Consumer medicine information

Synagis

Palivizumab

BRAND INFORMATION

Brand name

Synagis

Active ingredient

Palivizumab

Schedule

SUMMARY CMI

Synagis^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about your child using this medicine, speak to your doctor or pharmacist.

1. Why is my child being given Synagis?

Synagis contains the active ingredient palivizumab. Synagis is used to prevent a serious lung condition caused by a virus known as respiratory syncytial virus (RSV).

For more information, see Section 1. Why is my child being given Synagis? in the full CMI.

2. What should I know before my child is given Synagis?

Check the list of ingredients at the end of the CMI. Synagis should not be given if your child has ever had an allergic reaction to any of them, or to other medicines like Synagis.

Talk to your doctor before your child is given this medicine if he/she is not aware that your child has any other medical conditions or takes any other medicines.

For more information, see Section 2. What should I know before my child is given Synagis? in the full CMI.

3. What if my child is taking other medicines?

Some medicines can interfere with others and affect how they work. This is unlikely to be a concern for Synagis. An explanation is provided in Section 3. What if my child is taking other medicines? in the full CMI.

4. How is Synagis given?

The Synagis dose is calculated by your doctor according to your child's weight.
It is given by injection into the muscle by your doctor or other healthcare professional.

More instructions can be found in Section 4. How is Synagis given? in the full CMI.

5. What should I know while my child is receiving Synagis?

Things you should do	Tell your doctor if your child is unwell when treatment is about to start. Keep all your child's appointments to ensure he/she receives all the required injections. Remind any doctor, dentist or pharmacist you visit that your child is receiving Synagis.
Things you should not do	Once treatment has started, do not allow your child to miss any of the monthly injections of Synagis without checking with your doctor.
Driving or using machines	As Synagis is for use in children, there is no information on the effect of Synagis on the ability to drive or use machines.
Drinking alcohol	As Synagis is for use in children, there is no information on the effects of using Synagis with alcohol.
Looking after your medicine	Store Synagis in the refrigerator (2°C to 8°C).

For more information, see Section 5. What should I know while my child is using Synagis? in the full CMI.

6. Are there any side effects?

The most common side effects include fever, infection in the upper airways, middle ear infection, runny nose, wheezing, redness or pain at the injection site, rash, diarrhoea.

For more information, including what to do if your child has any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

Synagis^® (sin-a-jiss)

Active ingredient(s): [palivizumab] (pal-e-viz-you-mab)

Consumer Medicine Information (CMI)

This leaflet provides important information about using Synagis. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Synagis.

Where to find information in this leaflet:

1. Why is my child being given Synagis?
2. What should I know before my child is given Synagis?
3. What if my child is taking other medicines?
4. How is Synagis given?
5. What should I know while my child is receiving Synagis?
6. Are there any side effects?
7. Product details

1. Why is my child being given Synagis?

Synagis contains the active ingredient palivizumab.

Synagis is used to prevent a serious lung condition caused by a virus known as respiratory syncytial virus (RSV) in children at high risk.

2. What should I know before my child is given Synagis?

Warnings

Serious allergic reactions, including anaphylaxis, can occur in some children receiving Synagis. These can be fatal. Your doctor will have medicines on stand-by if your child shows symptoms of anaphylaxis straight away.

Do not use Synagis if:

your child is allergic to palivizumab, or any of the ingredients listed at the end of this leaflet.
your child is allergic to similar medicines.

Check with your doctor if your child:

is not well or has a temperature when treatment is about to start
has thrombocytopenia, not having enough platelets in the blood (cells that form clots when injured)
has any bleeding disorder
takes any medicines for any other condition

During treatment, your child may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

As Synagis is for use in children, there is no information in use in pregnancy or breastfeeding.

3. What if my child is taking other medicines?

Tell your doctor or pharmacist if your child is taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

It is not expected that Synagis will be affected by other medicines or will affect how other medicines work, but tell your doctor about all the medicines your child is taking, regardless.

4. How is Synagis given?

How much is given

Your doctor will calculate the dose of Synagis based on your child's weight.

When to receive Synagis

Synagis is given every month while the risk of RSV infection remains.
It is given as an injection into the muscle, usually into the outer part of the thigh.

Please look for the QR code on the medicine pack. Scan this code with your smart phone for more information on Synagis.

If you forget an injection of Synagis

To best protect your child, it is necessary to follow the instructions from your doctor about return visits for additional doses.

If you miss an injection, contact your doctor straight away.

If too much Synagis is given

As Synagis is given by a doctor or other healthcare professional, it is not likely that your child will receive too much. If necessary, your doctor can manage the situation.

If you do think your child has received too much Synagis, you should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while my child is receiving Synagis?

Things you should do

Call your doctor straight away if your child:

Shows signs of an allergic reaction, including rash, swelling of the face, lips, mouth, throat or neck
Becomes ill while being treated with Synagis

Tell your doctor if your child is unwell or has a temperature when treatment is about to start.

Keep all your child's appointments to ensure he/she receives all the required injections.

If your child has any blood tests, tell the technician that he/she is receiving Synagis.

Remind any doctor, dentist or pharmacist you visit that your child is receiving Synagis.

Things you should not do

Once treatment has started, do not allow your child to miss any of the monthly injections of Synagis without checking with your doctor.

Driving or using machines

As Synagis is for use in children, there is no information on the effect of Synagis on the ability to drive or use machines.

Looking after your medicine

As Synagis is given to your child in hospital, you will not need to store the medicine yourself. The hospital staff will keep the medicine in a refrigerator until it is time to use it.

Getting rid of any unwanted medicine

The hospital staff will dispose of any unused medicine.

6. Are there any side effects?

All medicines can have side effects. If your child does experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects

What to do

Signs of an infection in the upper airways:

fever
sore throat
pain in the middle ear
runny nose
wheezing

Skin:

redness or pain at the injection site
rash

Other:

diarrhoea

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects	What to do
Symptoms of a serious allergic reaction (anaphylaxis): sudden appearance of skin rash swelling of lips, tongue or face difficulty swallowing shortness of breath difficulty breathing passing out	Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making your child feel unwell.

Other side effects not listed here may occur in some children.

Reporting side effects

After you have received medical advice for any side effects your child experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

Synagis is for injection by a doctor or other healthcare professional.

What Synagis contains

Active ingredient (main ingredient)	palivizumab
Other ingredients (inactive ingredients)	histidine glycine water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What Synagis looks like

Synagis is supplied as:

Clear colourless solution in a glass vial ready for injection, containing 50 mg/0.5 mL solution (AUST R 231133)
Clear colourless solution in a glass vial ready for injection, containing 100 mg/1 mL solution (AUST R 231139)

Who distributes Synagis?

AstraZeneca Pty Ltd
ABN 54 009 682 311
66 Talavera Road
MACQUARIE PARK NSW 2113
Telephone: - 1800 805 342

This leaflet was prepared in December 2021.

Synagis name is a registered trade mark of the AstraZeneca group of companies.

Doc ID-004752541 v 4.0

Published by MIMS February 2022

BRAND INFORMATION

Brand name

Synagis

Active ingredient

Palivizumab

Schedule

1 Name of Medicine

Palivizumab (rmc).

2 Qualitative and Quantitative Composition

Palivizumab is a humanized IgG1 monoclonal antibody directed to an epitope in the A antigenic site of the fusion protein of respiratory syncytial virus (RSV).
This humanized monoclonal antibody is composed of 95% human and 5% murine amino acid sequences.
Synagis 50 mg/0.5 mL vial: each single use vial contains 50 mg palivizumab.
Synagis 100 mg/1 mL vial: each single use vial contains 100 mg palivizumab.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Clear or slightly opalescent sterile solution supplied in clear glass vials.

4 Clinical Particulars

4.1 Therapeutic Indications

Synagis (palivizumab) is indicated for the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in children at high risk of RSV disease. Safety and efficacy were established in children with bronchopulmonary dysplasia (BPD), infants with a history of prematurity (gestational age less than or equal to 35 weeks at birth) and children with haemodynamically significant congenital heart disease (CHD). (See Section 5.1 Pharmacodynamic Properties, Clinical trials.)

4.2 Dose and Method of Administration

The recommended dose of palivizumab is 15 mg/kg of bodyweight, given once a month 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 palivizumab who become infected with RSV continue to receive monthly doses of palivizumab for the duration of the RSV season.
Palivizumab is administered in a dose of 15 mg/kg once a month intramuscularly, 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]. The injection should be given using standard aseptic technique. Injection volumes over 1 mL should be given as a divided dose.
The efficacy of Synagis at doses less than 15 mg/kg, or of dosing less frequently than monthly throughout the RSV season, has not been established.
Palivizumab is to be administered by intramuscular injection only.
Palivizumab solution for injection should not be mixed with any medications or diluents.

Administration instructions.

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 of equivalent. Insert the needle into the vial and withdraw an appropriate volume of solution into the syringe.
Palivizumab does not contain a preservative and should be administered immediately after drawing the dose into the syringe.
The product is for single use in one patient only. Do not re-enter the vial after withdrawal of drug. Discard unused contents.

4.3 Contraindications

Synagis is contraindicated in patients with known hypersensitivity to Synagis or to any of its excipients. It is also contraindicated in patients with known hypersensitivity to other humanised monoclonal antibodies.

4.4 Special Warnings and Precautions for Use

Allergic reactions including very rare anaphylaxis and anaphylactic shock have been reported following palivizumab administration. In some cases, fatalities have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)).
Medications for the treatment of severe hypersensitivity reactions, including anaphylaxis and anaphylactic shock, should be available for immediate use following administration of palivizumab. If a severe hypersensitivity reaction occurs, therapy with palivizumab should be discontinued. As with other agents administered to this population, if milder hypersensitivity reactions occur, caution should be used on readministration of palivizumab.
As with any intramuscular injection, palivizumab should be given with caution to patients with thrombocytopenia or any coagulation disorder.
Palivizumab does not contain a preservative and should be administered immediately after drawing the dose into the syringe.
A moderate to severe acute infection or febrile illness may warrant delaying the use of palivizumab, unless, in the opinion of the physician, withholding palivizumab entails a greater risk. A mild febrile illness, such as a mild upper respiratory infection, is not usually reason to defer administration of palivizumab.

Use in the elderly.

No data available.

Paediatric use.

For general warnings see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects) for further safety information.

Effects on laboratory tests.

Palivizumab may interfere with immune based RSV diagnostic tests, such as some antigen detection based assays. In addition, palivizumab inhibits virus replication in cell culture and, therefore, may also interfere with viral culture assays. Palivizumab 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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal drug-drug interaction studies were conducted, however no interactions have been described to date. In the IMpact-RSV study, the proportions of patients in the placebo and 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.
Since the monoclonal antibody is specific for RSV, palivizumab is not expected to interfere with the immune response to vaccines, including live viral vaccines.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Reproductive toxicity studies have not been performed.
Palivizumab is not indicated for adult usage and animal reproduction studies have not been conducted. It is also not known whether palivizumab can cause foetal harm when administered to a pregnant woman or could affect reproductive capacity.
No data available.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person’s ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Note.

To provide a complete safety profile of palivizumab in the approved indication(s), adverse events information for the lyophilised powder and solution for injection presentations studied in patients with RSV are outlined below. However, the only presentation currently registered in Australia is the solution for injection.
In the combined paediatric prophylaxis studies the proportions of subjects in the placebo and palivizumab groups who experienced any adverse event or any serious adverse event were similar. The majority of adverse events were transient, and mild to moderate in severity. In the study of premature infants and children with bronchopulmonary dysplasia, no medically important differences in adverse events by body system or in subgroups of children categorised by gender, age, gestational age, country, ethnicity or quartile serum palivizumab concentration were observed. No significant difference in safety profile was observed between children without active RSV infection and those hospitalised for RSV. Permanent discontinuation of palivizumab because of adverse events was rare (0.2%). Deaths were balanced between the placebo and palivizumab treatment groups, and were not drug related. As shown in Table 1, very common (≥ 10%) adverse events reported with Synagis include upper respiratory infection, otitis media, rhinitis, fever, rash, cough, diarrhoea and wheeze. Table 1 also provides a listing and incidence of all common (≥ 1%) adverse events when compared to placebo.

CHD study.

In the congenital heart disease study, no medically important differences were observed in adverse events 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 palivizumab group, as compared to the placebo group. No serious adverse events related to palivizumab 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 palivizumab group and 4 patients in the placebo group, and were not drug related.
Adverse events that occurred in more than 1% of patients receiving palivizumab and for which the incidence was 1% greater in the palivizumab group than in the placebo group are shown in Table 2.

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

Metabolic and nutritional disorders.

Anaemia, failure to thrive.

Nervous system.

Nervousness, somnolence.

Cardiovascular system.

Coagulation disorder, haemorrhage, hypokalaemia, congestive heart failure, thrombocytopenia, heart failure, cardiovascular disorder, pericardial effusion, tachycardia, bradycardia.

Respiratory system.

Otitis media, rhinitis, cough, wheeze, bronchiolitis, pneumonia, respiratory disorders, dyspnoea, pharyngitis, pleural effusion, hyperventilation, stridor, pulmonary hypertension, lung oedema, atelectasis, pneumothorax, hypoxia, bronchitis, RSV, apnoea, sinusitis, ear disorder, croup.

Digestive system.

Diarrhoea, vomiting, oral moniliasis, gastroenteritis, gastrointestinal disorder, constipation, flatulence, feeding abnormalities.

Skin and appendages.

Rash, fungal dermatitis, eczema.

Urogenital system.

Urinary tract infection.

Body as a whole.

Pain (primarily teething), viral infection, accidental injury, oedema, bacterial infection, fungal infection, sepsis, flu syndrome.

Extended dose study.

No reported adverse events were considered related to palivizumab and no deaths were recorded.

Palivizumab solution for injection studies.

Two clinical studies were conducted to directly compare the solution for injection and lyophilised powder for injection presentations of palivizumab. In the first study, all 153 premature infants received both palivizumab presentations in different sequences. In the second study, 211 and 202 premature infants or children with chronic lung disease received both palivizumab presentations, respectively. In two additional studies, palivizumab solution for injection was used as an active control (3918 paediatric subjects) to evaluate an investigational monoclonal antibody for prophylaxis of serious RSV disease in premature infants or children with BPD or haemodynamically 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 lyophilised formulation. No deaths were considered related to palivizumab and no new ADRs were identified in these studies.

Immunogenicity.

In the IMpact-RSV trial, the incidence of antipalivizumab antibody following the fourth injection was 1.1% in the placebo group and 0.7% in the palivizumab group. In paediatric patients receiving palivizumab for a second season, one of the fifty six patients had transient, low titre reactivity. This reactivity was not associated with adverse events or alteration in palivizumab serum concentrations. Immunogenicity was not assessed in the CHD study.
In one infant in the extended dose study (n = 18), after the second dose of palivizumab, transient low levels of antipalivizumab antibody, dropping to undetectable levels at the fifth and seventh dose, were observed.
A trial of high risk preterm children less than or equal to 24 months of age was conducted to evaluate the immunogenicity of the lyophilised formulation of Synagis and the solution for injection formulation of Synagis. Three hundred seventy nine children contributed to the 4 to 6 months postfinal dose analysis. The rate of antipalivizumab antibodies at this time point was low in both formulation groups (antipalivizumab antibodies were not detected in any subject in the solution for injection formulation group and were detected in one subject in the lyophilised group (0.5%), with an overall rate of 0.3% for both treatment groups combined).
These data reflect the percentage of children whose test results were considered positive for antibodies to palivizumab in an enzyme linked immunosorbent assay (ELISA) and are highly dependent on the sensitivity and specificity of the assay.
The ELISA has substantial limitations in detecting antipalivizumab antibodies in the presence of palivizumab. Immunogenicity samples tested with the ELISA assay likely contained palivizumab at levels that may interfere with the detection of antipalivizumab antibodies.
An electrochemical luminescence (ECL) based immunogenicity assay, with a higher tolerance for palivizumab presence compared to the ELISA, was used to evaluate the presence of antipalivizumab antibodies in subject samples from two additional clinical trials. The rates of antipalivizumab antibody positive results in these trials were 1.1% and 1.5%.

Postmarketing experience.

The following adverse reactions have been reported with palivizumab 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.

Blood and the lymphatic system disorders.

Thrombocytopenia.

Immune system disorders.

Allergic manifestations to palivizumab (including immediate hypersensitivity reactions such as anaphylaxis, anaphylactic shock, angioedema, dyspnoea, asthma, bronchospasm and pruritus). In some cases fatalities have been reported.

Nervous system disorders.

Convulsions.

Respiratory, thoracic and mediastinal disorders.

Apnoea.

Skin and subcutaneous tissue disorders.

Urticaria.
A compliance registry (REACH program) of nearly 20,000 palivizumab treated infants obtained treatment schedules and spontaneously reported adverse events. 1250 enrolled infants received 6 injections, 183 infants received 7 injections and 27 infants received either 8 or 9 injections. From this registry and from routine postmarketing reports, adverse events observed in patients following a sixth or greater dose were similar in character and frequency to those after the initial five doses.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

From postmarketing experience, overdoses with doses up to 85 mg/kg have been reported and in some cases, adverse reactions were reported which did not differ from those observed with 15 mg/kg dose (see Section 4.8 Adverse Effects (Undesirable Effects)). 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.
For advice on the management of overdose please contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Palivizumab exhibits neutralising 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 neutralised by palivizumab. Palivizumab serum concentrations of approximately 30 microgram/mL have been shown to produce a mean 99% reduction in pulmonary RSV replication in the cotton rat model.
The in vivo neutralising activity of the active ingredient in palivizumab was assessed in a randomised, placebo controlled study of 35 paediatric patients tracheally intubated because of RSV disease. A total of 17 of the 35 children enrolled received intravenous infusions of palivizumab at a dose of 15 mg/kg. For patients with both a day 0 and day 1 result the mean decline in RSV log pfu (plaque forming units) from day 0 to day 1, measured in tracheal aspirates, was 0.6 in patients given placebo and 1.7 in patients given palivizumab (p = 0.004, Wilcoxon rank sum test). There was no statistically significant difference between placebo and palivizumab in the reduction of RSV replication in nasal washings. Mean serum palivizumab levels were 131.3 microgram/mL (range: 33.4 to 198.4) on day 1 and 105.5 microgram/mL (range: 23.3 to 204.1) on day 2.

Clinical trials.

Note.

To provide a complete efficacy profile of palivizumab in the approved indication(s), clinical trial information for the lyophilised powder and solution for injection product presentations studied in patients with RSV are outlined below. However, the only presentation currently registered in Australia is the solution for injection.
The safety and efficacy of palivizumab were assessed in a randomised, double blind, placebo controlled trial (IMpact-RSV trial) of RSV disease prophylaxis among children with premature birth and children with bronchopulmonary dysplasia and in a randomised double blind, placebo controlled trial of RSV disease prophylaxis among children with haemodynamically significant congenital heart disease (CHD study). Additional clinical studies conducted following the initial approval of palivizumab have provided further data on the safety and effectiveness of palivizumab prophylaxis for the prevention of RSV related diseases among the similar paediatric populations.
Studies using lyophilised powder for injection.

IMpact-RSV trial.

This trial, conducted at 139 centres in the United States, Canada and the United Kingdom, studied patients less than or equal to 24 months of age with bronchopulmonary dysplasia (BPD) and patients with premature birth (less than or equal to 35 weeks gestation) who were less than or equal to 6 months of age at study entry. Patients with uncorrected congenital heart disease were excluded from enrolment. In this trial, 500 patients were randomised to receive five monthly placebo injections and 1,002 patients were randomised to receive five monthly injections of 15 mg/kg of lyophilised palivizumab. Subjects were randomised into the study 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 endpoint was the incidence of RSV hospitalisation.
The incidence of RSV related hospitalisation was 10.6% in the placebo group and 4.8% in the palivizumab group, a relative reduction of 54.8% (P < 0.001). There was also a statistically significant reduction in RSV hospitalisation for the subgroups of children with BPD (38.5% relative reduction, p = 0.038) and those with prematurity (78.1% relative reduction for children with gestation ≤ 35 weeks, p < 0.001 and 54% relative reduction for children with gestation ≤ 32 weeks, p < 0.05). The smallest relative risk reductions and therefore the least benefit occurred in children with the most severe BPD (those requiring ongoing oxygen (94% relative risk) or oxygen in the last 6 months (70% relative risk)). Children receiving ongoing steroids who were treated with palivizumab had a higher rate of hospitalisation for RSV infection than did those receiving ongoing steroids who were not treated with palivizumab (relative risk 139%). No statistical significance levels are available for the BPD subgroups.
Among secondary endpoints, the incidence of ICU admission during hospitalisation for RSV infection was lower among subjects receiving palivizumab (1.3%) than among those receiving placebo (3.0%) but there was no difference in the mean duration of ICU care between the two groups for patients requiring ICU care. Overall, the data do not suggest that RSV illness was less severe among patients who received palivizumab and who required hospitalisation due to RSV infection than among placebo patients who required hospitalisation due to RSV infection. Palivizumab did not alter the incidence and mean duration of hospitalisation of non-RSV respiratory illness or the incidence of otitis media. (See Tables 3, 4 and 5.)

CHD study.

This trial, conducted at 76 centres in the United States, Canada, France, Germany, Poland, Sweden and the United Kingdom, studied patients less than or equal to 24 months of age with haemodynamically significant CHD. In this trial, 648 patients were randomised to receive five monthly placebo injections and 639 patients were randomised to receive five monthly injections of 15 mg/kg of lyophilised palivizumab. The trial was conducted during four consecutive RSV seasons. Subjects were stratified by cardiac lesion (cyanotic vs other) and were followed for safety and efficacy for 150 days. Ninety six percent (96%) of all subjects completed the study and 92% received all five injections. The primary endpoint was the incidence of RSV hospitalisation.
RSV hospitalisations occurred among 63 of 648 (9.7%) patients in the placebo group and 34 of 639 (5.3%) patients in the palivizumab group, a 45% reduction (p = 0.003). The reduction of RSV hospitalisation was consistent over time, across geographic regions, across stratification by anatomical cardiac lesion (cyanotic vs other) and within subgroups of children defined by gender, age, weight, race and presence of RSV neutralising antibody at entry. The secondary efficacy endpoints that showed significant reductions in the palivizumab group compared to placebo included total days of RSV hospitalisation (56% reduction, p = 0.003) and total RSV days with increased supplemental oxygen (73% reduction, p = 0.014).
Studies using solution for injection.

Preterm infants and children with CLD of prematurity (CLDP).

This trial, conducted at 347 centres in the North America, European Union and 10 other countries, studied patients less than or equal to 24 months of age with CLDP and patients with premature birth (less than or equal to 35 weeks gestation) who were less than or equal to 6 months of age at study entry. Patients with haemodynamically significant congenital heart disease were excluded from enrolment in this study and were studied in a separate study. In this trial, patients were randomised to receive 5 monthly injections of 15 mg/kg of palivizumab solution for injection (N = 3306) used as active control for an investigational monoclonal antibody (N = 3329). Subjects were followed for safety and efficacy for 150 days. Ninety eight percent of all subjects receiving palivizumab completed the study and 97% received all five injections. The primary endpoint was the incidence of RSV hospitalisation.
RSV hospitalisations occurred among 62 of 3306 (1.9%) patients in the palivizumab group. The RSV hospitalisation rate observed in patients enrolled with a diagnosis of CLDP was 28/723 (3.9%) and in patients enrolled with a diagnosis of prematurity without CLDP was 34/2583 (1.3%).

CHD study 2.

This trial, conducted at 162 centres in North America, European Union and 4 other countries over two RSV seasons, studied patients less than or equal to 24 months of age with haemodynamically significant CHD. In this trial, patients were randomized to receive 5 monthly injections of 15 mg/kg of palivizumab solution for injection (N = 612) used as active control for an investigational monoclonal antibody (N = 624). Subjects were stratified by cardiac lesion (cyanotic vs. other) and were followed for safety and efficacy for 150 days. Ninety seven percent of all subjects receiving palivizumab completed the study and 95% receive all five injections. The primary endpoint was a summary of adverse events and serious adverse events, and the secondary endpoint was the incidence of RSV hospitalisation. The incidence of RSV hospitalisation was 16 of 612 (2.6%) in the palivizumab group.

Extended dose study.

An open label, prospective safety and pharmacokinetics study examined the safety, tolerance and pharmacokinetics of palivizumab when administered for up to 7 months in Saudi Arabia, a subtropical region where the reported RSV season is frequently longer than in temperate countries. Eighteen preterm infants (less than 34 weeks gestation), ranging in age from newborn to 29 weeks, with or without chronic lung disease (CLD), judged to be at risk for RSV infection, and palivizumab naïve, were included in the study. Lyophilised palivizumab 15 mg/kg was injected once per month, for up to 7 months during the RSV season.
Palivizumab levels in the extended dose study were comparable to those achieved in the IMpact RSV trial. No significant elevations of antipalivizumab antibody titre were observed.

5.2 Pharmacokinetic Properties

Note.

To provide a complete pharmacokinetic profile of palivizumab in the approved indication(s), data for the lyophilised powder and solution for injection product presentations studied in patients with RSV are outlined below. However, the only presentation currently registered in Australia is the solution for injection.

Lyophilised powder for injection.

Two formulations were studied in the clinical development of palivizumab. Early studies used a liquid phosphate buffered saline formulation with a concentration of 10 mg palivizumab/mL. All other studies used the commercial lyophilised formulation. In all studies, the collection of multiple serum samples from children was intentionally limited to reduce the number of blood draws in these patients. Therefore, a complete assessment of the pharmacokinetics on the commercial formulation by intramuscular administration could only be obtained from a study performed in adult volunteers. Given the volume constraints for intramuscular dosing, the maximum dose that could be studied in adults was 3 mg/kg. Repeat single 3 mg/kg intramuscular doses were studied in four healthy adults with the results as follows. (See Table 6.)

There have been three studies in paediatric patients using the commercial formulation intramuscularly including the IMpact-RSV trial. The overall mean 30 day serum trough levels and ranges are given in Table 7.

The pharmacokinetics of palivizumab appear to show a linear relationship between dose and mean area under the serum concentration time curve. Metabolism has not been assessed. The 30 days postdose mean serum concentration was > 30 microgram/mL, which is the level associated in preclinical studies with a 2 log reduction in pulmonary RSV titres. There is considerable individual variation in palivizumab serum concentration at any timepoint and some individuals will be below 30 microgram/mL at 30 days postdose.
In a phase III/IV, multicentre evaluation of the immunogenicity of palivizumab in children who previously received palivizumab prophylaxis and children receiving the drug for the first time (W99-310), the mean serum concentrations following the first and fourth injections were approximately 60 and 90 microgram/mL.
In paediatric patients less than or equal to 24 months of age with haemodynamically significant congenital heart disease (CHD) who received palivizumab, underwent cardiopulmonary bypass for open heart surgery, and were assessed for palivizumab serum concentrations pre and postcardiac bypass surgery (N = 139), the mean serum palivizumab concentration was approximately 100 microgram/mL precardiac bypass and declined to approximately 40 microgram/mL after bypass.
A prospective, phase II, open label trial, designed to evaluate pharmacokinetics, safety and immunogenicity after administration of 7 doses of palivizumab within a single RSV season was conducted in 18 preterm infants born at less than 34 weeks gestation. Results indicated that adequate mean palivizumab levels were achieved in all 18 participants.

Solution for injection.

The pharmacokinetics and safety of palivizumab solution for injection and lyophilised powder for injection, following 15 mg per kg intramuscular administration, were compared in a crossover trial of 153 infants less than or equal to 6 months of age with a history of prematurity (less than or equal to 35 weeks gestational age). The results of this trial indicated that the trough serum concentrations of palivizumab were similar between both presentations, i.e. solution for injection and lyophilised powder for injection, and bioequivalence between both presentations was demonstrated.

5.3 Preclinical Safety Data

In a human tissue cross-reactivity study, biotinylated palivizumab did not stain in a specific fashion to the more than 30 human adult and neonatal tissues studied.
Acute toxicity studies in three species, the Sprague Dawley rat, the cynomolgus monkey and the NZW rabbit demonstrated tolerance at the site of injection as well as lack of specific systemic toxicity.
In the cotton rat model, pretreatment with palivizumab was shown to reduce mean pulmonary viral titres (replication) by a mean of 99% at serum concentrations of approximately 30 microgram/mL. At no concentration was increased viral replication seen, nor was there an increase in pulmonary inflammation or histopathology at any palivizumab concentration examined. No RSV mutants escaped therapy and reinfection with RSV after palivizumab exposure did not enhance RSV viral titres (replication) or the resultant pulmonary histopathology.

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Palivizumab contains the following excipients: 25 mM histidine and 1.6 mM glycine and the active ingredient, palivizumab, at a concentration of 100 milligrams per mL.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2°C to 8°C. Refrigerate. Do not freeze.
Store in the original container.
Do not use beyond the expiration date.

6.5 Nature and Contents of Container

Palivizumab 50 mg/0.5 mL single-use vial.

Clear, colourless Type I glass vial with stopper and flip-off seal containing 0.5 mL palivizumab solution for injection with a concentration of 100 mg/mL.

Palivizumab 100 mg/1 mL single-use vial.

Clear, colourless Type I glass vial with stopper and flip-off seal containing 1 mL palivizumab solution for injection with a concentration of 100 mg/mL.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Palivizumab is composed of two heavy chains and two light chains having a molecular weight of approximately 148,000 Daltons.

CAS number.

188039-54-5.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

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