Multiple Sclerosis Medication
Gilenya (fingolimod) capsules 0.5 mg - Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)
- Patients who have had a hypersensitivity reaction to fingolimod or any of the excipients in GILENYA. Observed reactions include rash, urticaria and angioedema upon treatment initiation
Risk of Infections
- In the postmarketing setting, serious infections with opportunistic pathogens including viruses (e.g., John Cunningham virus (JCV), herpes simplex viruses 1 and 2, varicella-zoster virus), fungi (e.g., cryptococci), and bacteria (e.g., atypical mycobacteria) have been reported with GILENYA. Patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and appropriate treatment.
- Cases of Kaposi’s sarcoma have been reported in the postmarketing setting. Kaposi’s sarcoma is an angioproliferative disorder that is associated with infection with human herpes virus 8 (HHV-8). Patients with symptoms or signs consistent with Kaposi’s sarcoma should be referred for prompt diagnostic evaluation and management.
- Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients with MS who received GILENYA in the postmarketing setting. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. PML has occurred in patients who had not been treated previously with natalizumab, which has a known association with PML, and who were also not taking any immunosuppressive or immunomodulatory medications concomitantly. The patients had no other ongoing identified systemic medical conditions resulting in compromised immune system function, although one patient had a history of cancer treated with chemotherapy several years prior to taking Gilenya. The cases have occurred in patients treated with GILENYA for at least 2 years. The relationship between the risk of PML and the duration of treatment is unknown.
- Cases of liver injury with hepatocellular and/or cholestatic hepatitis have been reported with GILENYA in the postmarketing setting.
- Basal cell carcinoma (BCC) is associated with use of GILENYA. In two-year placebo-controlled trials the incidence of BCC was 2% in patients on GILENYA 0.5 mg and 1% in patients on placebo [see Adverse reactions (6)]. Providers and patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly evaluated.
- Hypersensitivity reactions, including rash, urticaria, and angioedema have been reported with GILENYA in the postmarketing setting. GILENYA is contraindicated in patients with history of hypersensitivity to fingolimod or any of its excipients
Source : FDA (March 2016)
MS Drug May Trigger Lymphopenia in Slim Women. Fingolimod also increases risk in patients with low lymphocyte count.
Underweight women taking the oral multiple sclerosis drug fingolimod (Gilenya) and patients with low baseline lymphocyte counts appear to have an increased risk for drug-induced lymphopenia and may need to be closely monitored, researchers reported.
Women with BMIs lower than 18.5 kg/m2 had a 26% increased risk for developing fingolimod-induced lymphopenia during treatment (95% CI, 20%-31%) in an analysis of data from studies in Germany and Sweden conducted by Clemens Warnke, MD, of Heinrick-Heine University, Dusseldorf, Germany, and colleagues in the Dec. 2 issue ofNeurology.
Patients with baseline lymphocyte counts below 1.6 x 109/L also had a 46% increase in lymphopenia risk (95% CI, 23%-71%) while taking the drug.
Fingolimod, which is a sphingosine-2-phosphate receptor agonist, was approved by the FDA in 2010 as the first oral disease-modifying drug for multiple sclerosis.
"The clinical effect has been attributed to its capacity to sequester circulating lymphocytes into secondary lymphoid tissues. In pivotal studies, fingolimod treatment reduced circulating lymphocytes to a mean of about 0.5 x 109/L," Warnke and colleagues wrote.
Patient Age Did Not Appear to Impact Risk
Side affects associated with fingolimod include bradycardia and varicella-zoster virus infection (VZV), and the drug has been implicated in at least two VZV deaths.
Drug-induced lymphopenia is a concern due to fingolimod's method of action, but it has not been clear if and/or how factors like pre-treatment lymphocyte count, treatment before fingolimod, age, sex, or BMI impact the risk for this complication, Warnke and colleagues noted.
Their analysis included 418 patients with relapsing/remitting rheumatoid arthritis enrolled in a multicenter, single arm, open label study in Germany receiving 0.5 mg of fingolimod daily. Blood samples were taken immediately before treatment (baseline) and 1, 4, and 6 months after treatment was initiated.
A second group of 438 patients enrolled in a nationwide study in Sweden were also included in the analysis to validate the findings.
Lymphocyte counts were found to be reduced below (German cohort) or at 0.2 x 109/L (Swedish cohort) on at least one of the time points during therapy in 16% (95% CI 13%-20%) and 13% (95% CI 11%-17%) of patients, respectively. Eight of the German patients (2% 95% CI 1%-4%) and 23 of the Swedish patients (5%, 95% CI 3%-8%) reached this nadir two or more times during treatment.
Cox regression sensitivity analysis revealed an increase in risk with initial lymphocyte count below 1.6 x 109/L separately in both cohorts, which increased the estimated percentage of patients with lymphopenia in the combined dataset to 26% (95% CI 20%-31%; OR2.60, 95% CI 1.80-3.76; P=3.4 x 10-7).
"Accordingly, there was a moderate positive correlation for the initial lymphocyte count and the lowest count during the study, independently observed in the German and Swedish cohorts," the researchers wrote.
When the researchers examined the effect of BMI on lymphopenia risk, they found that women, but not men, with BMIs lower than 18.5 kg/m2 had a higher risk of lymphocyte counts falling below or at 0.2 x 109/L in the German cohort. A similar direction was seen in the Swedish cohort, but BMI information was available for only 55 of the Swedish patients.
Prior treatment with immunosuppressive drugs (mitoxantrone or azathioprine) or natalizumab was not associated with an increased risk for lymphopenia.
Age also had no effect on risk of reaching a nadir of 0.2 x 109/L or below in the German study, which was the only study to report infections. In the 66 patients who reached this level during 6 months of observation, 27 (41%; 95% CI 30%-53%) had one or more infections, which was similar to the overall infection rate of the total cohort.
Prior Treatment With Glatiramer Appeared Protective
Pretreatment with glatiramer acetate showed a protective trend in both cohorts, decreasing the proportion of patients with lymphopenia in the pooled dataset to 6% (95% CI 3%-12%; OR 0.33, 95% CI 0.15-0.73; P=0.006).
Female sex was associated with a greater risk of lymphopenia in the Swedish cohort, with the German cohort showing a similar direction. In the pooled analysis, 17% of patients developed lymphopenia (95% CI 14%-20%; OR 1.87; P=0.004).
In the two previously published phase III trials of fingolimod, lymphocyte counts declined to an average of approximately 0.4± 0.26 x 109/L in patients receiving 1.25 mg and 0.5 ±0.31 x 109/L in patients treated at a dosage of 0.5 mg. This drop was not related to the timing of meals and did not appear to be influenced by the use of other medications, such as corticosteroids.
"The relevance of the reduced lymphocyte count remains uncertain, although the absolute lymphocyte count did not correlate with the rate of infections in the phase III studies," the researchers wrote.
In their pooled analysis, 15% of patients developed lymphopenia (below 0.2 x 109/L) during at least one of the approximately 3.2 time points, with patients having low initial lymphocyte counts and underweight women, exhibiting a 2.6- and 3.6-fold increased risk, respectively.
"Pretreatment with glatiramer acetate, based on our statistical analysis, suggested a protective effect in our pooled dataset, with only 6% reaching a lymphocyte nadir of ≤0.2 x 109/L; however, it remains questionable to which extent this mathematical observation mirrors a relevant immunologic effect of glatiramer acetate," Warnke and colleagues wrote.
Potential study limitations cited by the researchers included the low total number of underweight patients (n=13), and an observational period limited to 6- (German) and 24- (Swedish) months.
Despite these possible confounders, the researchers concluded that it may be prudent to monitor patients with low baseline lymphocyte counts and underweight women closely when they are taking fingolimod.
More Study Needed to Confirm Findings
"Our observation may in addition be relevant for patients with childhood MS, in whom clinical efficacy and safety of fingolimod have not yet been established," they wrote.
Warnke and colleagues concluded that larger studies and studies of longer duration are needed to confirm the findings, and National MS Society executive vice president of research Bruce Bebo, PhD, agreed.
In an interview with MedPage Today, Bebo said the research was interesting, but preliminary, and he added that the findings were not too surprising.
"It certainly makes sense that someone who starts off with a lower lymphocyte count would have a greater risk, and it probably isn't all that surprising that someone with low body mass would also be at risk given that they are getting a higher exposure to the medication," he said.
With the FDA's approval last month of the disease-modifying drug alemtuzumab (Lemtrada, Genzyme), patients with relapsing-remitting MS now have about a dozen effective treatments available to them, Bebo said.
About 85% of MS patients have relapsing/remitting disease at the time of diagnosis, but a large percentage eventually develop the progressive form.
"About half of people with MS right now are living with the progressive form of the disease, and it is important to remember that there are no good disease-modifying therapies for progressive MS," he said.
Source : Science Daily (Dec 2014)
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FDA warns about case of rare brain infection PML with MS drug Tecfidera (dimethyl fumarate)
The U.S. Food and Drug Administration (FDA) is warning that a patient with multiple sclerosis (MS) who was being treated with Tecfidera (dimethyl fumarate), developed a rare and serious brain infection called PML, and later died. As a result, information describing this case of PML, or progressive multifocal leukoencephalopathy, is being added to the Tecfidera drug label. Patients taking Tecfidera should contact their health care professionals right away if they experience symptoms that concern them, such as new or worsening weakness; trouble using their arms or legs; or changes to thinking, eyesight, strength or balance. Health care professionals should stop Tecfidera if PML is suspected.
Tecfidera has been shown to benefit patients with relapsing forms of MS. This type of MS causes attacks or relapses – periods of time when symptoms get distinctly worse.
The patient who died was not taking any other drugs that affect the immune system or drugs that are thought to be associated with PML. This is the only confirmed case of this rare and serious brain infection reported in patients taking Tecfidera.
PML is a rare and serious brain infection caused by the John Cunningham (JC) virus. The JC virus is a common virus that is harmless in most people but can cause PML in some patients who have weakened immune systems. Symptoms of PML are diverse and may include progressive weakness on one side of the body, clumsiness, vision problems, confusion, and changes in thinking, personality, memory, and orientation. The progression of deficits can lead to severe disability or death.
The drug manufacturer, Biogen Idec, notified FDA when the MS patient died after developing PML. The patient had taken Tecfidera for more than four years. Prior to developing PML, the patient had a very low number of lymphocytes, a type of white blood cell, in her blood. Reduced lymphocyte counts can weaken the immune system, which increases the risk for PML. It is unknown whether the low lymphocyte count contributed to the development of PML in this patient, or if low lymphocyte counts are a risk factor for PML development in Tecfidera-treated patients.
Source : FDA (November 2014)
FDA Drug Safety Communication: FDA investigating rare brain infection in patient taking Gilenya (fingolimod)
The U.S. Food and Drug Administration (FDA) is alerting the public that a patient in Europe diagnosed with possible multiple sclerosis (MS) has developed a rare and serious brain infection after taking the drug Gilenya (fingolimod). This is the first case of this disease, called progressive multifocal leukoencephalopathy or PML, reported following the administration of Gilenya to a patient who had not previously received Tysabri (natalizumab), an MS drug associated with a higher risk of PML.
Patients should not stop taking Gilenya without first discussing any questions or concerns with their health care professionals. We are providing this alert while we continue to investigate the PML case, and we are working with Gilenya’s manufacturer, Novartis, to obtain and review all available information about this occurrence. We will communicate our final conclusions and recommendations after our evaluation is complete.
PML is a rare and serious brain infection caused by the John Cunningham (JC) virus that damages the fatty covering of the brain called myelin. Myelin is essential for the proper functioning of nerves in the white matter of the brain. PML usually causes death or severe disability. The JC virus is a common virus that is harmless in most people but can cause PML in people who have weakened immune systems. Some medications, including Gilenya, can weaken the immune system.
Gilenya is used to treat relapsing forms of MS, a nervous system disease that affects the brain and spinal cord. MS is thought to affect more than 2 million people worldwide. The drug was approved for use in the United States in September 2010. Novartis reports that approximately 71,000 patients worldwide have been treated with Gilenya.
The patient who developed PML received nearly eight months of Gilenya treatment before being diagnosed with PML. The patient had been treated with interferon beta-1a and azathioprine for one month before initiating Gilenya treatment; those medications were stopped when Gilenya was started. The patient also received multiple courses of intravenous corticosteroids for several months before and during Gilenya treatment. The diagnosis was made based on clinical symptoms and the detection of JC viral DNA in the cerebrospinal fluid. Gilenya treatment was stopped.
Source : FDA (August 2013)
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Two cases of progressive multifocal leukoencephalopathy (PML) in Europe with Fumarate
Two cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients treated with oral dimethyl fumarate, a form of which won FDA approval last month for multiple sclerosis.
One patient in the Netherlands and another in Germany developed PML after several years of treatment with European formulations of the drug, long available as psoriasis treatments, according to two separate case reports in the April 25 issue of the New England Journal of Medicine.
Both patients had psoriasis, although the Dutch patient had developed neurological symptoms leading to a diagnosis of "possible" MS 6 months before PML was detected.
In a response also published in the NEJM, researchers from dimethyl fumarate's U.S. manufacturer, Biogen Idec, said they were aware of two other cases of PML in patients taking drugs containing dimethyl fumarate, both involving its European product sold as Fumaderm.
But they also pointed out that Fumaderm, as well as a compounded product known as Psorinovo -- involved in one of the NEJM reports -- contained other active ingredients, and the patients had additional "significant confounding factors" as well.
PML has been a significant issue for the MS drug natalizumab (Tysabri), with more than 300 PML cases reported worldwide since the drug was approved in 2004. PML has also been reported with rituximab (Rituxan), but in much smaller numbers.
The condition develops when latent JC virus infections become reactivated in patients with certain patterns of immunosuppression. It was first seen in the context of cancer chemotherapy and later in patients with AIDS.
However, PML had not been reported in conjunction with any of the newer oral drugs used in MS until now. In addition to the new FDA-approved formulation of dimethyl fumarate (BG-12, Tecfidera), others include fingolimod (Gilenya) and teriflunomide (Aubagio).
The first of the two PML cases reported in the NEJM involved a 74-year-old man in Germany who had received Fumaderm, which consists of dimethyl fumarate plus monoethyl fumarate, for 3 years before neurological symptoms consistent with PML developed in 2010.
In the second case, a 42-year-old Dutch woman with psoriasis had been treated for 5 years with Psorinovo from a compounding pharmacy when PML was detected in November 2012. Beginning in May of that year, the woman had developed progressive right-side hemiparesis that had been diagnosed as possible MS.
In both cases, PML was diagnosed on the basis of MRI scans and detection of JC virus in cerebrospinal fluid, following long periods of serious lymphopenia. Other causes such as HIV infection were ruled out. Both patients recovered after the fumarate drugs were stopped.
Jörg Schultz, MD, of Rheinisch-Westfälisch Technische Hochschule Aachen in Germany, and colleagues, noted that their patient had received a variety of other drugs including acitretin and methotrexate prior to initiating Fumaderm therapy.
The Dutch woman had not received other immunosuppressive drugs, according to Bob W. van Oosten, MD, PhD, of VU University Medical Center in Amsterdam, and colleagues. But Psorinovo contained copper gluconate as an additive until 2010.
Biogen Idec researchers led by Marianne Sweetser, MD, PhD, argued in their response that the other compounds administered along with dimethyl fumarate complicate the interpretation of these cases.
That was also true in the other two cases of PML seen previously in conjunction with Fumaderm. One of those patients was also on methotrexate and steroids, while the other had been taking efalizumab, another drug connected to PML.
Sweetser and colleagues commented that, overall, PML has been rare in patients receiving dimethyl fumarate-containing drugs, "on the basis of more than 180,000 patient-years of experience with Fumaderm."
They also pointed to the fact that both cases in the NEJM reports involved long periods of lymphopenia prior to development of PML.
"Severe lymphopenia is a [known] risk factor for PML and can be mitigated through the periodic monitoring of lymphocytes," they wrote.
Finally, Sweetser and colleagues noted that no cases of PML have been seen with the U.S.-approved formulation, which has no active ingredients other than dimethyl fumarate. "More than 2,600 patients with MS have been treated for periods of up to 4 years or more, with a median follow-up of approximately 2 years," they wrote, with lymphocyte reductions of about 30% from baseline typically seen.
Source : MedPage Today
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MS Patient Dies From Anti-Drug Antibodies
A reaction to anti-natalizumab (Tysabri) antibodies appears to have killed a Swedish woman with multiple sclerosis who received the drug, researchers said.
Significant neurological abnormalities developed after she had received six infusions of natalizumab, and her doctors found that she had extremely high titers of antibodies against the drug, reported Anders Svenningsson, MD, PhD, of Umeå University in Sweden, and colleagues.
Seven months after starting on the drug, she was dead, the researchers wrote online in Neurology. Her physicians ruled out progressive multifocal leukoencephalopathy (PML), a known and frequently fatal side effect of natalizumab therapy.
Svenningsson and colleagues concluded that her death resulted from "rebound neuroinflammation as a result of the development of natalizumab anti-drug antibodies."
Noteworthy was that the patient had shown unusual reactions to the drug starting with the fourth infusion, including chills and fever, they suggested.
"We recommend that repeated moderate to severe infusion reactions in the beginning of natalizumab treatment should prompt the cessation of treatment and assessment for the development of natalizumab anti-drug antibodies," Svenningsson and colleagues wrote.
The patient was first diagnosed with MS in 2001 when she was 32. She was initially treated with interferon-beta-1a, but was switched to natalizumab in November 2007 when MRI scans showed growth in brain lesions. Because the scans did not show contrast enhancement, her doctors determined that her blood-brain barrier remained intact.
Natalizumab was given at the standard dose of 300 mg every 4 weeks by infusion.
The chills and fever that started with the fourth treatment became progressively more severe with subsequent infusions, the researchers indicated. After the sixth, she developed progressive gait abnormalities, ataxia, and significant mental deterioration.
MRI scans showed new hyperintense T2 lesions as well as multiple areas of contrast enhancement. Molecular tests of the patient's cerebrospinal fluid for the JC virus were negative, arguing against PML, which is caused by reactivation of latent JC virus infection.
At that point, she was transferred to a regional hospital. Her disability level progressed to 9 on the EDSS scale, compared with a level of 3 when she started on natalizumab. She was unable to get out of bed and was uncommunicative.
Another MRI scan showed additional contrast-enhancing lesion growth. Brain biopsy results were consistent with acute MS inflammation, Svenningsson and colleagues reported, "with infiltrating activated macrophages as well as signs of blood-brain barrier breakdown."
Most important, anti-natalizumab antibodies were found at a level of 335 mg/L, "among the highest recorded among anti-drug antibody positive patients identified in Sweden," the researchers indicated. The antibodies were predominantly of the IgG3 complement-fixing class.
The woman underwent plasmapheresis and her doctors wanted to perform an autologous stem cell transplant, but her condition was too poor for that, and she died in June 2008.
Autopsy findings showed no evidence of infectious pathogens in the central nervous system. The conclusion was that acute MS inflammation was the cause of her symptoms and eventual death.
Svenningsson and colleagues considered the possibility that the anti-natalizumab antibodies had triggered an anti-idiotype reaction, which could have led to an autoimmune attack on ligands of VLA-4, VCAM-1, and fibronectin. But in vitro studies using serum samples from the patient showed no signs of anti-idiotype reactivity.
Other clinicians have reported cases in which patients worsened while on natalizumab or who showed severe relapses after stopping the drug, Svenningsson and colleagues said, but their case was unusual in its fatal outcome.
Source : MedPage Today
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FDA Drug Safety Communication: Seizure risk for multiple sclerosis patients who take Ampyra (dalfampridine)
The U.S. Food and Drug Administration (FDA) is updating health care professionals and the public about the risk of seizures in patients with multiple sclerosis (MS) who are starting Ampyra (dalfampridine). Using information received from post-market adverse event reports, FDA recently evaluated seizure risk in MS patients taking Ampyra (dalfampridine). The majority of seizures happened within days to weeks after starting the recommended dose and occurred in patients having no history of seizures (see Data Summary).
In addition, FDA is updating the Ampyra drug label to clarify recommendations that kidney function should be checked in patients before starting Ampyra and monitored at least annually while Ampyra treatment continues. Additionally, patients who miss a dose should not take extra doses—an extra dose of Ampyra can increase seizure risk.
Seizures are a known side effect of Ampyra, and seizure risk increases with higher blood levels of the drug. Ampyra is eliminated from the body through the kidneys, and patients with kidney impairment may develop higher blood levels of the drug, thereby increasing their seizure risk. Ampyra should not be used in patients with a history of seizures or who have moderate to severe renal (kidney) impairment (measured as creatinine clearance [CrCl] less than or equal to 50 mL/min).
In patients with mild renal impairment (CrCl 51-80 mL/min), the blood levels of Ampyra may reach levels associated with increased seizure risk. Therefore for patients with mild renal impairment, the use of Ampyra requires careful consideration of the potential benefits of treatment as well as the potential risk of seizure.
FDA reminds health care professionals that there are age-related decreases in renal function, and mild renal impairment is common after age 50, even when serum creatinine is normal. Renal function should be assessed by estimating creatinine clearance (see Data Summary).
Additional Information for Patients
- Ampyra can cause seizures, even if you have never had a seizure before.
- Stop taking Ampyra and call your doctor right away if you have a seizure.
- The chance of having a seizure is higher if you take too much Ampyra or if your kidneys have decreased function. Loss of some kidney function is common after age 50.
- Tell your health care professional if you have kidney problems.
- Your health care professional should order blood tests periodically to evaluate your kidney function.
- Do not take Ampyra if you have ever had a seizure.
- Read the Medication Guide that comes with your Ampyra prescription.
- Ampyra tablets should be taken whole and not divided, crushed, chewed, or dissolved.
- Do not take double or extra doses of Ampyra if a dose is missed. Side effects, including seizures, are more frequent at higher doses.
- Discuss any questions you have about Ampyra with your health care professional.
- Report any side effects you experience to the FDA MedWatch program using the information in the “Contact FDA” box at the bottom of the page.
- Ampyra is contraindicated in patients with a history of seizures or with moderate to severe renal impairment (CrCl < 50 mL/min).
- Mild renal impairment is common after age 50.
- The potential benefits of Ampyra treatment should be carefully considered against the risk of seizures before using Ampyra in patients with mild renal impairment (CrCl 51-80 mL/min).
- Most of the seizures reported with Ampyra treatment occurred in patients without a history of seizures.
- A patient’s CrCl (calculated using the Cockroft-Gault equation) should be known before initiating Ampyra treatment and monitored at least annually while Ampyra treatment continues, even when serum creatinine levels appear to be normal.
- The maximum recommended dose of Ampyra is 10 mg twice daily (taken 12 hours apart). Ampyra tablets should be taken whole and not divided, crushed, chewed, or dissolved.
- Tell patients they should not take double or extra doses of Ampyra if a dose is missed. Adverse effects, including seizures, are more frequent at higher doses.
- Ampyra should be discontinued permanently if a seizure occurs.
- Report adverse events involving Ampyra to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.
Seizures are a known side effect of Ampyra, and seizure risk increases with higher blood levels of the drug. Using information from FDA’s Adverse Event Reporting System (AERS), FDA further evaluated the risk of seizures in MS patients taking Ampyra (dalfampridine). FDA’s analysis identified postmarketing case reports of seizures associated with Ampyra at the labeled recommended dose, with many cases of seizures occurring within the first week of starting Ampyra. The vast majority of seizures occurred in patients without a prior history of seizures. Some patients had been taking other drugs that could have increased the risk of seizures or lowered the seizure threshold. Potentially, age-related renal dysfunction and resultant increases in Ampyra plasma concentrations contributed to the risk of seizure.
Mild renal impairment is common after age 50, even when serum creatinine levels are in the normal range. FDA noted that most patients who experienced a seizure were at least 50 years old and were at risk for mild age-related renal impairment. In patients with mild renal impairment (CrCl 51-80 mL/min), the blood levels of Ampyra may reach levels that have been associated with an increased risk of seizures. The potential benefits of Ampyra treatment must therefore be carefully considered against the potential risk of seizures before using Ampyra in patients with mild renal impairment.
Before starting treatment with Ampyra, renal function should be assessed; if CrCl is unknown, it can be estimated using the Cockcroft-Gault equation (multiplied by 0.85 for women)
Patients with a creatinine clearance between 51-80 mL/min are considered to have mild renal impairment and are at a greater risk of seizure when taking Ampyra. Use of Ampyra remains contraindicated in patients with a creatinine clearance ≤ 50 mL/min.
- Acorda Therapeutics, Response to FDA's Information Request dated July 11, 2012, Submitted on July 11, 2012.
Facts about (Ampyra) dalfampridine
- Approved January 22, 2010, to improve walking in patients with MS; Approval was based on increased walking speed.
- Although the mechanism of action in MS patients is not fully understood, studies in animals show increased neuronal activity in response to the drug.
- According to Acorda (manufacturer of Ampyra), approximately 46,000 patients received prescriptions for Ampyra between March 2010 and March 2011.1
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FDA Drug Safety Communication: Revised recommendations for cardiovascular monitoring and use of multiple sclerosis drug Gilenya (fingolimod)
The U.S. Food and Drug Administration (FDA) has completed its evaluation of a report of a patient who died after the first dose of multiple sclerosis drug Gilenya (fingolimod). The agency also has evaluated additional clinical trial and postmarket data for Gilenya, including reports of patients who died of cardiovascular events or unknown causes. FDA could not definitively conclude that Gilenya was related to any of the deaths (see Data Summary, below). However, based on its reevaluation of the data, FDA remains concerned about the cardiovascular effects of Gilenya after the first dose. Data show that, although the maximum heart rate lowering effect of Gilenya usually occurs within 6 hours of the first dose, the maximum effect may occur as late as 20 hours after the first dose in some patients (See Data Summary). For this reason, Gilenya is now contraindicated (FDA advises against its use) in patients with certain pre-existing or recent (within last 6 months) heart conditions or stroke, or who are taking certain antiarrhythmic medications. See CONTRAINDICATION section of the drug label.
FDA continues to recommend that all patients starting Gilenya be monitored for signs of a slow heart rate (bradycardia) for at least 6 hours after the first dose. FDA is now recommending hourly pulse and blood pressure measurement for all patients starting Gilenya. Electrocardiogram (ECG or EKG) testing should be performed prior to dosing and at the end of the observation period. Cardiovascular monitoring should continue until any symptoms resolve.
In addition, FDA is now also recommending that the time of cardiovascular monitoring be extended past 6 hours in patients who are at higher risk for or who may not tolerate bradycardia. Extended monitoring should include continuous ECG monitoring that continues overnight. See DOSAGE AND ADMINISTRATION section of the drug label. These higher risk patients include those:
- Who develop severe bradycardia after administration of the first dose of Gilenya
- With certain pre-existing conditions in whom bradycardia may be poorly tolerated
- Receiving therapy with other drugs that slow the heart rate or atrioventricular conduction
- With QT interval prolongation (a type of heart rhythm abnormality) prior to starting Gilenya, or at any time during the cardiovascular monitoring period
- Receiving therapy with other drugs that prolong the QT interval and that can cause a serious and life-threatening abnormal heart rhythm called Torsades de pointes
Patients should not stop taking Gilenya without talking to their healthcare professional. They should contact their healthcare professional and seek immediate care if they develop dizziness, tiredness, irregular heart beat, or palpitations--signs of a slowing heart rate. FDA continues to believe that the benefits of treatment with Gilenya outweigh its potential risks when it is used as described in the updated drug label.
FDA will update the public if any additional information on the cardiovascular risks of Gilenya becomes available.
Data Summary In December 2011, FDA issued a Drug Safety Communication (DSC) concerning a patient with multiple sclerosis (MS) who died within 24 hours of taking the first dose of Gilenya (fingolimod). Based on the reported information, a cause of death could not be identified. The patient also had extensive brainstem MS lesions; such lesions have been associated with sudden death. The patient was also taking two blood pressure medications (metoprolol and amlodipine), which can also affect heart rate; whether they could have played a role in the patient’s death is unknown. On the basis of the available data, a link between the first dose of Gilenya and the patient’s death could not be ruled out, however, there is not clear evidence that the drug played any role in the death.
After receipt of this case, FDA re-evaluated clinical trial data related to the effects of Gilenya on heart rate and blood pressure, including data from trials that were ongoing at the time the drug was approved by FDA. Analyses of changes in heart rate by 24 hour Holter monitoring confirmed that the heart rate-lowering effect of Gilenya is biphasic, with an initial decrease within 6 hours, and a second decrease, in part related to a circadian rhythm, around 12 to 20 hours post-dose. In order to allow an adequate response to possible severe symptomatic bradycardia in the 6- to 24-hour period after the first dose, FDA concluded that it would be prudent to extend the monitoring period beyond 6 hours in patients who experience a heart rate of less than 45 beats per minute in the first 6 hours, or in those who had their lowest heart rate at 6 hours post-dose, as further bradycardia is still possible after 6 hours. In addition, in order to reduce the risks related to bradycardia or atrioventricular block, extended monitoring is now recommended in patients with certain pre-existing conditions, such as QT prolongation, and in patients receiving concurrent drugs that slow the heart rate or atrioventricular conduction.
FDA also reviewed postmarket data reported for Gilenya, including other deaths from apparent cardiovascular origin or of unknown origin. For each of these deaths, Gilenya’s contribution to the death was unclear. The number of deaths of apparent cardiovascular origin or of unknown origin does not appear to be higher than in MS patients not treated with Gilenya.
In light of the findings of the clinical trial data and postmarketing data, including all reported deaths of cardiovascular or unknown origin, FDA has revised the Gilenya drug label with specific recommendations for monitoring patients and with new contraindications for use of Gilenya in certain patients.
FDA will communicate any important new information about the cardiovascular safety of Gilenya when it becomes available.
Source : FDA
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FDA Drug Safety Communication: New risk factor for Progressive Multifocal Leukoencephalopathy (PML) associated with Tysabri (natalizumab)
The U.S. Food and Drug Administration (FDA) is informing the public that testing positive for anti-JC virus (JCV) antibodies has been identified as a risk factor for progressive multifocal leukoencephalopathy (PML). PML is a rare but serious brain infection associated with use of Tysabri (natalizumab) for the treatment of multiple sclerosis (MS) or Crohn's disease.
The risks and benefits of continuing treatment with Tysabri should be carefully considered in patients who are found to be anti-JCV antibody positive and have one or more of the other known risk factors for PML. Patients with all three known risk factors have an estimated risk of PML of 11/1,000 users. The risk factors are:
- The presence of anti-JCV antibodies.
- Longer duration of Tysabri treatment, especially beyond 2 years.
- Prior treatment with an immunosuppressant medication (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, or mycophenolate mofetil).
A patient's anti-JCV antibody status may be determined using an anti-JCV antibody detection test that has been analytically and clinically validated, and has been ordered by a healthcare professional. The Stratify JCV Antibody ELISA test was cleared by FDA on January 20, 2012. Testing positive for anti-JCV antibodies means that a person has been exposed to JCV in the past.
PML is a rare disorder in which the coating (myelin) of some brain nerve fibers gets damaged. Although JCV is a common virus that is generally harmless and does not cause symptoms in people whose immune systems function normally, it can cause PML in people with weakened immune systems. Causes of a weakened immune system may include human immunodeficiency virus (HIV) infection, leukemia or lymphoma, or taking a medication such as Tysabri.
The FDA issued two previous Drug Safety Communications (DSCs) on the risk of PML with the use of Tysabri on February 5, 2010 and on April 22, 2011.
Additional Information for Patients
- As a result of this new information, your healthcare professional may recommend a blood test to see if you have ever been exposed to JCV, the virus that causes PML. This test measures antibodies to the virus, which are often referred to as "anti-JCV antibodies."
- The risk of developing PML increases if you have tested positive for anti-JCV antibodies and have one or two of the other known risk factors.
- The risk of PML is greatest if you have all three known risk factors.
- Discuss any questions or concerns about Tysabri and the risk of PML with your healthcare professional.
- Report any side effects you experience to your healthcare professional and the FDA MedWatch program using the information in the "Contact Us" box at the bottom of the page.
- Inform your patients that PML continues to occur in patients treated with Tysabri.
- The Tysabri label has been updated with information about a newly identified third risk factor for PML (see Data Summary).
- For purposes of risk assessment, a patient with a positive anti-JCV antibody test at any time is considered to be anti-JCV antibody positive regardless of the results of any prior or subsequent anti-JCV antibody test.
- Consideration should be given to testing patients prior to treatment or during treatment if antibody status is unknown.
- Patients who test negative for anti-JCV antibodies are still at risk for the development of PML due to the potential for a new JCV infection or a false negative test result. Consideration should be given to periodic re-testing of patients previously determined to be anti-JCV antibody negative.
- When assessed, anti-JCV antibody status should be determined using an analytically and clinically validated immunoassay.
- Tell your patients to contact you if they develop any symptoms suggestive of PML. Symptoms of PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory and orientation, leading to confusion and personality changes. The progression of deficits can lead to death or severe disability over weeks or months.
- Monitor your patients and withhold Tysabri immediately at the first sign or symptom of PML.
- Report adverse events involving Tysabri to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of the page.
201 cases of PML have been reported among approximately 96,582 patients treated with Tysabri worldwide through January 4, 2012.
New data have identified the presence of anti-JCV antibodies as a risk factor for developing PML in Tysabri-treated patients. The Stratify JCV Antibody ELISA test, which can detect these antibodies, was cleared by FDA on January 20, 2012.
The risks and benefits of continuing treatment with Tysabri should be carefully considered in patients who are found to be anti-JCV antibody positive and have one or more additional risk factors. Patients with all three known risk factors have an estimated risk of PML of 11/1,000. (See Table 1).
The PML incidence information in Table 1 below is being added to the Tysabri label:
Table 1: Estimated PML Incidence Stratified by Risk Factor
Anti-JCV Antibody Positive* Anti-JCV Antibody Positive* Tysabri Exposure† No Prior Immunosuppressant Use Prior Immunosuppressant Use 1-24 months <1/1,000 2/1,000 25-48 months 4/1,000 11/1,000
Notes: Based on postmarketing PML data and Tysabri use data as of September 1, 2011.
†Data beyond 4 years of treatment are limited.
* Risk in anti-JCV antibody positive patients was estimated based on the assumptions that 18% of Tysabri-treated MS patients have a history of prior immunosuppressant treatment and that 55% of Tysabri-treated MS patients are anti-JCV antibody positive.
* The anti-JCV antibody status was determined using an anti-JCV antibody test (ELISA) that has been analytically and clinically validated and is configured with detection and inhibition steps to confirm the presence of JCV-specific antibodies with a false negative rate of 3%.
FDA continues to evaluate the reports of PML and consider new ways to help patients and healthcare professionals understand the risk.
- U.S. National Library of Medicine. National Institutes of Health. Health Topics-Progressive multifocal leukoencephalopathy. Available at http://www.nlm.nih.gov/medlineplus/ency/article/000674.htm Accessed January 11, 2012.
Source : FDA (January 2012)
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FDA Drug Safety Communication: Safety review of a reported death after the first dose of Multiple Sclerosis drug Gilenya (fingolimod)
[12-20-2011] The U.S. Food and Drug Administration (FDA) has received a report of a patient with multiple sclerosis (MS) who died within 24 hours of taking the first dose of Gilenya (fingolimod). At this time, FDA cannot conclude whether the drug resulted in the patient's death. FDA is continuing to evaluate the case and will communicate any new information that results from this investigation.
.At this time, FDA continues to believe that Gilenya provides an important health benefit when used as directed and recommends that healthcare professionals who prescribe Gilenya follow the recommendations in the approved drug label (See Additional Information for Healthcare Professionals).
Patients with MS should not stop taking Gilenya without talking to their healthcare professional.
FDA will communicate any new information on Gilenya and this case when it becomes available.
Additional Information for Patients
- Gilenya may cause serious side effects, such as slow heart rate (bradycardia), which may be related to slowed conduction of electrical impulses from the upper chambers of the heart to the lower chambers of the heart. These effects usually do not cause symptoms, but they can cause dizziness, fatigue, and palpitations.
- A slowing of the heart rate due to Gilenya mostly occurs after the first dose, and your heart rate usually returns to normal within 1 month after you start taking the drug.
- Call your healthcare professional and seek immediate care if you develop any signs or symptoms of slow heart rate such as
- Slow or irregular heart beat or palpitations
- Discuss any questions or concerns about Gilenya with your healthcare professional.
- Report any side effects you experience to your healthcare professional and the FDA MedWatch program using the information in the "Contact Us" box at the bottom of the page.
- If you prescribe Gilenya, carefully follow the recommendations in the Gilenya drug label.
- Observe all patients for signs and symptoms of bradycardia for 6 hours after the first dose.
- Obtain a baseline ECG before the first dose if one was not recently performed for those patients at higher risk of bradyarrhythmias.
- Gilenya has not been studied in patients with ischemic heart disease, congestive heart failure, second degree or higher conduction block, sick sinus syndrome, or prolonged QT interval. Gilenya has not been studied with concomitant use of Class Ia or Class III antiarrhythmic agents. These patients, as well as patients receiving beta blockers, calcium channel blockers, and those with a low heart rate or history of syncope, are at increased risk of developing bradycardia and conduction block. Carefully monitor these patients during initiation of therapy.
- If Gilenya therapy is discontinued for more than two weeks, the effects on heart rate and atrioventricular (AV) conduction may recur on reintroduction of Gilenya treatment and the same precautions and monitoring as for initial dosing should be followed.
- Make sure your patients know the signs and symptoms of bradycardia and when to seek care.
- Report adverse events involving Gilenya to the FDA MedWatch program, using the information in the “Contact Us” box at the bottom of the page.
FDA is evaluating a post-marketing report submitted to FDA's Adverse Events Reporting System (AERS) database regarding a patient who died within 24 hours of taking the first dose of Gilenya (fingolimod). The patient was also treated with metoprolol, a beta blocker, and amlodipine, a calcium channel blocker. The patient had completed 6 hours of monitoring after the first dose without incident, but died less than 24 hours after the first dose. The exact cause of death has not been established. FDA is working closely with the manufacturer of Gilenya (Novartis Pharmaceuticals) to evaluate the post-market report of death.
Gilenya has several known side effects which include a decrease in heart rate and/or atrioventricular conduction after the first dose. Patients receiving Class Ia or Class III antiarrhythmic drugs, beta blockers, calcium channel blockers, those with a low heart rate, history of syncope, sick sinus syndrome, 2nd degree or higher conduction block, ischemic heart disease, or congestive heart failure are at increased risk of developing bradycardia or heart blocks. [See the Gilenya drug label for complete information on Warnings and Precautions]
At this time, FDA believes the benefits of Gilenya continue to exceed the potential risks when the drug is used appropriately as described in the approved drug label. FDA recommends that healthcare professionals continue to prescribe Gilenya following the recommendations in the drug label.
Facts about Gilenya (fingolimod)
- An oral medication for the treatment of relapsing forms of Multiple Sclerosis (MS) in adults.
- Used to reduce the frequency of flare-ups (clinical exacerbations) and delay physical disability.
- Available as 0.5 mg oral capsules.
Source : FDA
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