Drug Class Description
Natalizumab

Generic Name
Selective Immunosuppressive Agent

Drug Description
Concentrate: Each ml of concentrate contains 20 mg of natalizumab.Natalizumab is a recombinant humanised anti?4integrin antibody produced in a murine cell line by recombinant DNA technology.When diluted, the solution for infusion contains approximately 2.6 mg/ml of natalizumab.

Presentation
Concentrate for solution for infusion.Colourless, clear to slightly opalescent solution.

Indications
TYSABRI is indicated as single disease modifying therapy in highly active relapsing remitting multiple sclerosis for the following patient groups:• Patients with high disease activity despite treatment with a beta-interferon; or• Patients with rapidly evolving severe relapsing remitting multiple sclerosis.

Adult Dosage
TYSABRI therapy is to be initiated and supervised by specialised physicians experienced in the diagnosis and treatment of neurological conditions, in centres with timely access to MRI.Patients treated with TYSABRI must be given the patient alert card.Resources for the management of hypersensitivity reactions and access to MRI should be available.After dilution, the infusion is to be administered over approximately 1 hour and patients are to be observed during the infusion and for 1 hour after the completion of the infusion for signs and symptoms of hypersensitivity reactions.TYSABRI must not be administered as a bolus injection.Patients can switch directly from beta interferon or glatiramer acetate to natalizumab providing there are no signs of relevant treatmentrelated abnormalities e.g. neutropenia. If there are signs of treatmentrelated abnormalities these must return to normal before treatment with natalizumab is started.Some patients may have been exposed to immunosuppressive medications (e.g. mitoxantrone, cyclophosphamide, azathioprine). These drugs have the potential to cause prolonged immunosuppression, even after dosing is discontinued. Therefore the physician must confirm that such patients are not immunocompromised before starting treatment with TYSABRI.Continued therapy must be carefully reconsidered in patients who show no evidence of therapeutic benefit beyond 6 months.Data on the safety and efficacy of natalizumab beyond 2 years are not available. Continued therapy beyond this time should be considered only following a reassessment of the potential for benefit and risk.AdultsTYSABRI 300 mg is administered by intravenous infusion once every 4 weeks.ElderlyTYSABRI is not recommended for use in patients aged over 65 due to a lack of data in this population.Children and adolescentsTYSABRI is contraindicated in children and adolescents.Renal and hepatic impairmentStudies have not been conducted to examine the effects of renal or hepatic impairment.The mechanism for elimination and results from population pharmacokinetics suggest that dose adjustment would not be necessary in patients with renal or hepatic impairment.ReadministrationThe efficacy of re-administration has not been established

Child Dosage
Children and adolescents - TYSABRI is contraindicated in children and adolescents (See Contraindications).

Elderly Dosage
TYSABRI is not recommended for use in patients aged over 65 due to a lack of data in this population.

Contra Indications
Hypersensitivity to natalizumab or to any of the excipients.Progressive multifocal leukoencephalopathy (PML).Patients with increased risk for opportunistic infections, including immunocompromised patients (including those currently receiving immunosuppressive therapies or those immunocompromised by prior therapies, e.g. mitoxantrone or cyclophosphamide.Combination with beta-interferons or glatiramer acetate.Known active malignancies, except for patients with cutaneous basal cell carcinoma.Children and adolescents.

Special Precautions
Progressive Multifocal Leukoencephalopathy (PML)Use of TYSABRI has been associated with an increased risk of PML.Before initiation of treatment with TYSABRI, a recent (usually within 3 months) Magnetic Resonance Image should be available. Patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML.If PML is suspected, further dosing must be suspended until PML has been excluded. The clinician should eva luate the patient to determine if the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms are typical of MS or possibly suggestive of PML. If any doubt exists, further eva luation, including MRI scan preferably with contrast (compared with pre-treatment MRI), CSF testing for JC Viral DNA and repeat neurological assessments, should be considered as described in the Physician Information and Management Guidelines (see educational guidance). Once the clinician has excluded PML (if necessary, by repeating clinical, imaging and/or laboratory investigations if clinical suspicion remains), dosing of natalizumab may resume.The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g. cognitive or psychiatric symptoms). Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of.If a patient develops PML the dosing of TYSABRI must be permanently discontinued.Following reconstitution of the immune system in immunocompromised patients with PML, stabilisation or improved outcome has been seen. It remains unknown if early detection of PML and suspension of TYSABRI therapy may lead to similar stabilisation or improved outcome.Other Opportunistic InfectionsOther opportunistic infections have been reported with use of TYSABRI, primarily in patients with Crohn's disease who were immunocompromised or where significant comorbidity existed, however increased risk of other opportunistic infections with use of TYSABRI in patients without these co-morbidities cannot currently be excluded. Opportunistic infections were also detected in MS patients treated with TYSABRI as a monotherapy.Prescribers should be aware of the possibility that other opportunistic infections may occur during TYSABRI therapy and should include them in the differential diagnosis of infections that occur in TYSABRItreated patients. If an opportunistic infection is suspected, dosing with TYSABRI is to be suspended until such infections can be excluded through further eva luations.If a patient receiving TYSABRI develops an opportunistic infection, dosing of TYSABRI must be permanently discontinued.Educational guidanceAll physicians who intend to prescribe TYSABRI must ensure they are familiar with the Physician Information and Management Guidelines.Physicians must discuss the benefits and risks of TYSABRI therapy with the patient and provide them with a Patient Alert Card. Patients should be instructed that if they develop any infection then they should inform their physician that they are being treated with TYSABRI.Physicians should counsel patients on the importance of uninterrupted dosing, particularly in the early months of treatment (see hypersensitivity).HypersensitivityHypersensitivity reactions have been associated with TYSABRI, including serious systemic reactions. These reactions usually occurred during the infusion or up to 1 hour after completion of the infusion. The risk for hypersensitivity was greatest with early infusions and in patients re-exposed to TYSABRI following an initial short exposure (one or two infusions) and extended period (three months or more) without treatment. However, the risk of hypersensitivity reactions should be considered for every infusion administered.Patients are to be observed during the infusion and for 1 hour after the completion of the infusion. Resources for the management of hypersensitivity reactions should be available.Discontinue administration of TYSABRI and initiate appropriate therapy at the first symptoms or signs of hypersensitivity.Patients who have experienced a hypersensitivity reaction must be permanently discontinued from treatment with TYSABRI.Concurrent or prior treatment with immunosuppressantsThe safety and efficacy of TYSABRI in combination with other immunosuppressive and antineoplastic therapies have not been fully established. Concurrent use of these agents with TYSABRI may increase the risk of infections, including opportunistic infections, and is contraindicated.Patients with a treatment history of immunosuppressant medications, including cyclophosphamide and mitoxantrone, may experience prolonged immunosuppression and therefore may be at increased risk for PML. Care should be taken with patients who have previously received immunosuppressants to allow sufficient time for immune function recovery to occur. Physicians must eva luate each individual case to determine whether there is evidence of an immunocompromised state prior to commencing treatment with TYSABRI.In Phase 3 MS clinical trials, concomitant treatment of relapses with a short course of corticosteroids was not associated with an increased rate of infection. Short courses of corticosteroids can be used in combination with TYSABRI.ImmunogenicityDisease exacerbations or infusion related events may indicate the development of antibodies against natalizumab. In these cases the presence of antibodies should be eva luated and if these remain positive in a confirmatory test after 6 weeks, treatment should be discontinued, as persistent antibodies are associated with a substantial decrease in efficacy of TYSABRI and an increased incidence of hypersensitivity reactions.Since patients who have received an initial short exposure to TYSABRI and then had an extended period without treatment are more at risk for hypersensitivity upon redosing, the presence of antibodies should be eva luated and if these remain positive in a confirmatory test after 6 weeks treatment should not be resumed.Hepatic EventsSpontaneous serious adverse reactions of liver injury have been reported during the post marketing phase. These liver injuries may occur at any time during treatment, even after the first dose. In some instances, the reaction reoccurred when TYSABRI was reintroduced. Some patients with a past medical history of an abnormal liver test have experienced an exacerbation of abnormal liver test while on TYSABRI. Patients should be monitored as appropriate for impaired liver function, and be instructed to contact their physician in case signs and symptoms suggestive of liver injury occur, such as jaundice and vomiting. In cases of significant liver injury TYSABRI should be discontinued.Stopping TYSABRI therapyIf 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 a concomitant exposure to natalizumab. For drugs such as interferon and glatiramer acetate, concomitant exposure of this duration was not associated with safety risks in clinical trials. No data are available in MS patients regarding concomitant exposure with immunosuppressant medication. Use of these medicines soon after the discontinuation of natalizumab may lead to an additive immunosuppressive effect. This should be carefully considered on a casebycase basis, and a wash-out period of natalizumab might be appropriate. Short courses of steroids used to treat relapses were not associated with increased infections in clinical trials.

Interactions
See Contraindications. Pregnancy and lactation There are no adequate data from the use of natalizumab in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Natalizumab should not be used during pregnancy unless clearly necessary. If a woman becomes pregnant while taking TYSABRI, discontinuation of TYSABRI should be considered.It is not known whether TYSABRI is excreted in human milk, but it has been observed in animal studies. Patients receiving TYSABRI should not breastfeed their infants.

Adverse Reactions
In placebo-controlled trials in 1,617 MS patients treated with natalizumab for up to 2 years (placebo: 1,135), adverse events leading to discontinuation of therapy occurred in 5.8% of patients treated with natalizumab (placebo: 4.8%). Over the 2year duration of the studies, 43.5% of patients treated with natalizumab reported adverse drug reactions (placebo: 39.6%)[1]. Adverse drug reactions reported with natalizumab with an incidence of 0.5% greater than reported with placebo are shown below. The reactions are reported as MedDRA preferred terms under the MedDRA primary system organ class. Frequencies were defined as follows:Common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100).Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.[1] An adverse event judged related to therapy by the investigating physician. Nervous system disorders CommonHeadache DizzinessGastrointestinal disorders CommonVomiting NauseaMusculoskeletal and connective tissue disorders CommonArthralgiaInfections and infestations CommonUrinary tract infection NasopharyngitisGeneral disorders and administration site conditions CommonRigors Pyrexia FatigueImmune system disorders CommonUrticariaUncommonHypersensitivityInfusion reactionsIn 2-year controlled clinical trials in MS patients, an infusionrelated event was defined as an adverse event occurring during the infusion or within 1 hour of the completion of the infusion. These occurred in 23.1% of MS patients treated with natalizumab (placebo: 18.7%). Events reported more commonly with natalizumab than with placebo included dizziness, nausea, urticaria and rigors.Hypersensitivity reactionsIn 2-year controlled clinical trials in MS patients, hypersensitivity reactions occurred in up to 4% of patients. Anaphylactic/anaphylactoid reactions occurred in less than 1% of patients receiving TYSABRI. Hypersensitivity reactions usually occurred during the infusion or within the 1hour period after the completion of the infusion. In post-marketing experience, there have been reports of hypersensitivity reactions which have occurred with one or more of the following associated symptoms: hypotension, hypertension, chest pain, chest discomfort, dyspnoea, angioedema, in addition to more usual symptoms such as rash and urticaria.ImmunogenicityIn 10% of patients antibodies against natalizumab were detected in 2-year controlled clinical trials in MS patients. Persistent anti-natalizumab antibodies (one positive test reproducible on retesting at least 6 weeks later) developed in approximately 6% of patients. Antibodies were detected on only one occasion in an additional 4% of patients. Persistent antibodies were associated with a substantial decrease in the effectiveness of TYSABRI and an increased incidence of hypersensitivity reactions. Additional infusion-related reactions associated with persistent antibodies included rigors, nausea, vomiting and flushing.If, after approximately 6 months of therapy, persistent antibodies are suspected, either due to reduced efficacy or due to occurrence of infusion-related events, they may be detected and confirmed with a subsequent test 6 weeks after the first positive test. Given that efficacy may be reduced or the incidence of hypersensitivity or infusion-related reactions may be increased in a patient with persistent antibodies, treatment should be discontinued in patients who develop persistent antibodies.Infections, including PML and opportunistic infectionsIn 2-year controlled clinical trials in MS patients, the rate of infection was approximately 1.5 per patientyear in both natalizumab- and placebotreated patients. The nature of the infections was generally similar in natalizumab- and placebotreated patients. A case of cryptosporidium diarrhoea was reported in MS clinical trials. In other clinical trials, cases of additional opportunistic infections have been reported, some of which were fatal. In clinical trials, herpes infections (Varicella-Zoster virus, Herpes-simplex virus) occurred slightly more frequently in natalizumab-treated patients than in placebo-treated patients. In post marketing experience, there have been reports of serious cases, including one fatal case of herpes encephalitis.The majority of patients did not interrupt natalizumab therapy during infections and recovery occurred with appropriate treatment.In clinical trials, cases of PML have been reported. PML usually leads to severe disability or death. In pivotal clinical trials, two cases, including one fatality, occurred in MS patients who were being treated with concomitant interferon beta1a therapy for more than 2 years. In another trial, one patient with Crohn's disease, who had a long history of treatment with immunosuppressants and associated lymphopenia also developed PML and died.PML has been reported in post-marketing experience in patients treated with TYSABRI monotherapy.Hepatic EventsSpontaneous cases of serious liver injuries, increased liver enzymes, hyperbilirubinaemia have been reported during the post marketing phase.MalignanciesNo differences in incidence rates or the nature of malignancies between natalizumab- and placebotreated patients were observed over 2 years of treatment. However, observation over longer treatment periods is required before any effect of natalizumab on malignancies can be excluded.Effects on laboratory testsTYSABRI treatment was associated with increases in circulating lymphocytes, monocytes, eosinophils, basophils and nucleated red blood cells. Elevations in neutrophils were not seen. Increases from baseline for lymphocytes, monocytes, eosinophils and basophils ranged from 35% to 140% for individual cell types but mean cell counts remained within normal ranges. During treatment with TYSABRI, small reductions in haemoglobin (mean decrease 0.6 g/dl), haematocrit (mean decrease 2%) and red blood cell counts (mean decrease 0.1 x 106/l) were seen. All changes in haematological variables returned to pretreatment values, usually within 16 weeks of last dose of TYSABRI and the changes were not associated with clinical symptoms.

Manufacturer
Biogen Idec Ltd

Drug Availability
(POM)

Updated
12 August 2009