Natalizumab

Registered South African indications: 

• Highly active relapsing remitting multiple sclerosis

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Progressive multifocal leukoencephalopathy
• Patients with increased risk for opportunistic infections, including immunocompromised patients (including those currently receiving immunosuppressive therapies or those immunocompromised by prior therapies)
• Known active malignancies, except for patients with cutaneous basal cell carcinoma
• Coadministration with other disease modifying therapies

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• Previous history of abnormal liver function test
• The presence of anti-John Cunningham virus (JCV) antibodies
• Prolonged therapy beyond 2 years
• Prior immunosuppressant use
• Crohn's disease associated with being immunocompromised or with significant co-morbidities
• Switching from another disease modifying therapy to natalizumab (see additional prescribing points)
• Discontinuation of therapy and starting other therapies within 12 weeks (see additional prescribing points)
• Live vaccines
• Sodium controlled diet
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj

Highly active relapsing-remitting multiple sclerosis
- Patients with high disease activity despite full and adequate course of treatment with at least one disease modifying therapy
- Patients with rapidly evolving severe relapse remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or significant increase in T2 lesion load as compared to a previous MRI

• IV: 300mg infusion over 1 hour, 4 weekly

Natalizumab therapy to be initiated and continuously supervised by specialists experienced in diagnosis and treatment of neurological conditions with access to MRIs

After 2 years of treatment, patients should be re-informed of the risks of natalizumab, especially the increased risk of progressive multifocal leukoencephalopathy (PML)

Physician to confirm that patients on prior immunosuppressive therapy are not immunocompromised prior to initiation of natalizumab therapy

Reconsider continuing therapy in patients who show no evidence of therapeutic benefit beyond 6 months

Efficacy of re-administration has not been established

Intravenous use; do not administer as a bolus

Not established for use in children below 18 years

Pregnancy

• Caution
• Studies from animal studies have shown reproductive toxicity
• Data from clinical trials, a prospective pregnancy registry, post-marketing cases and available literature do not suggest an effect of natalizumab exposure on pregnancy outcomes
• The completed prospective natalizumab pregnancy registry contained 355 pregnancies with available outcomes. There were 316 live births, 29 of which were reported to have birth defects. 16 of the 29 were classified as major defects. The rate of defects corresponds to the defect rates reported in other pregnancy registries involving MS patients. There is no evidence of a specific pattern of birth defects with natalizumab
• Cases from published literature reported transient mild to moderate thrombocytopaenia and anaemia observed in infants born to women exposed to natalizumab in their third trimester of pregnancy. Therefore, it is recommended that newborns of women exposed to the medicinal product during the third trimester of pregnancy are monitored for potential haematological abnormalities
• If a woman becomes pregnant while taking natalizumab, discontinuation of the medicinal product should be considered. A benefit-risk evaluation of the use of natalizumab during pregnancy should take into account the patient's clinical condition and the possible return of disease activity after stopping the medicinal product

Breastfeeding

• Caution; not recommended
• Natalizumab is excreted in human milk. The effect on newborns/infants is unknown
• Breastfeeding should be discontinued during treatment with natalizumab

Fertility

• Reductions in female guinea pig fertility were observed in one study at doses in excess of the human dose; natalizumab did not affect male fertility
• It is considered unlikely that natalizumab will affect fertility performance in humans following the maximum recommended dose

Renal Impairment

• Caution; no information available
  Studies have not been conducted to examine the effects of renal impairment. The mechanism for elimination and results from population pharmacokinetics suggest that dose adjustment would not be necessary in patients with renal impairment

Hepatic Impairment

• Caution; no information available
  Studies have not been conducted to examine the effects of hepatic impairment. The mechanism for elimination and results from population pharmacokinetics suggest that dose adjustment would not be necessary in patients with hepatic impairment

Elderly

• Caution; no information available
  Natalizumab is not recommended for use in patients >65 years due to lack of data

Porphyria Information

• Probably not porphyrinogenic (PNP)
  Immunosuppressive therapy increases infection risk and may trigger acute cases of porphyria

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Dizziness
• Progressive multifocal leukoencephalopathy
• Fatigue

Respiratory Disorders

• Nasopharyngitis

Gastrointestinal Disorders

• Nausea and vomiting

Genitourinary Disorders

• Urinary tract infection

Hepatobiliary Disorders

• Serious liver injuries
• Increased liver enzymes
• Hyperbilirubinaemia

Musculoskeletal Disorders

• Arthralgia

Immune, Blood and Lymphatic System Disorders

• Urticaria
• Hypersensitivity
  - Hypotension
  - Hypertension
  - Chest pain
  - Chest discomfort
  - Dyspnoea
  - Angioedema
  - Rash
• Anaphylactic/anaphylactoid reactions
• Rigors
• Fever
• Immunogenicity
• Opportunistic infections
  - Varicella-zoster
  - Herpes-simplex
  - Encephalitis
  - Meningitis
  - Acute retinal necrosis
• JCV granule cell neuronopathy
• Anaemia
• Haemolytic anaemia
• Increased lymphocytes
• Increased monocytes
• Increased eosinophils
• Increased basophils
• Increased nucleated red blood cells
• Decreased haemoglobin
• Decreased red blood cell counts
• Eosinophilia
• Immune reconstitution inflammatory syndrome (IRIS)

Other

• Infusion reactions

• Disease modifying therapies
• Alemtuzumab
• Teriflunomide

• Hepatic function

None routine. Specific cases may require

• MRI
• Antibody testing
• Cerebrospinal fluid analysis
• Complete blood count, including lymphocytes

Administrative directions

• Remove 50ml of concentrate for infusion to 100ml 0.9% sodium chloride
• Invert bag to mix completely
• Use within 8 hours of dilution
• Infusion to be given over 1 hour at a rate on 2ml/min
• Flush line with sodium chloride following infusion

Switching from another disease modifying therapy (DMT) to natalizumab

• When switching patients from another DMT to natalizumab, the half-life and mode of action of the other therapy must be considered in order to avoid an additive immune effect whilst at the same time minimising the risk of disease reactivation
• A complete blood count (CBC, including lymphocytes) is recommended prior to initiating natalizumab to ensure that immune effects of the previous therapy (i.e. cytopenia) have resolved
• Patients can switch from beta interferon or glatiramer acetate to natalizumab providing there are no signs of relevant treatment-related abnormalities e.g. neutropenia and lymphopenia
• When switching from dimethyl fumarate, the washout period should be sufficient for lymphocyte count to recover before treatment with natalizumab is started
• Following discontinuation of fingolimod, lymphocyte count progressively returns to normal range within 1 to 2 months after stopping therapy. The washout period should be sufficient for lymphocyte count to recover before treatment with natalizumab is started
• Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure, clearance of teriflunomide from plasma can take several months up to 2 years. An accelerated elimination procedure is recommended or alternatively washout period should not be shorter than 3.5 months. Caution regarding potential concomitant immune effects is required when switching patients from teriflunomide to natalizumab
• Alemtuzumab has profound prolonged immunosuppressive effects. As the actual duration of these effects is unknown, initiating treatment with natalizumab after alemtuzumab is not recommended unless the benefits clearly outweigh the risks for the individual patient

Stopping natalizumab therapy

• If a decision is made to stop treatment with natalizumab, the physician needs to be aware that natalizumab remains in the blood, and has pharmacodynamic effects (e.g. increased lymphocyte counts) for approximately 12 weeks following the last dose
• Starting other therapies during this interval will result in concomitant exposure to natalizumab
• For medicinal products such as interferon and glatiramer acetate, concomitant exposure of this duration was not associated with safety risks in clinical trials
• No data is available in multiple sclerosis patients regarding concomitant exposure with immunosuppressant medication. Use of these medicinal products soon after the discontinuation of natalizumab may lead to an additive immunosuppressive effect
• This should be carefully considered on a case-by-case basis, and a washout period of natalizumab might be appropriate
• Short courses of steroids used to treat relapses were not associated with increased infections in clinical trials

Natalizumab is a selective adhesion-molecule inhibitor and binds to the α4-subunit of human integrins, which is highly expressed on the surface of all leukocytes, with the exception of neutrophils. Specifically, natalizumab binds to the α4β1 integrin, blocking the interaction with its cognate receptor, vascular cell adhesion molecule-1 (VCAM-1), and ligands osteopontin, and an alternatively spliced domain of fibronectin, connecting segment-1 (CS-1). Natalizumab blocks the interaction of α4β7 integrin with the mucosal addressin cell adhesion molecule-1 (MadCAM-1). Disruption of these molecular interactions prevents transmigration of mononuclear leukocytes across the endothelium into inflamed parenchymal tissue. A further mechanism of action of natalizumab may be to suppress ongoing inflammatory reactions in diseased tissues by inhibiting the interaction of α4-expressing leukocytes with their ligands in the extracellular matrix and on parenchymal cells. As such, natalizumab may act to suppress inflammatory activity present at the disease site, and inhibit further recruitment of immune cells into inflamed tissues.

Injection (per ml) 20mg

• Tysarbri (Acino Pharma) originator