Drugs List

Therapeutic Indications

Uses

Highly active relapsing and remitting MS after failure of prior therapy
Rapidly evolving severe relapsing remitting multiple sclerosis

Treatment of highly active relapsing remitting multiple sclerosis in patients:

With high disease activity despite treatment with at least one disease modifying therapy (DMT).

With rapidly evolving severe relapsing remitting multiple sclerosis. Defined by two or more disabling relapses in one year, and with one or more gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load compared to a previous MRI.

Administration

To be diluted and given by intravenous infusion.

After dilution the infusion should be administered over 1 hour (rate of approximately 2ml/minute) and the line flushed with sodium chloride 0.9% solution for injection.

The patient should be observed for hypersensitivity reactions during administration and for a further hour following administration.

Contraindications

Children under 18 years
Immunosuppression
Patients over 65 years
Predisposition to infection
Severe infection
Active malignancies, except cutaneous basal cell carcinoma
Breastfeeding
Pregnancy
Progressive multifocal leukoencephalopathy (PML)

Precautions and Warnings

Antibodies to JC virus
History of immunosuppressant treatment
Restricted sodium intake
Crohn's disease
Hepatic disorder

Contains more than 1 mmol (23 mg) sodium per dose
Advise ability to drive/operate machinery may be affected by side effects
Intermittent therapy increases the risk of hypersensitivity reactions
Treatment to be initiated and supervised by a specialist
Never rechallenge treatment after a hypersensitivity reaction
Record name and batch number of administered product
Resuscitation facilities must be immediately available
A recent (within 3 months) MRI should be available prior to treatment
Continue to monitor for PML 6 months following discontinuation
If visual disturbances occur, perform ophthalmic evaluation
Increased monitoring required in patient at high risk of PML
Monitor for JC virus antibodies before and six monthly during treatment
Monitor for the presence of antibodies
Monitor hepatic function
Monitor neurological function
On discontinuation, monitor for immune reconstitution inflammatory syndrome
Repeat MRI at yearly intervals during treatment
Advise patient to report headaches, seizures, confusion, visual disturbance
Advise patient to report symptoms of infection immediately
Advise patients to report signs of hepatic damage (malaise, jaundice etc.)
Monitor for hypersensitivity reactions for 1 hour after administration
Risk of developing opportunistic infections
Discontinue if acute retinal necrosis (ARN) develops
Discontinue if hypersensitivity reactions occur
Discontinue if meningitis or encephalitis occurs
Discontinue if Progressive multifocal leukoencephalopathy (PML) develops
Discontinue if severe hepatic changes occur
Discontinue treatment if patient develops a serious infection
Suspend treatment if opportunistic infection is suspected
Remind patient of importance of carrying Alert Card with them at all times

Opportunistic infections
Opportunistic infections in patients using natalizumab have primarily been reported in immunocompromised patients with Crohn's disease or with other significant co-morbidities but can occur in any patient. Following diagnosis, permanent treatment discontinuation versus suspension (whilst the infection is treated) should be considered. Natalizumab increases the risk of developing encephalitis and meningitis due to herpes viruses and cases of acute retinal necrosis (ARN) have also been rarely reported. All patients presenting with eye symptoms e.g. decreased visual acuity, redness and painful eye should be immediately referred for retinal screening for ARN.

Progressive Multifocal Leukoencephalopathy Syndrome (PML)
Progressive multifocal leukoencephalopathy syndrome (PML) is a serious opportunistic infection caused by John Cunningham virus (JCV) which has been reported in some patients treated with this agent. Long treatment duration (beyond 2 years), previous immunosuppressant use and the presence of anti-JC virus antibodies is associated with an increased risk. Where all 3 of these risk factors are present treatment should only continue if the benefits outweigh the risks.

All patients must undergo MRI scans before treatment initiation and at least annually thereafter. This should be increased to every 3 to 6 months using an abbreviated protocol in patients with all 3 risk factors for PML and in patients with a high anti-JCV antibody index that have received more than 2 years of natalizumab with no previous immunosuppressant therapy.

Serum anti-JCV antibody testing is also recommended prior to initiation and in patients currently on natalizumab with unknown antibody status. Re-testing is recommended every 6 months for patients that are negative for anti-JCV antibodies and for patients with a low index who have received more than 2 years of natalizumab with no previous immunosuppressant therapy. Anti-JCV antibody testing should not be performed during or for at least 2 weeks following, plasma exchange due to the removal of antibodies from the serum or within 6 months of intravenous immunoglobulin (IVIg).

If a patient develops symptoms suggestive of PML (e.g. worsening neurological, cognitive or behavioural signs or symptoms), suspend treatment and perform an MRI (preferably with contrast), CSF testing for JC viral DNA and repeat neurological assessments. If PML is confirmed, permanently discontinue treatment. Following discontinuation monitor patients for signs of Immune Reconstitution Inflammatory Syndrome (IRIS) as it commonly presents in PML patients days to several weeks after treatment is withdrawn. Results of MRI testing and anti-JCV antibody testing should always be closely scrutinised as there have also been reports of asymptomatic PML identified solely through these investigations.

In addition to PML, JCV has also been reported to cause JCV granule cell neuronopathy (JCV GCN) in patients treated with natalizumab. Symptoms of JCV GCN are similar to PML but are predominantly cerebellar in nature. It should be considered as a potential differential diagnosis to PML and investigated in the same manner.

Following treatment discontinuation the same monitoring protocol should be continued for 6 months as PML has been reported during this time.

Previous or concurrent treatment with immunosuppressants or immunomodulatory therapies
Frequency of monitoring for PML should be increased in patients previously treated with immunosuppressants or DMTs with immunosuppressant effects as prolonged immunosuppression is possible which increases PML risk. The effects of natalizumab can also continue for approximately 12 weeks after it is discontinued so use of other immunosuppressants during this time period may also lead to additive immunosuppressant effects. Short courses of corticosteroids used to treat relapses have not however been associated with increased infections in clinical trials.

Immunogenicity Patients may develop antibodies against natalizumab leading to disease exacerbations and/or infusion reactions. If suspected, antibody presence should be confirmed and if results remain positive following a repeat test, natalizumab should be discontinued. The risk of immunogenicity is higher following treatment breaks. This should be routinely avoided but if treatment suspension is essential monitoring for antibody presence is advised.

Pregnancy and Lactation

Pregnancy

Natalizumab is contraindicated during pregnancy.

The manufacturer recommends infants are monitored for haematological abnormalities if the mother was exposed to natalizumab during the third trimester. Studies have shown transient mild to moderate thrombocytopenia and anaemia in newborns of women exposed to natalizumab during the third trimester.

Animal studies with natalizumab showed no evidence of teratogenicity but other toxicity in the form of reduced pup survival (in guinea pigs) and increased abortion (in cynomolgus monkeys) was seen. A study in pregnant cynomolgus monkeys demonstrated mild anaemia, reduced platelet count, increased spleen weights and reduced liver and thymus weights in foetuses. All effects were seen at doses in excess of the human dose.

Lactation

Natalizumab is contraindicated during breastfeeding.

The manufacturer recommends that breastfeeding is discontinued during treatment with natalizumab. Natalizumab is excreted into human milk. Absorption is unlikely as natalizumab is a large protein (molecular weight around 149,000), therefore it is likely to be destroyed in the infant's gastrointestinal tract. The effect of natalizumab on the infant is unknown.

Side Effects

Acute retinal necrosis
Anaemia
Anaphylactic reaction
Anaphylactoid reaction
Angioedema
Antibody formation
Arthralgia
Basophilia
Chest discomfort
Chest pain
Decrease in haemoglobin and haematocrit
Decreased erythrocyte count
Dizziness
Dyspnoea
Encephalitis
Eosinophilia
Fatigue
Flushing
Granule cell neuronopathy
Haemolytic anaemia
Headache
Hepatic impairment
Herpes infections
Hyperbilirubinaemia
Hypersensitivity reactions
Hypertension
Hypotension
Increased nucleated red blood cells
Increases in hepatic enzymes
Liver toxicity
Lymphocytosis
Meningitis
Monocytosis
Nasopharyngitis
Nausea
Opportunistic infections
Progressive multifocal leukoencephalopathy (PML)
Pyrexia
Rash
Rigors
Urinary tract infections
Urticaria
Vomiting

Presentation

Infusions of natalizumab.

Drugs List

Therapeutic Indications

Uses

Highly active relapsing and remitting MS after failure of prior therapy
Rapidly evolving severe relapsing remitting multiple sclerosis

Treatment of highly active relapsing remitting multiple sclerosis in patients:

With high disease activity despite treatment with at least one disease modifying therapy (DMT).

With rapidly evolving severe relapsing remitting multiple sclerosis. Defined by two or more disabling relapses in one year, and with one or more gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load compared to a previous MRI.

Dosage

Adults

Children

Additional Dosage Information

Administration

To be diluted and given by intravenous infusion.

After dilution the infusion should be administered over 1 hour (rate of approximately 2ml/minute) and the line flushed with sodium chloride 0.9% solution for injection.

The patient should be observed for hypersensitivity reactions during administration and for a further hour following administration.

Contraindications

Children under 18 years
Immunosuppression
Patients over 65 years
Predisposition to infection
Severe infection
Active malignancies, except cutaneous basal cell carcinoma
Breastfeeding
Pregnancy
Progressive multifocal leukoencephalopathy (PML)

Precautions and Warnings

Antibodies to JC virus
History of immunosuppressant treatment
Restricted sodium intake
Crohn's disease
Hepatic disorder

Contains more than 1 mmol (23 mg) sodium per dose
Advise ability to drive/operate machinery may be affected by side effects
Intermittent therapy increases the risk of hypersensitivity reactions
Treatment to be initiated and supervised by a specialist
Never rechallenge treatment after a hypersensitivity reaction
Record name and batch number of administered product
Resuscitation facilities must be immediately available
A recent (within 3 months) MRI should be available prior to treatment
Continue to monitor for PML 6 months following discontinuation
If visual disturbances occur, perform ophthalmic evaluation
Increased monitoring required in patient at high risk of PML
Monitor for JC virus antibodies before and six monthly during treatment
Monitor for the presence of antibodies
Monitor hepatic function
Monitor neurological function
On discontinuation, monitor for immune reconstitution inflammatory syndrome
Repeat MRI at yearly intervals during treatment
Advise patient to report headaches, seizures, confusion, visual disturbance
Advise patient to report symptoms of infection immediately
Advise patients to report signs of hepatic damage (malaise, jaundice etc.)
Monitor for hypersensitivity reactions for 1 hour after administration
Risk of developing opportunistic infections
Discontinue if acute retinal necrosis (ARN) develops
Discontinue if hypersensitivity reactions occur
Discontinue if meningitis or encephalitis occurs
Discontinue if Progressive multifocal leukoencephalopathy (PML) develops
Discontinue if severe hepatic changes occur
Discontinue treatment if patient develops a serious infection
Suspend treatment if opportunistic infection is suspected
Remind patient of importance of carrying Alert Card with them at all times

Opportunistic infections
Opportunistic infections in patients using natalizumab have primarily been reported in immunocompromised patients with Crohn's disease or with other significant co-morbidities but can occur in any patient. Following diagnosis, permanent treatment discontinuation versus suspension (whilst the infection is treated) should be considered. Natalizumab increases the risk of developing encephalitis and meningitis due to herpes viruses and cases of acute retinal necrosis (ARN) have also been rarely reported. All patients presenting with eye symptoms e.g. decreased visual acuity, redness and painful eye should be immediately referred for retinal screening for ARN.

Progressive Multifocal Leukoencephalopathy Syndrome (PML)
Progressive multifocal leukoencephalopathy syndrome (PML) is a serious opportunistic infection caused by John Cunningham virus (JCV) which has been reported in some patients treated with this agent. Long treatment duration (beyond 2 years), previous immunosuppressant use and the presence of anti-JC virus antibodies is associated with an increased risk. Where all 3 of these risk factors are present treatment should only continue if the benefits outweigh the risks.

All patients must undergo MRI scans before treatment initiation and at least annually thereafter. This should be increased to every 3 to 6 months using an abbreviated protocol in patients with all 3 risk factors for PML and in patients with a high anti-JCV antibody index that have received more than 2 years of natalizumab with no previous immunosuppressant therapy.

Serum anti-JCV antibody testing is also recommended prior to initiation and in patients currently on natalizumab with unknown antibody status. Re-testing is recommended every 6 months for patients that are negative for anti-JCV antibodies and for patients with a low index who have received more than 2 years of natalizumab with no previous immunosuppressant therapy. Anti-JCV antibody testing should not be performed during or for at least 2 weeks following, plasma exchange due to the removal of antibodies from the serum or within 6 months of intravenous immunoglobulin (IVIg).

If a patient develops symptoms suggestive of PML (e.g. worsening neurological, cognitive or behavioural signs or symptoms), suspend treatment and perform an MRI (preferably with contrast), CSF testing for JC viral DNA and repeat neurological assessments. If PML is confirmed, permanently discontinue treatment. Following discontinuation monitor patients for signs of Immune Reconstitution Inflammatory Syndrome (IRIS) as it commonly presents in PML patients days to several weeks after treatment is withdrawn. Results of MRI testing and anti-JCV antibody testing should always be closely scrutinised as there have also been reports of asymptomatic PML identified solely through these investigations.

In addition to PML, JCV has also been reported to cause JCV granule cell neuronopathy (JCV GCN) in patients treated with natalizumab. Symptoms of JCV GCN are similar to PML but are predominantly cerebellar in nature. It should be considered as a potential differential diagnosis to PML and investigated in the same manner.

Following treatment discontinuation the same monitoring protocol should be continued for 6 months as PML has been reported during this time.

Previous or concurrent treatment with immunosuppressants or immunomodulatory therapies
Frequency of monitoring for PML should be increased in patients previously treated with immunosuppressants or DMTs with immunosuppressant effects as prolonged immunosuppression is possible which increases PML risk. The effects of natalizumab can also continue for approximately 12 weeks after it is discontinued so use of other immunosuppressants during this time period may also lead to additive immunosuppressant effects. Short courses of corticosteroids used to treat relapses have not however been associated with increased infections in clinical trials.

Immunogenicity Patients may develop antibodies against natalizumab leading to disease exacerbations and/or infusion reactions. If suspected, antibody presence should be confirmed and if results remain positive following a repeat test, natalizumab should be discontinued. The risk of immunogenicity is higher following treatment breaks. This should be routinely avoided but if treatment suspension is essential monitoring for antibody presence is advised.

Pregnancy and Lactation

Pregnancy

Natalizumab is contraindicated during pregnancy.

The manufacturer recommends infants are monitored for haematological abnormalities if the mother was exposed to natalizumab during the third trimester. Studies have shown transient mild to moderate thrombocytopenia and anaemia in newborns of women exposed to natalizumab during the third trimester.

Animal studies with natalizumab showed no evidence of teratogenicity but other toxicity in the form of reduced pup survival (in guinea pigs) and increased abortion (in cynomolgus monkeys) was seen. A study in pregnant cynomolgus monkeys demonstrated mild anaemia, reduced platelet count, increased spleen weights and reduced liver and thymus weights in foetuses. All effects were seen at doses in excess of the human dose.

Lactation

Natalizumab is contraindicated during breastfeeding.

The manufacturer recommends that breastfeeding is discontinued during treatment with natalizumab. Natalizumab is excreted into human milk. Absorption is unlikely as natalizumab is a large protein (molecular weight around 149,000), therefore it is likely to be destroyed in the infant's gastrointestinal tract. The effect of natalizumab on the infant is unknown.

Counselling

Advise patient on the importance of uninterrupted dosing particularly during early treatment. Supply patient with a patient alert card.
Discuss with patient potential treatment risks including PML prior to initiation.
Repeat this discussion after 2 years of treatment with a revised assessment of the individual patient's risk(s) in particular highlighting that the risk of PML increases in patients treated for more than 2 years.

Advise patient and any caregivers how to identify signs of adverse effects (in particular PML).
Advise patient to report any symptoms of an infection and inform the treating physician that they are prescribed natalizumab therapy (or show them their alert card). Advise patient to report any signs of liver injury (e.g. jaundice, vomiting). Advise patient to report any eye symptoms including decreased visual acuity, redness and painful eye.
Advise patient some side effects may affect their ability to safely drive or operate machinery.
On discontinuation of treatment advise patient to be alert for signs or symptoms of PML for approximately 6 months.

Side Effects

Acute retinal necrosis
Anaemia
Anaphylactic reaction
Anaphylactoid reaction
Angioedema
Antibody formation
Arthralgia
Basophilia
Chest discomfort
Chest pain
Decrease in haemoglobin and haematocrit
Decreased erythrocyte count
Dizziness
Dyspnoea
Encephalitis
Eosinophilia
Fatigue
Flushing
Granule cell neuronopathy
Haemolytic anaemia
Headache
Hepatic impairment
Herpes infections
Hyperbilirubinaemia
Hypersensitivity reactions
Hypertension
Hypotension
Increased nucleated red blood cells
Increases in hepatic enzymes
Liver toxicity
Lymphocytosis
Meningitis
Monocytosis
Nasopharyngitis
Nausea
Opportunistic infections
Progressive multifocal leukoencephalopathy (PML)
Pyrexia
Rash
Rigors
Urinary tract infections
Urticaria
Vomiting

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: February 2021

Reference Sources

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Summary of Product Characteristics: Tysabri 300mg concentration for solution for infusion. Biogen Idec Ltd. Revised August 2018.

MHRA Drug Safety Update April 2016
Available at: https://www.mhra.gov.uk
Last accessed: 23 August 2017

NICE Evidence Services Available at: www.nice.org.uk
Last accessed: 29 July 2019
Drugs and Lactation Database (LactMed) - NCBI
Available at: https://www.ncbi.nlm.nih.gov/books/NBK501613/
Natalizumab Last revised: 20 July 2020
Last accessed: 10 February 2021

The Drug Database for Acute Porphyria (NAPOS)
Available at: https://www.drugs-porphyria.org
Natalizumab Last revised: 31 August 2010
Last accessed: 10 February 2021