129, in a process which involved the grafting of the murine complementarity determining regions into the human antibody frameworks. Palivizumab is composed of two heavy chains and two light chains and has a molecular weight of approximately 148,000 Daltons.

Indications and Clinical Use

SYNAGIS (palivizumab) is indicated for:

  • prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in pediatric patients at high risk of RSV disease. Safety and efficacy were established in infants with bronchopulmonary dysplasia (BPD), infants with a history of prematurity (≤ 35 weeks gestational age), and children with hemodynamically significant congenital heart disease (CHD). See (CLINICAL TRIALS). The safety and efficacy of SYNAGIS have not been established for treatment of RSV disease.

Distribution restrictions - this product should be administered under the supervision of a qualified health professional.

Geriatrics (≥ 65 years of age)

SYNAGIS is not indicated for adult usage.

Pediatrics

The safety and effectiveness of SYNAGIS in children greater than 24 months of age at the start of dosing have not been established.

There is no efficacy data of clinical outcome for infants who received less than 5 monthly doses of palivizumab during a single RSV season.

See (INDICATIONS AND CLINICAL USE) section.

Contraindications

  • SYNAGIS (palivizumab) is contraindicated in patients with known hypersensitivity to palivizumab or to any of its excipients. It is also contraindicated in patients with known hypersensitivity to other humanized monoclonal antibodies. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING section.

Warnings and Precautions

Serious Warnings and Precautions

- If anaphylaxis, anaphylactic shock or severe allergic reaction occurs, administer epinephrine in appropriate pediatric dosage, and provide supportive care as required.

General

No studies have been performed to assess the administration of more than seven SYNAGIS (palivizumab) doses in an RSV season.

The single-use vials of SYNAGIS lyophilized powder and SYNAGIS solution for injection do not contain a preservative. Reconstituted SYNAGIS lyophilized powder is stable for up to 6 hours when left at room temperature. However, since the single-use vial of SYNAGIS lyophilized powder does not contain a preservative, unless it is reconstituted under controlled and validated aseptic conditions, the product should be administered within 3 hours of reconstitution.

Carcinogenesis and Mutagenesis

Carcinogenesis and mutagenesis studies have not been performed with SYNAGIS.

Hematologic

SYNAGIS is FOR INTRAMUSCULAR USE ONLY. As with any intramuscular injection, SYNAGIS should be given with caution to patients with thrombocytopenia or any coagulation disorder.

Hypersensitivity

Allergic reactions including very rare cases of anaphylaxis and anaphylactic shock have been reported following SYNAGIS administration. In some cases, fatalities have been reported. See (ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).

In one of the pharmacodynamic studies, symptoms of immediate hypersensitivity and anaphylaxis were observed in two adult volunteers receiving a single intravenous dose of reconstituted lyophilized palivizumab at 30 mg/kg.

Medications for the treatment of severe hypersensitivity reactions, including anaphylaxis and anaphylactic shock, should be available for immediate use following administration of SYNAGIS. If a severe hypersensitivity reaction occurs, therapy with SYNAGIS should be permanently discontinued. If a mild hypersensitivity reaction occurs, clinical judgement should be used regarding cautious re-administration of SYNAGIS.

Immune

In Study MI-CP018 (see CLINICAL TRIALS, Study Results, Study MI-CP018), the incidence of anti-humanized antibody following the fourth injection was 1.1% in the placebo group and 0.7% in the SYNAGIS group. In pediatric patients receiving SYNAGIS for a second season, 1 of 56 patients had transient, low titer reactivity. This reactivity was not associated with adverse events or alteration in palivizumab serum concentrations. Immunogenicity was not assessed in Study MI-CP048.

These data reflect the percentage of patients whose test results were considered positive for antibodies to palivizumab in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SYNAGIS with the incidence of antibodies to other products may be misleading.

In the Extended Dose Study (Study W00-350), there were 18 subjects who received study drug. Transient, low levels of anti-palivizumab antibody (1:20) were observed in one child after the second dose of SYNAGIS that dropped to undetectable levels (< 1:10) at the fifth and seventh dose.

Antibody to palivizumab was also evaluated in 4 additional studies in 4337 palivizumab-treated patients (children born at 35 weeks of gestation or less and 6 month of age or less, or < 24 months of age with BPD or with hemodynamically significant CHD were included in these studies). The frequency of anti-palivizumab antibodies detected in these subjects ranged from 0 to 1.5%. Timing of serum samples for determination of anti-palivizumab antibody titers was variable across the 4 studies. There was no association observed between the presence of antibody and adverse events.

Respiratory

A moderate to severe acute infection or febrile illness may warrant delaying the use of SYNAGIS, unless, in the opinion of the physician, withholding SYNAGIS entails a greater risk. A mild febrile illness, such as a mild upper respiratory infection, is not usually reason to defer administration of SYNAGIS.

Sexual Function/Reproduction

Reproductive toxicity studies have not been performed with SYNAGIS.

Special Populations

Pregnant Women

SYNAGIS is not indicated for adult usage and animal reproduction studies have not been conducted. It is also not known whether palivizumab can cause fetal harm when administered to a pregnant woman or whether it could affect reproductive capacity.

Pediatrics

See (INDICATIONS AND CLINICAL USE) section.

Geriatrics (≥ 65 years of age)

SYNAGIS is not indicated for adult usage.

Monitoring and Laboratory Tests

SYNAGIS may interfere with immune-based RSV diagnostic tests, such as some antigen-detection-based assays. In addition, SYNAGIS inhibits virus replication in cell culture, and, therefore, may also interfere with viral culture assays. SYNAGIS does not interfere with reverse transcriptase polymerase chain reaction-based assays. Assay interference could lead to false-negative RSV diagnostic test results. Therefore, diagnostic test results, when obtained, should be used in conjunction with clinical findings to guide medical decisions. See (DRUG INTERACTIONS, Drug-Laboratory Interactions).

Adverse Reactions

Adverse Drug Reaction Overview

The safety profile of SYNAGIS (palivizumab) solution for injection is similar to that of the lyophilized powder formulation. The most serious adverse reactions with SYNAGIS are anaphylaxis and other acute hypersensitivity reactions. See (WARNINGS AND PRECAUTIONS, Hypersensitivity).

SYNAGIS Lyophilized Powder

Adverse drug reactions reported in the prophylactic pediatric studies were similar in the placebo and SYNAGIS (palivizumab) groups. The majority of adverse drug reactions were transient and mild to moderate in severity. The most frequently reported adverse drug reactions in the combined prophylactic clinical studies with premature infants and BPD or CHD pediatric populations are rash and pyrexia.

In the study of premature infants and children with BPD (Study MI-CP018) involving 500 subjects receiving placebo and 1002 subjects receiving SYNAGIS lyophilized powder formulation, no medically important differences in adverse drug reactions by body system or in subgroups of children categorized by gender, age, gestational age, country, race/ethnicity or quartile serum palivizumab concentration were observed. No significant difference in safety profile was observed between children without active RSV infection and those hospitalized for RSV. Permanent discontinuation of SYNAGIS because of adverse drug reactions was rare (0.2%). Deaths were balanced between the placebo and SYNAGIS treatment groups and were not drug-related.

In the CHD study (Study MI-CP048) involving 639 subjects receiving placebo and 648 subjects receiving SYNAGIS lyophilized powder formulation, no medically important differences were observed in adverse drug reactions by body system or when evaluated in subgroups of children by cardiac category (cyanotic versus acyanotic). The incidence of serious adverse events was significantly lower in the SYNAGIS groups, as compared to the placebo group. No serious adverse events related to SYNAGIS were reported. The incidences of cardiac surgeries classified as planned, earlier than planned, or urgent, were balanced between the groups. Deaths associated with RSV infection occurred in 2 patients in the SYNAGIS group and 4 patients in the placebo group and were not drug-related.

SYNAGIS Solution for Injection

Two clinical studies (MI-CP097 and MI-CP116) were conducted to directly compare the solution for injection and lyophilized powder formulations of SYNAGIS. In study MI-CP097, all 153 premature infants received both formulations in different sequences. In study MI-CP116, 211 and 202 premature infants or children with chronic lung disease received solution for injection and lyophilized SYNAGIS, respectively. In two additional studies (MI-CP110 and MI-CP124), SYNAGIS solution for injection was used as an active control (3918 pediatric subjects) to evaluate an investigational monoclonal antibody for prophylaxis of serious RSV disease in premature infants or children with BPD or hemodynamically significant CHD. The overall rate and pattern of adverse events, study drug discontinuation due to AEs, and the number of deaths reported in these clinical studies were consistent with those observed during the clinical development programs for the lyophilized powder formulation. No deaths were considered related to SYNAGIS and no new ADRs were identified in these studies.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

SYNAGIS Lyophilized Powder

Study MI-CP018 (IMpact RSV Study)

Adverse events which occurred in more than 1% of patients receiving SYNAGIS lyophilized powder formulation in Study MI-CP018 for which the incidence in the SYNAGIS group was 1% greater than in the placebo group are presented in Table 1.

Table 1. Adverse Events Occurring in Study MI-CP018 at Greater Frequency in the SYNAGIS Group
SYNAGIS
Lyophilized Powder
Formulation
n = 1002
(%)
Placebo
n = 500
(%)
Body as a Whole 49.6 49.4
Upper respiratory infection 52.6 49.0
Otitis media 41.9 40.0
Rhinitis 28.7 23.4
Rash 25.6 22.4
Pain 8.5 6.8
Hernia 6.3 5.0
SGOT increased 4.9 3.8
Pharyngitis 2.6 1.4

Other adverse events reported in more than 1% of the SYNAGIS group included:

Blood and Lymphatic
System Disorders:
Anemia.
Ear and Labyrinth Disorders:/td> Ear disorder.
Gastrointestinal Disorders: Constipation, diarrhea, flatulence, gastrointestinal disorder and vomiting.
General Disorders and
Administration Site
Conditions:
Fever and study drug injection site reaction.
Hepato-biliary disorders: Liver function abnormality.
Infections and Infestations: Bronchitis, bronchiolitis, croup, conjunctivitis, flu syndrome, fungal dermatitis, gastroenteritis, oral moniliasis, pneumonia, RSV, sinusitis and viral infection.
Injury, Poisoning and Procedural Complications: Accidental injury and miscellaneous procedure.
Investigations: SGPT increase.
Metabolism and Nutrition Disorders: Failure to thrive and feeding abnormalities.
Psychiatric Disorders: Nervousness.
Respiratory, Thoracic and Mediastinal Disorders: Asthma, apnea, cough, dyspnea, respiratory disorder and wheeze.
Skin and Subcutaneous Tissue Disorders: Eczema and seborrhoea.

There were no statistically significant differences in the incidence of adverse events between the SYNAGIS and placebo groups.

Study MI-CP048

In the randomized, double-blind, placebo-controlled trial of RSV disease prophylaxis among children with hemodynamically significant CHD, the proportion of subjects in the placebo and SYNAGIS lyophilized powder formulation groups who experienced any adverse event or any serious adverse events were similar. No significant differences in morbidity or mortality were observed.

Adverse events that occurred in more than 1% of patients receiving SYNAGIS and for which the incidence was 1% greater in the SYNAGIS group than in the placebo group are shown in Table 2.

Table 2 Adverse Events Occurring in Study MI-CP048 at Greater Frequency in the SYNAGIS Group
SYNAGIS
Lyophilized Powder
Formulation
n = 639
(%)
Placebo
n = 648
(%)
Upper respiratory infection 47.4 46.1
Fever 27.1 23.9
Conjunctivitis 11.3 9.3
Cyanosis 9.1 6.9
Infection 5.6 2.9
Study drug injection site reaction 3.4 2.2
Arrhythmia 3.1 1.7

Other adverse events reported in 1% or more of the SYNAGIS group included:

Blood and Lymphatic
System Disorders:
Anemia, coagulation disorder and thrombocytopenia.
Cardiac Disorders: Bradycardia, congestive heart failure, heart failure, cardiovascular disorder, pericardial effusion and tachycardia.
Ear and Labyrinth Disorders: Ear disorder.
Gastrointestinal Disorders: Constipation, diarrhea, flatulence, gastrointestinal disorder, pain (primarily teething) and vomiting.
General Disorders and
Administration Site
Conditions:
Asthenia and edema.
Infections and Infestations: Bacterial infection, bronchitis, bronchiolitis, croup, flu syndrome, fungal infection, fungal dermatitis, gastroenteritis, otitis media, oral moniliasis, pneumonia, pharyngitis, RSV, rhinitis, urinary tract infection, sepsis, sinusitis and viral infection.
Injury, Poisoning and
Procedural Complications:
Accidental injury.
Metabolism and Nutrition
Disorders:
Failure to thrive, feeding abnormalities and hypokalemia.
Nervous System Disorders: Hyperkinesia and somnolence.
Psychiatric Disorders: Nervousness
Respiratory, Thoracic and
Mediastinal Disorders:
Apnea, atelectasis, cough, dyspnea, hypoxia, hyperventilation, lung edema, respiratory disorders, pleural effusion, pulmonary hypertension, pneumothorax, stridor and wheeze.
Skin and Subcutaneous
Tissue Disorders:
Eczema and rash.
Vascular Disorders Hemorrhage.
Study W00-350

No reported adverse events were considered related to SYNAGIS and no deaths were reported in any of the 18 patients in this study.

Less Common Clinical Trial Adverse Drug Reactions (< 1%) Observed with SYNAGIS Lyophilized Powder Formulation

Both clinical and laboratory adverse drug reactions are displayed by system organ class.

Gastrointestinal Disorders: Diarrhea and vomiting.
General Disorders and
Administration Site
Conditions:
Pain.
Infections and Infestations: Upper respiratory infections, rhinitis and viral infection.
Investigations: Aspartate aminotransferase (AST) increase, abnormal liver function test, and alanine aminotransferase (ALT) increase.
Respiratory, Thoracic and
Mediastinal Disorders:
Cough and wheeze.
Skin and Subcutaneous
Tissue Disorders:
Rash.

SYNAGIS Solution for Injection

The safety profile of SYNAGIS solution for injection is similar to that of the lyophilized powder formulation. No new ADRs were identified in the studies using SYNAGIS solution for injection.

Abnormal Hematologic and Clinical Chemistry Findings

SYNAGIS Lyophilized Powder

In study MI-CP018, mild or moderate elevations of AST occurred in 1.6% placebo and 3.7% SYNAGIS; for ALT, these percentages were 2.0% and 2.3% respectively. Reported adverse events related to the liver and deemed by the blinded investigator to be related to study drug were balanced between the two groups.

Post-Market Adverse Drug Reactions

The following adverse reactions have been reported with SYNAGIS therapy. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to palivizumab exposure. See also (WARNINGS AND PRECAUTIONS).

Blood and Lymphatic
System Disorders:
Thrombocytopenia
Immune System Disorders: Anaphylaxis, anaphylactic shock (In some cases, fatalities have been reported)
Nervous System Disorders: Convulsion
Skin and Subcutaneous
Tissue Disorders:
Urticaria

SYNAGIS treatment schedule and adverse events were monitored in a group of nearly 20,000 infants receiving SYNAGIS lyophilized powder formulation tracked through a patient compliance registry, the REACH program. Of this group, 1250 enrolled infants received 6 injections, 183 infants received 7 injections, and 27 infants received either 8 or 9 injections each respectively. Fifteen (1%) adverse events were observed in patients following a sixth or greater dose. All 15 of the adverse events occurred following the administration of the sixth dose and not with subsequent doses (up to 9 doses). Adverse events from this registry as well as through routine post-marketing surveillance were similar in character and frequency to those after the initial 5 doses.

Congenital Heart Disease (CHD) Post-marketing Study

A retrospective observational study was conducted in young children with hemodynamically significant CHD comparing the occurrence of primary serious adverse events (PSAEs: infection, arrhythmia, and death) between those who did (1009) and historical controls who did not receive SYNAGIS lyophilized powder prophylactically (1009) matched by age, type of cardiac lesion, and prior corrective surgery. The incidence of arrhythmia and death PSAEs was similar in children who did and did not receive prophylaxis. The incidence of infection PSAEs was lower in children who received prophylaxis as compared to those children who did not receive prophylaxis. The results of the study indicate no increased risk of serious infection, serious arrhythmia, or death in children with hemodynamically significant CHD who received RSV prophylaxis with SYNAGIS lyophilized powder compared with children who did not receive prophylaxis.

Drug Interactions

Overview

No formal drug-drug interaction studies were conducted. In Study MI-CP018, the proportions of patients in the placebo and SYNAGIS (palivizumab) groups who received routine childhood vaccines, influenza vaccine, bronchodilators or corticosteroids were similar and no incremental increase in adverse reactions was observed among patients receiving these agents, in either of the two groups. Since the monoclonal antibody is specific for RSV, SYNAGIS is not expected to interfere with the immune response to vaccines, including live viral vaccines.

Drug-Drug Interactions

No formal drug-drug interaction studies were conducted with SYNAGIS.

Drug-Food Interactions

Interactions with food have not been established with SYNAGIS.

Drug-Herb Interactions

Interactions with herbal products have not been established with SYNAGIS.

Drug-Laboratory Interactions

SYNAGIS may interfere with immune-based RSV diagnostic tests, such as some antigen-detection-based assays. In addition, SYNAGIS inhibits virus replication in cell culture, and, therefore, may also interfere with viral culture assays. SYNAGIS does not interfere with reverse transcriptase polymerase chain reaction-based assays. Assay interference could lead to false-negative RSV diagnostic test results. Therefore, diagnostic test results, when obtained, should be used in conjunction with clinical findings to guide medical decisions. See (WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests) and (MICROBIOLOGY).

Drug-Lifestyle Interactions

No data available.

Dosage and Administration

Recommended Dose and Dosage adjustment

The recommended dose of SYNAGIS (palivizumab) is 15 mg/kg of body weight, INTRAMUSCULAR INJECTION ONLY, given every 28 to 30 days during anticipated periods of RSV risk in the community. Where possible, the first dose should be administered prior to commencement of the RSV season, and subsequent doses should be administered monthly throughout the RSV season. To avoid risk of reinfection, it is recommended that children receiving SYNAGIS who become infected with RSV continue to receive monthly doses of SYNAGIS throughout 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. During this period, children normally receive 5 consecutive monthly intramuscular doses of palivizumab. See (WARNINGS AND PRECAUTIONS).

Missed Dose

SYNAGIS is needed every 28 to 30 days during the RSV season. Each dose of SYNAGIS helps protect from severe RSV disease for about a month. If a child misses an injection, another injection should be scheduled as soon as possible.

Administration

SYNAGIS should be administered in a once monthly dose of 15 mg/kg intramuscularly using aseptic technique, preferably in the anterolateral aspect of the thigh. The gluteal muscle should not be used routinely as an injection site because of the risk of damage to the sciatic nerve. The dose per month = [patient weight (kg) x 15 mg/kg ÷ 100 mg/mL of SYNAGIS]. Injection volumes over 1 mL should be given as a divided dose.

The efficacy of SYNAGIS at doses < 15 mg/kg, or of dosing less frequently than monthly throughout the RSV season has not been established.

Do not mix the lyophilized powder and the solution for injection formulations.

Reconstituted SYNAGIS lyophilized powder or SYNAGIS solution for injection is to be administered by INTRAMUSCULAR INJECTION ONLY.

To prevent the transmission of infectious diseases, sterile disposable syringes and needles should be used. Do not reuse syringes and needles.

SYNAGIS Lyophilized Powder

Reconstitution
Vial Size Volume of Diluent to be Added
to Vial
Approximate Available
Volume
Nominal Concentration per
mL
50 mg 0.6 mL 0.6 mL 50 mg / 0.5 mL
100 mg 1.0 mL 1.0 mL 100 mg / mL

Note: Both the 50 mg and 100 mg vial contain an overfill to allow the withdrawal of 50 mg or 100 mg respectively when reconstituted if following the directions described below.

Reconstituted product is stable for up to 6 hours when left at room temperature. However, since the single-use vial of SYNAGIS does not contain a preservative, unless it is reconstituted under controlled and validated aseptic conditions, the product should be administered within 3 hours of reconstitution.

SYNAGIS lyophilized powder should not be mixed with any medications or diluents other than sterile water for injection (WFI). WFI is provided in the SYNAGIS lyophilized powder kit and it is to be used solely for reconstitution with SYNAGIS lyophilized powder.

Reconstitution of the 50 mg Vial (Lyophilized Powder)

  • Using aseptic technique, to reconstitute, remove the tab portion of the vial cap and clean the rubber stopper with 70% ethanol or equivalent.
  • Carefully tap the top of the ampoule of sterile water for injection, provided in the kit, until all the droplets have fallen to the bottom of the ampoule. In one hand, hold the ampoule with the red dot facing you. With the other hand, hold a 2x2 gauze pad or equivalent at the top, near the red dot, and snap off the upper portion of the ampoule away from you. The glass will break off cleanly and easily.
  • To minimize foaming, SLOWLY add 0.6 mL of sterile water for injection, provided in the kit, along the inner side of the 50 mg vial. Ideally, the sterile water should be “dripped in” along the inner side of the vial. Rotate the sides of the vial after half the sterile water has been added to the SYNAGIS powder, and add the balance of the sterile water down the other side of the vial.
  • After removing the syringe from the vial, gently turn the vial between your fingers for approximately 30 seconds. This allows you to visually ensure that all the SYNAGIS has BEEN SATURATED by the sterile water. DO NOT SHAKE OR VIGOROUSLY AGITATE THE VIAL.
  • DO NOT INVERT THE VIAL DURING THE RECONSTITUTION PROCESS.

Reconstitution of the 100 mg Vial (Lyophilized Powder)

  • Using aseptic technique, to reconstitute, remove the tab portion of the vial cap and clean the rubber stopper with 70% ethanol or equivalent.
  • Carefully tap the top of the ampoule of sterile water for injection, provided in the kit, until all the droplets have fallen to the bottom of the ampoule. In one hand, hold the ampoule with the red dot facing you. With the other hand, hold a 2x2 gauze pad or equivalent at the top, near the red dot, and snap off the upper portion of the ampoule away from you. The glass will break off cleanly and easily.
  • To minimize foaming, SLOWLY add 1.0 mL of sterile water for injection, provided in the kit, along the inner side of the 100 mg vial. Ideally, the sterile water should be “dripped in” along the inner side of the vial. Rotate the sides of the vial after half the sterile water has been added to the SYNAGIS powder and add the balance of the sterile water down the other side of the vial.
  • After removing the syringe from the vial, gently turn the vial between your fingers for approximately 30 seconds. This allows you to visually ensure that all the SYNAGIS has BEEN SATURATED by the sterile water. DO NOT SHAKE OR VIGOROUSLY AGITATE THE VIAL.
  • DO NOT INVERT THE VIAL DURING THE RECONSTITUTION PROCESS.

Reconstituted SYNAGIS should stand undisturbed at room temperature for a minimum of 20 minutes until the solution clarifies. If excessive foaming has occurred and a full dose of either 1.0 mL or 0.5 mL is required, allow more time for the foam to dissipate (typically 1 hour or longer). The reconstituted solution should appear clear or slightly opalescent.

Before drawing up the solution, invert the vial for approximately 30 seconds. This allows the solution to collect at the bottom of the vial, and facilitates the withdrawal process.

It is most important to work slowly and not rush the reconstitution process.

Reconstituted product is stable for up to 6 hours when left at room temperature. SYNAGIS is supplied as a single-use vial and does not contain a preservative. It is recommended that unless it is reconstituted under controlled and validated aseptic conditions, the product should be administered within 3 hours of reconstitution.

Single-use vial. Discard any unused product.

To prevent the transmission of infectious diseases, sterile disposable syringes and needles should be used. Do not reuse syringes and needles.

SYNAGIS Solution for Injection

SYNAGIS solution for injection should not be mixed with any medications or diluents.

Administration Instructions (Solution for Injection)

Both the 0.5 mL and 1 mL vials contain an overfill to allow the withdrawal of 50 mg or 100 mg, respectively.

  • DO NOT DILUTE THE PRODUCT.
  • DO NOT SHAKE VIAL.
  • To administer, remove the tab portion of the vial cap and clean the stopper with 70% ethanol or equivalent. Insert the needle into the vial and withdraw an appropriate volume of solution into the syringe.
  • SYNAGIS does not contain a preservative and should be administered immediately after drawing the dose into the syringe.
  • Single-use vial. Do not re-enter the vial after withdrawal of drug. Discard unused contents.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

In clinical studies MI-CP018 and MI-CP048, three children received an overdose of more than 15 mg/kg. These doses were 20.25 mg/kg, 21.1 mg/kg and 22.27 mg/kg. No medical consequences were identified in these instances. From the post-marketing experience, excessive doses, including the report of one infant receiving 85 mg/kg, have been reported. In some instances these excessive doses were associated with adverse reactions. However, the nature of these reactions was similar to those observed with the 15 mg/kg dose (see ADVERSE REACTIONS). In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.

No clinical data are available from human subjects who have received more than 7 monthly SYNAGIS doses during a single RSV season.

Action and Clinical Pharmacology

Mechanism of Action

SYNAGIS (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 clinical RSV isolates were all neutralized by SYNAGIS. Palivizumab serum concentrations of approximately 30 mcg/mL have been shown to produce a mean 99% reduction in pulmonary RSV replication in the cotton rat model.

The in vivo neutralizing activity of the active ingredient in SYNAGIS was assessed in a randomized, placebo-controlled study of 35 pediatric patients tracheally intubated because of RSV disease. In these patients, SYNAGIS significantly reduced the quantity of RSV in the lower respiratory tract compared to control patients.

Pharmacodynamics

A discussion on animal pre-clinical studies can be found under (DETAILED PHARMACOLOGY, Animal, Pharmacodynamics).

Pharmacokinetics

Absorption

Adult (intramuscular and intravenous)

Palivizumab has a time to maximum serum concentration of 1.6 hours when administered intravenously, and 5 days when administered intramuscularly.

In adult volunteer studies, SYNAGIS administered either intravenously or intramuscularly had a pharmacokinetic profile similar to a human IgG1 antibody in regards to the volume of distribution (mean 57 mL/kg) and the half-life (mean 18 days).

Pediatric (intramuscular and intravenous)

In pediatric patients < 24 months of age, the mean half-life of palivizumab was 20 days (range 16.8 to 26.8 days), and monthly intramuscular doses of 15 mg/kg achieved mean ± SD 30-day trough serum drug concentrations of 37 ± 21 mcg/mL after the first injection, 57 ± 41 mcg/mL after the second injection, 68 ± 51 mcg/mL after the third injection, and 72 ± 50 mcg/mL after the fourth injection. In pediatric patients given palivizumab for a second season, the mean ± SD serum concentrations following the first and fourth injections were 61 ± 17 mcg/mL and 86 ± 31 mcg/mL, respectively.

In an initial dose-escalation study, thirty days after the first intravenous infusion, the mean trough concentration in patients receiving 15 mg/kg was 60.6 mcg/mL (range 21.4 to 149.8 mcg/mL). Thirty days after the second infusion, the mean trough concentration in patients receiving 15 mg/kg was 70.7 mcg/mL (range 20.2 to 112.6 mcg/mL).

In pediatric patients ≤ 24 months of age with hemodynamically significant CHD who received palivizumab and underwent cardio-pulmonary bypass for open-heart surgery, the mean serum palivizumab concentration was 98 ± 52 mcg/mL before bypass and declined to 41 ± 33 mcg/mL after bypass, a reduction of 58%.

The results of a prospective, phase 2, open-label trial designed to evaluate pharmacokinetics, safety and immunogenicity after administration of 7 doses of palivizumab within a single RSV season showed that adequate mean palivizumab target levels (30 mcg/mL or greater) were achieved in all 18 children enrolled. See [DETAILED PHARMACOLOGY, Human, Pharmacokinetics, Extended Dose Study (Study W00-350)].

Special Populations and Conditions

Pediatrics

See [ACTION and CLINICAL PHARMACOLOGY, Pharmacokinetics, Absorption, Pediatric (intramuscular and intravenous)] for details.

Geriatrics

SYNAGIS pharmacokinetics has not been studied in geriatric population. SYNAGIS is not indicated for adult usage.

Gender

No gender related pharmacokinetic differences have been observed in adult patients.

Race

Pharmacokinetics differences due to race have not been identified.

Hepatic Insufficiency

No pharmacokinetic data are available in patients with hepatic impairment.

Renal Insufficiency

No pharmacokinetic data are available in patients with renal impairment.

Genetic Polymorphism

No data available on genetic polymorphism.

Storage and Stability

Upon receipt and until reconstitution for use, SYNAGIS should be stored between 2 and 8°C in its original container. Do not freeze. Do not use beyond the expiration date.

Special Handling Instructions

Single-use vials. Discard any unused product.

SYNAGIS Lyophilized Powder

After Reconstitution

Reconstituted SYNAGIS should stand at room temperature for a minimum of 20 minutes until the solution clarifies. The reconstituted solution should appear clear or slightly opalescent.

Reconstituted product is stable for up to 6 hours when left at room temperature. However, since the single-use vial of SYNAGIS does not contain a preservative, unless it is reconstituted under controlled and validated aseptic conditions, the product should be administered within 3 hours of reconstitution.

Dosage Forms, Composition and Packaging

SYNAGIS Lyophilized Powder

SYNAGIS (palivizumab) lyophilized powder is available in two strengths: 50 mg and 100 mg.

SYNAGIS lyophilized powder 50 mg is supplied as a kit, in a single-use 4 mL vial containing 50 mg of lyophilized powder with a 1 mL ampoule of sterile water for injection. See (DOSAGE AND ADMINISTRATION, Administration, SYNAGIS Lyophilized Powder, Reconstitution) and (SPECIAL HANDLING INSTRUCTIONS, SYNAGIS Lyophilized Powder, After Reconstitution) for more information on the reconstituted solution.

SYNAGIS lyophilized powder 100 mg is supplied as a kit, in a single-use 10 mL vial containing 100 mg of lyophilized powder with a 1 mL ampoule of sterile water for injection. See (DOSAGE AND ADMINISTRATION, Administration, SYNAGIS Lyophilized Powder, Reconstitution) and (SPECIAL HANDLING INSTRUCTIONS, SYNAGIS Lyophilized Powder, After Reconstitution) for more information on the reconstituted solution.

Listing of Non-Medicinal Ingredients

Each kit of SYNAGIS 50 mg lyophilized powder contains the following non-medicinal ingredients: glycine, histidine, mannitol and sterile water for injection.

Each kit of SYNAGIS 100 mg lyophilized powder contains the following non-medicinal ingredients: glycine, histidine, mannitol and sterile water for injection.

SYNAGIS Solution for Injection

SYNAGIS solution for injection is available in vials of either 0.5 mL or 1.0 mL.

SYNAGIS 0.5 mL solution for injection is supplied as a single-use 3 mL vial containing 0.5 mL of SYNAGIS solution for injection with a concentration of 100 mg/mL.

SYNAGIS 1.0 mL solution for injection is supplied as a single-use 3 mL vial containing 1 mL of SYNAGIS solution for injection with a concentration of 100 mg/mL.

Listing of Non-Medicinal Ingredients

Each SYNAGIS solution for injection 0.5 mL vial contains the following non-medicinal ingredients: chloride, glycine, histidine and water for injection.

Each SYNAGIS solution for injection 1.0 mL vial contains the following non-medicinal ingredients: chloride, glycine, histidine and water for injection.