, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have liver enzymes checked and Gilenya should be discontinued if significant liver injury is confirmed (for example liver transaminase levels greater than 5-fold the ULN and/or serum bilirubin elevations). Resumption of therapy will be dependent on whether or not another cause of liver injury is determined and on the benefits to patient of resuming therapy versus the risks of recurrence of liver dysfunction.
Although there are no data to establish that patients with pre-existing liver disease are at increased risk of developing elevated liver function tests when taking Gilenya, caution in the use of Gilenya should be exercised in patients with a history of significant liver disease.
Interference with serological testing
Since fingolimod reduces blood lymphocyte counts via re-distribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilised to eva luate the lymphocyte subset status of a patient treated with Gilenya. Laboratory tests involving the use of circulating mononuclear cells require larger blood volumes due to reduction in the number of circulating lymphocytes.
Blood pressure effects
Patients with hypertension uncontrolled by medication were excluded from participation in premarketing clinical trials and special care is indicated if patients with uncontrolled hypertension are treated with Gilenya.
In MS clinical trials, patients treated with fingolimod 0.5 mg had an average increase of approximately 2 mmHg in systolic pressure, and approximately 1 mmHg in diastolic pressure, first detected approximately 2 months after treatment initiation, and persisting with continued treatment. In the two-year placebo-controlled study, hypertension was reported as an adverse event in 6.1% of patients on fingolimod 0.5 mg and in 3.8% of patients on placebo. Therefore, blood pressure should be regularly monitored during treatment with Gilenya.
Respiratory effects
Minor dose-dependent reductions in values for forced expiratory volume (FEV1) and diffusion capacity for carbon monoxide (DLCO) were observed with Gilenya treatment starting at Month 1 and remaining stable thereafter. Gilenya should be used with caution in patients with severe respiratory disease, pulmonary fibrosis and chronic obstructive pulmonary disease (see also section 4.8).
Prior treatment with immunosuppressants
When switching patients from interferon or glatiramer acetate to Gilenya, a washout is not necessary, assuming any immune effects (i.e. cytopenia) of such therapies have resolved.
Due to the long half-life of natalizumab, concomitant exposure, and thus concomitant immune effects, could occur for up to 2-3 months following discontinuation of natalizumab if Gilenya was immediately started. Therefore caution is required when switching patients from natalizumab to Gilenya.
When switching from other immunosuppressive medications, the duration and mode of action of such substances must be considered when initiating Gilenya to avoid additive immune suppressive effects.
Stopping therapy
If a decision is made to stop treatment with Gilenya a 6 week interval without therapy is needed, based on half-life, to clear fingolimod from the circulation (see section 5.2). Lymphocyte counts progressively return to normal range within 1-2 months of stopping therapy (see se
