- ACRONYMS
- AAN - American Academy of Neurology
- AV - Atrioventricular
- CSF - Cerebrospinal fluid
- CIS - Clinically isolated syndrome
- CNS - Central nervous system (brain and spinal cord)
- DIS - Dissemination in space
- DIT - Dissemination in time
- DMT - Disease-modifying therapy
- EAN - European Academy of Neurology
- ECTRIMS - European Committee for Treatment and Research in Multiple Sclerosis
- HSCT - Haematopoietic stem cell transplant
- JCV - John Cunningham virus
- MRI - Magnetic resonance imaging
- MS - Multiple sclerosis
- Nrf2 - Nuclear factor (erythroid-derived 2)-like 2
- PML - Progressive multifocal leukoencephalopathy
- PP - Primary progressive
- RR - Relapsing-remitting
- SP - Secondary progressive
- UC - Ulcerative colitis
- ULN - Upper limit of normal
- DEFINITIONS
- Clinically isolated syndrome (CIS) - a single episode lasting at least 24 hours that includes MRI findings of a demyelinating event and objective clinicalsymptoms that coincide with those findings. If the patient goes on to have another event and is diagnosed with MS, then the clinically isolated event becomes the patient's first MS attack.In studies lasting up to 20 years, 65 - 80% of patients with a CIS and an abnormal baseline MRI have gone on to be diagnosed with MS.
- Dissemination in space (DIS) - the development of demyelinating lesions during a single attack in at least two of the four regions that are characteristic for MS. The four areas that are characteristic for MS include periventricular, cortical or juxtacortical, infratentorial, and the spinal cord.
- Dissemination in time (DIT) - the development of demyelinating lesions during two distinctly different time periods. DIT can be demonstrated by new lesions appearing on a follow-up MRI or by the presence of gadolinium-enhancing and nonenhancing lesions on the same MRI. New MS lesions typically enhance for 2 - 6 weeks before they become non-enhancing lesions; therefore, the presence of enhancing and nonenhancing lesions on the same MRI indicates DIT.
- Myelin - lipid-rich substance produced and maintained by oligodendrocytes in the CNS. Myelin forms an insulating sheath around neuronal axons that increases the speed of nerve conduction. In MS, the myelin sheath is destroyed by autoimmune inflammation.
- Primary progressive MS - MS that is characterized by objective neurologic disability that continues to progress over time independent of relapses and remissions. In primary progressive MS, progressive disability begins with the onset of MS compared to secondary progressive MS where progressive disability occurs after a period of relapsing-remitting MS. About 10 - 15% of patients diagnosed with MS have the primary progressive type.
- Radiologically isolated syndrome - MRI findings consistent with MS in a patient who has no neurologic symptoms. About 34% of patients with radiologically isolated syndrome will go on to develop clinically isolated syndrome or MS over the next 5 years.
- Relapsing-remitting MS - most common type of MS (85 - 90% of patients). It is marked by MS attacks lasting at least 24 hours that are followed by periods of stable remission that can last weeks to years. Recovery from relapses is variable and residual disability may persist. About 15 - 30% of patients with relapsing-remitting MS will go on to develop secondary progressive MS, although treatment with disease-modifying drugs lowers the risk to around 11% over a ten-year period
- Secondary progressive MS - MS that is characterized by objective neurologic disability that continues to progress over time independent of relapses and remissions. In secondary progressive MS, progressive disability develops after a period of relapsing-remitting MS which typically lasts 10 - 15 years. About 15 - 30% of patients with relapsing-remitting MS will go on to develop secondary progressive MS, although treatment with disease-modifying drugs lowers the risk to around 11% over a ten-year period.
- T2-hyperintense lesion - MRI finding that is typical for MS lesions. T2-hyperintensities occur in areas of demyelination and axonal loss.
- White matter - areas of the brain that are primarily made up of myelinated axons. In a dissected brain, white matter appears lighter because it is full of myelin which is lipid-rich. Grey matter is primarily made of cell bodies and appears darker. [1,2,3,4,5,6]
- EPIDEMIOLOGY
- The prevalence of MS is between 50 - 300 cases per 100,000 people. It is estimated that 2.3 million people in the world have MS with at least 400,000 people in the U.S. being affected.
- The estimated lifetime risk of MS in the general population is around 0.1%
- MS is one of the most common causes of serious physical disability in working adults [5,6,8]
- RISK FACTORS
- Female sex - around 75% of patients diagnosed with MS are female
- Age
- Relapsing remitting MS has a mean age of onset of 30 years
- Primary progressive MS has a mean age of onset of 40 years
- Family history
- People with an affected first-degree relative have 2 - 4% lifetime risk
- Monozygotic twins have 30 - 50% concordance
- White race - whites have a higher prevalence than other races
- Northern latitudes - risk increases with higher latitudes
- Genetics (HLA-DR15 and HLA-DR16)
- Vitamin D deficiency
- Obesity
- Cigarette smoking
- Epstein-Barr virus infection [5,6,8,23,24]
- PATHOPHYSIOLOGY
- Overview
- The precise cause of MS is unknown. It is believed to occur from the autoimmune destruction of myelin sheaths that surround the axons of nerve cells in the CNS. Over time, demyelination leads to axonal degeneration and neuronal loss. In some cases, remyelination can occur.
- The stimulus for autoimmunity in MS has not been confirmed but it is believed to be caused by an interplay of genetic and environmental factors. Because MS pathology only occurs in the CNS, two theories have arisen that attempt to explain its origin. In the intrinsic model, an initial event is believed to occur in the CNS that leads to the release of CNS antigens into the periphery where they stimulate an autoimmune response against the CNS. In the extrinsic model, an initial event takes place outside the CNS that leads to an autoimmune attack against the CNS.
- Demyelinating lesions appear as hyperintense white areas on T2-weighted MRI images
- MS lesions are typically found in the following areas:
- Periventricular - next to the lateral ventricles
- Juxtacortical - next to the cerebral cortex
- Infratentorial - area of the brain below the tentorium cerebelli that includes the brainstem, cerebellum, pons, and medulla
- Optic nerve - nerve that connects the retina to the brain
- Spinal cord - cervical cord is most often affected [1,5,6,8]
- The first two images below show examples of periventricular and juxtacortical lesions on transverse MRI images. The third image shows examples of infratentorial, optic nerve, and spinal cord lesions.
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- SYMPTOMS
- Overview
- Patients with MS typically develop symptoms in their late twenties to early thirties. Presenting symptoms typically have an acute onset (hours to days) and are dependent on the area of the CNS that is affected. Maximum deficit typically occurs within 4 weeks of onset and is followed by spontaneous remission.
- Common neurologic symptoms seen in MS
- Unilateral optic neuritis - symptoms include visual impairment, visual abnormalities (e.g. flashing lights, rings of light), and pain on eye movement
- Double vision - caused by brainstem lesions that affect conjugate gaze
- Facial numbness or paresthesia
- Loss of motor coordination (ataxia) - indicative of cerebellar lesions
- Partial myelopathy - spinal cord symptoms (e.g. limb weakness, numbness, or paresthesia) that only affect one side of the body
- Lhermitte's sign - sudden sensation of electric shock that runs down the spine and sometimes into the extremities that is usually triggered by bending the head forward
- Urinary urge incontinence
- Erectile dysfunction [1,5,6]
- DIAGNOSIS
- Overview
- The diagnosis of MS is based on a combination of clinical findings and MRI findings. In some cases, CSF-specific oligoclonal bands may also be a part of the diagnosis.
- A number of other conditions can mimic findings in MS (see differential below) so it is important to make the correct diagnosis in order to initiate prompt and appropriate treatment. The McDonald criteria which were last updated in 2017 are the primary tool used to establish a diagnosis of MS.
- Magnetic resonance imaging (MRI)
- Brain MRI findings are the primary tool used to diagnose MS. MS lesions are characterized as T2-hyperintensities that occur in areas of demyelination and axonal loss. MS lesions are typically seen in the following areas: periventricualr, juxtacortical, infratentorial, optic nerve, and spinal cord (see pathophysiology above).
- Lesions should be classified as those that are consistent with objective clinical findings and those that are not
- The terms below are used to characterize MRI lesions in MS
- Clinically isolated syndrome (CIS) - a single episode lasting at least 24 hours that includes MRI findings of a demyelinating event and objective clinicalsymptoms that coincide with those findings. If the patient goes on to have another event and is diagnosed with MS, then the clinically isolated event becomes the patient's first MS attack.In studies lasting up to 20 years, 65 - 80% of patients with a CIS and an abnormal baseline MRI have gone on to be diagnosed with MS.
- Dissemination in space (DIS) - the development of demyelinating lesions during a single attack in at least two of the four regions that are characteristic for MS. The four areas that are characteristic for MS include periventricular, cortical or juxtacortical, infratentorial, and the spinal cord (see pathophysiology above).
- Dissemination in time (DIT) - the development of demyelinating lesions during two distinctly different time periods. DIT can be demonstrated by new lesions appearing on a follow-up MRI or by the presence of gadolinium-enhancing and nonenhancing lesions on the same MRI. New MS lesions typically enhance for 2 - 6 weeks before they become nonenhancing lesions; therefore, the presence of enhancing and nonenhancing lesions on the same MRI indicates DIT.
- Radiologically isolated syndrome - MRI findings consistent with MS in a patient who has no neurologic symptoms. About 34% of patients with radiologically isolated syndrome will go on to develop clinically isolated syndrome or MS over the next 5 years. [1,2,3,4,5,6]
- Oligoclonal bands
- The only laboratory used in the diagnosis of MS is CSF-specific oligoclonal bands. CSF-specific oligoclonal bands are defined as antibodies (typically IgG) that are produced specifically in the CNS. In order to detect oligoclonal bands, cerebrospinal fluid (CSF) and serum must both be obtained. Electrophoresis is then performed on both samples and proteins including immunoglobulins are separated out. The difference in antibodies between the two samples is then compared. If immunoglobulin-secreting B-cells and plasma cells are active in the CNS and not the periphery, then bands of immunoglobulins will appear on the CSF sample that are not present on the serum sample. These bands are referred to as "oligoclonal bands," and the presence of two or more bands is considered a positive test. Oligoclonal bands are present in about 90% of patients with MS, but they are not specific for the disease.
2017 McDonald Criteria for Diagnosing MS | ||
---|---|---|
# of clinical attacks | MRI lesions with objective clinical findings✝ | Additional diagnostic criteria necessary for MS diagnosis |
≥ 2 | ≥ 2 | None |
≥ 2 | 1 along with clear-cut historical evidence of a previous attack involving a lesion in a distinct anatomical location | None |
≥ 2 | 1 |
One of the following:
|
1 | ≥ 2 |
One of the following:
|
1 | 1 |
DIS on MRI and one of the following:
|
2017 McDonald Criteria for Diagnosing Primary Progressive MS |
---|
Primary progressive MS can be diagnosed in patients with 1 year of progressive disability (retrospectively or prospectively determined) independent of clinical relapse who meet two of the following criteria:
|
- DIFFERENTIAL
- Overview
- The differential diagnosis for MS is broad and given the lifelong implications of an MS diagnosis, careful consideration of other conditions should be made. In some studies, misdiagnosis of MS has been as high as 10%.
- The table below lists some other conditions that can mimic MS. Most of these conditions are rare or represent uncommon sequelae of other diseases.
MS differential | |
---|---|
Condition | Comment |
Acute disseminated encephalomyelitis |
|
Neuromyelitis optica spectrum disorder |
|
Neurosarcoidosis |
|
CNS vasculitis |
|
CNS hypoxic events |
|
Susac's syndrome |
|
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) |
|
Connective tissue diseases |
|
Neuro-Behcet's disease |
|
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) |
|
Fabry's disease |
|
- CLINICAL COURSE AND PROGNOSIS
- Overview
- The clinical course of MS is highly variable with most patients experiencing attacks followed by periods of stabilization while others have progressive disability from the onset
- New disease-modifying therapies have been effective in improving outcomes in relapsing-remitting MS, but less options are available for primary progressive MS
- The table below gives some guidance on the typical clinical course of MS and its related syndromes along with prognostic factors that may be helpful in predicting disease progression
- TREATMENT
- Overview
- In 1993, interferon beta became the first drug approved for the treatment of MS. Since that time, MS treatment has evolved rapidly. There are currently 9 distinct drugs that are approved to treat MS in the U.S.
- In 2018, the AAN and the EAN/ECTRIMS issued guidelines on the treatment of MS. The guidelines offer some guidance on choosing medications, but in general, only make broad recommendations. The recommendations in the tables below are derived from a combination of the AAN and EAN/ECTRIMS recommendations along with review articles that give expert opinion.
Clinically Isolated Syndrome (CIS) Treatment Recommendations |
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AAN recommendations
EAN/ECTRIMS recommendations
Studies in CIS
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Relapsing-remitting MS Treatment Recommendations |
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AAN recommendations
EAN/ECTRIMS recommendations
Expert opinion recommendations
|
Primary Progressive MS Treatment Recommendations |
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AAN recommendations
EAN/ECTRIMS recommendations
Studies in primary progressive MS
|
Secondary Progressive MS Treatment Recommendations |
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AAN recommendations
EAN/ECTRIMS recommendations
|
Monitoring Therapy Recommendations |
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AAN recommendations
EAN/ECTRIMS recommendations
|
Therapy Failure / Intolerance Recommendations |
---|
AAN recommendations
EAN/ECTRIMS recommendations
Expert opinion recommendations for relapsing-remitting MS
|
Stopping Therapy Recommendations |
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AAN recommendations
EAN/ECTRIMS recommendations
|
Pregnancy Recommendations |
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AAN recommendations
EAN/ECTRIMS recommendations
|
- SYMPTOMATIC TREATMENT
Fatigue |
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Overview
Treatment
|
Spasticity |
Overview
Treatment
|
Oscillopsia |
Overview
Treatment
|
Gait disturbance |
Overview
Treatment
|
Tremor |
Overview
Treatment
|
Bladder dysfunction |
Overview
Treatment
|
Sexual dysfunction |
Overview
Treatment
|
Bowel dysfunction |
Overview
Treatment
|
Mood and cognition |
Overview
Treatment
|
Pain |
Overview
Treatment
|
- FDA-APPROVED MEDICATIONS
Alemtuzumab (Lemtrada®)
Dosage forms | Maintenance dosing
- Lemtrada® (alemtuzumab) - 12 mg vial | 12 mg/day IV for 2 treatment courses: First course: 12 mg/day on 5 consecutive days (60 mg total dose); Second course: 12 mg/day on 3 consecutive days (36 mg total dose) administered 12 months after the first course; Subsequent courses: 12 mg per day on 3 consecutive days (36 mg total dose) as needed at least 12 months after the last dose
- Prescribers, pharmacies, patients, and healthcare facilities must complete the Lemtrada REMS program in order to prescribe and receive Lemtrada
FDA-approved indications
MS in adults with:
- Relapsing-remitting disease
- Active secondary progressive disease
- Because of its safety profile, the use of alemtuzumab should generally be reserved for patients who have had an inadequate response to two or more drugs
Efficacy
Lab / other monitoring
Before therapy
- Complete any necessary immunizations at least 6 weeks prior to treatment
- Determine whether patients have a history of varicella or have been vaccinated for varicella zoster virus (VZV). If not, test the patient for antibodies to VZV and consider vaccination for those who are antibody-negative. Postpone treatment with LEMTRADA until 6 weeks after VZV vaccination
- Perform tuberculosis screening according to local guidelines
- Consider hepatitis B and C screening in high-risk patients
- Instruct patients to avoid potential sources of Listeria monocytogenes (e.g., deli meat, dairy products made with unpasteurized milk, soft cheeses, or undercooked meat, seafood, or poultry)
- Inspect skin for melanoma
- Obtain baseline ECG
- Measure CBC, serum creatinine, liver function tests, TSH, urinalysis with urine cell counts, urine protein to creatinine ratio prior to treatment
- CBC monthly
- Serum creatinine monthly
- Urinalysis with urine cell counts monthly
- TSH every 3 months
- Liver function tests periodically
- Yearly skin exams to monitor for melanoma
Mechanism of action
- Alemtuzumab is a recombinant humanized IgG1 kappa monoclonal antibody directed against the cell surface glycoprotein, CD52. CD52 is a cell surface antigen present on T and B lymphocytes, natural killer cells, monocytes, and macrophages. Following cell surface binding to T and B lymphocytes, alemtuzumab results in antibody-dependent cellular cytolysis and complement-mediated lysis. After alemtuzumab treatment, B cells recover within 7 months, but T cells do not reach the lower limit of normal before the second treatment.
Side effects
- NOTE: Only side effects with an incidence ≥ 6% and more than placebo are listed
Side effect | Lemtrada (N=811) |
Interferon beta-1a (N=389) |
---|---|---|
Rash | 53% | 6% |
Headache | 52% | 23% |
Pyrexia | 29% | 9% |
Nasopharyngitis | 25% | 19% |
Nausea | 21% | 9% |
Urinary tract infection | 19% | 8% |
Fatigue | 18% | 13% |
Insomnia | 16% | 15% |
Upper respiratory tract infection | 16% | 13% |
Herpes viral infection | 16% | 3% |
Urticaria | 16% | 2% |
Pruritus | 14% | 2% |
Thyroid gland disorders | 13% | 3% |
Fungal infection | 13% | 4% |
Arthralgia | 12% | 9% |
Pain in extremity | 12% | 9% |
Back pain | 12% | 8% |
Diarrhea | 12% | 6% |
Sinusitis | 11% | 8% |
Oropharyngeal pain | 11% | 5% |
Paresthesia | 10% | 8% |
Dizziness | 10% | 5% |
Abdominal pain | 10% | 5% |
Flushing | 10% | 4% |
Vomiting | 10% | 3% |
Cough | 9% | 4% |
Chills | 9% | 3% |
Dysgeusia | 8% | 7% |
Influenza | 8% | 6% |
Dermatitis | 8% | 5% |
Dyspepsia | 8% | 4% |
Blood in urine | 8% | 3% |
Dyspnea | 8% | 1% |
Tachycardia | 8% | 1% |
Anxiety | 7% | 6% |
Muscular weakness | 7% | 6% |
Bronchitis | 7% | 4% |
Chest discomfort | 7% | 2% |
Muscle spasms | 6% | 5% |
Myalgia | 6% | 5% |
Decrease in CD4 lymphocytes | 6% | 2% |
Decrease in CD8 lymphocytes | 6% | 2% |
Contraindications / Precautions
- Pregnancy - risk unknown
- HIV - DO NOT USE. Lowers CD4 count.
- Active infection - DO NOT USE
- Autoimmunity - Treatment with alemtuzumab can result in the formation of autoantibodies and increase the risk of serious autoimmune mediated conditions. In clinical studies, thyroid disorders (36.8%), immune thrombocytopenia (2%), glomerulonephropathies (0.3%) vitiligo (0.3%), autoimmune hemolytic anemia (0.3%), autoimmune pancytopenia (0.2%), undifferentiated connective tissue disorders (0.2%), type 1 diabetes (0.2%), rheumatoid arthritis (0.1%), retinal pigment epitheliopathy (0.1%), and acquired hemophilia A (anti-Factor VIII antibodies) (0.1%) have occurred in alemtuzumab-treated patients. Guillain-Barré syndrome, thrombotic thrombocytopenic purpura (TTP), and autoimmune encephalitis have been reported in postmarketing use. Chronic inflammatory demyelinating polyradiculoneuropathy has been reported in the treatment of patients with B-cell chronic lymphocytic leukemia (B-CLL), as well as other autoimmune disorders, generally at higher and more frequent doses than recommended in MS. Autoantibodies may be transferred from the mother to the fetus during pregnancy. A case of transplacental transfer of anti-thyrotropin receptor antibodies resulting in neonatal Graves' disease occurred after alemtuzumab treatment in the mother.
- Infusion reactions - Alemtuzumab causes cytokine release syndrome which can cause serious infusion reactions. In studies, 92% of alemtuzumab-treated patients experienced infusion reactions. In some patients, infusion reactions were reported up to 3 days after alemtuzumab infusion. Serious reactions including anaphylaxis occurred in 3% of patients. Cases of pulmonary alveolar hemorrhage, myocardial ischemia, myocardial infarction, stroke (including ischemic and hemorrhagic stroke), and cervicocephalic (e.g. vertebral, carotid) arterial dissection have also been reported within 1 - 3 days of infusion. In trials, patients were premedicated with 1,000 mg of methylprednisolone for the first 3 days of each alemtuzumab treatment course. Patients should be monitored for 2 hours after each infusion in a setting that is equipped to handle serious infusion reactions.
- Stroke and cervicocephalic arterial dissection - cases have been reported within 3 days of alemtuzumab administration
- Malignancies - in trials, thyroid cancer and melanoma occurred in 0.3% of alemtuzumab-treated patients. Lymphoma and lymphoproliferative disorders have also been reported.
- Immune thrombocytopenia (ITP) - immune thrombocytopenia (ITP) occurred in 2% of alemtuzumab-treated patients in MS trials (controlled and open-label extension). Nadir platelet counts ≤ 20,000/μL as a result of ITP occurred in 2% of all alemtuzumab-treated patients in MS trials. ITP has been diagnosed more than 3 years after the last dose.
- Thrombotic thrombocytopenic purpura (TTP) - TTP has been reported in patients treated with alemtuzumab. If signs of TTP develop (e.g. thrombocytopenia, microangiopathic hemolytic anemia, neurological sequelae, renal impairment), discontinue alemtuzumab and treat accordingly.
- Glomerulonephropathies including anti-glomerular basement membrane disease - glomerular nephropathies occurred in 0.3% of alemtuzumab-treated patients in MS clinical studies. Cases of anti-GBM disease have been diagnosed up to 40 months after the last dose of alemtuzumab. Symptoms of nephropathy may include edema, hematuria, change in urine color, decreased urine output, fatigue, dyspnea, and hemoptysis. For urine dipstick results of 1+ protein or greater, measure the urine protein to creatinine ratio. For urine protein to creatinine ratio greater than 200 mg/g, increase in serum creatinine greater than 30%, or unexplained hematuria, perform further evaluation for nephropathies. Increased serum creatinine with hematuria or signs of pulmonary involvement of anti-GBM disease (e.g., hemoptysis, exertional dyspnea) warrant immediate evaluation. Early detection and treatment of nephropathies may decrease the risk of poor outcomes.
- Thyroid disorders - thyroid disorders including hyper/hypothyroidism, Grave's disease, autoimmune thyroiditis, and goiter occurred in 36.8% of alemtuzumab-treated patients in MS clinical studies (controlled and open-label extension). Newly diagnosed thyroid disorders have occurred more than 7 years after the first alemtuzumab dose.
- Other autoimmune cytopenias - autoimmune cytopenias including neutropenia (0.1%), hemolytic anemia (0.3%), and pancytopenia (0.2%) occurred in alemtuzumab-treated patients in MS clinical studies.
- Infections - In MS trials lasting up to 2 years, infections occurred in 71% of alemtuzumab-treated patients compared to 53% of interferon beta-1a-treated patients. Infections that occurred more often in alemtuzumab-treated patients than interferon beta-1a patients included nasopharyngitis, urinary tract infection, upper respiratory tract infection, sinusitis, herpetic infections, influenza, and bronchitis. Serious infections occurred in 3% of patients treated with alemtuzumab as compared to 1% of patients treated with interferon beta-1a. Herpes virus infections (16%) and oral and vaginal candidiasis (12%) were the most common infections in alemtuzumab-treated patients. Screen for TB before treatment and consider screening for hepatitis B and C in high-risk individuals. Treat patients with TB before initiating therapy.
- Listeria monocytogenes infections - Listeria monocytogenes infections (e.g., meningitis, encephalitis, sepsis, and gastroenteritis), including fatal cases of Listeria meningoencephalitis, have occurred in alemtuzumab-treated patients. Listeria infections have occurred as early as 3 days after treatment and up to 8 months after the last alemtuzumab dose. Advise patients to avoid or adequately heat foods that are potential sources of Listeria monocytogenes (e.g., deli meat, dairy products made with unpasteurized milk, soft cheeses, or undercooked meat, seafood, or poultry). Initiate these Listeria precautions prior to starting alemtuzumab treatment.
- Progressive multifocal leukoencephalopathy (PML) - one case of PML has been reported in a patient receiving alemtuzumab for MS.The diagnosis was made two months after the second course of alemtuzumab.
- Acquired hemophilia A - cases of acquired hemophilia A have been reported in clinical trials and the postmarketing setting in patients receiving Lemtrada. Patients should be warned about the possibility of hemophilia, and a coagulopathy panel that includes an aPTT should be obtained in any patient that experiences unusual bleeding while receiving Lemtrada.
- Autoimmune encephalitis - cases of autoimmune encephalitis have been reported in patients receiving alemtuzumab. Autoimmune encephalitis may present as memory impairment, altered mental status, psychiatric symptoms, neurological findings, and seizures. Discontinue alemtuzumab if autoimmune encephalitis is confirmed by the presence of neural autoantibodies or an alternate etiology cannot be established.
- Alemtuzumab antibodies - in trials, anti-alemtuzumab antibodies were detected in up to 83% of patients. Antibodydevelopment had no clear effect on clinical outcomes, total lymphocyte count, or adverse events.
- Autoimmune hepatitis - cases of autoimmune hepatitis has been reported in patients receiving alemtuzumab
- Acute acalculous cholecystitis - in controlled clinical studies, 0.2% of alemtuzumab-treated MS patients developed acute acalculous cholecystitis, compared to 0% of patients treated with interferon beta-1a. Time to onset of symptoms ranged from less than 24 hours to 2 months after alemtuzumab infusion.
- Pneumonitis - in clinical trials, 0.5% alemtuzumab-treated patients had pneumonitis of varying severity
- Hemophagocytic lymphohistiocytosis (HLH) - HLH is a life-threatening syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme systemic inflammation. It is associated with high mortality rates if not recognized early and treated. Common findings include fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms (e.g., mental status changes, ataxia, or seizures), cytopenias, high serum ferritin, hypertriglyceridemia, and liver function and coagulation abnormalities. Hemophagocytosis may be seen on histologic examination of bone marrow, spleen, or lymph nodes. In cases of HLH reported with alemtuzumab, most patients presented with fever, elevated ferritin, transaminitis, hypertriglyceridemia, and all patients required hospitalization. Although the small number of cases limits the ability to draw conclusions pertaining to mean or range of latency for HLH, symptoms have been reported to occur within approximately thirteen months to thirty-three months following the initiation of treatment. Patients who develop early manifestations of pathologic immune activation should be evaluated immediately, and a diagnosis of HLH should be considered. Alemtuzumab should be discontinued if an alternate etiology for the signs of symptoms cannot be established.
- Adult-onset Still's disease (AOSD) - postmarketing reports of AOSD have been reported in patients receiving alemtuzumab. Still's disease is marked by fever, arthritis, rash, and leukocytosis in the absence of infection, malignancy, or other rheumatic conditions. If symptoms of AOSD develop and no other etiologies to explain the symptoms are identified, alemtuzumab should be stopped.
- Live vaccines - do not administer live vaccines during therapy, after therapy, or in the 6 weeks before therapy.
- Kidney disease - alemtuzumab may cause glomerular nephropathies. Use caution in patients with kidney disease
- Liver disease - alemtuzumab has been associated with cases of autoimmune hepatitis
Cladribine (Mavenclad®)
Dosage forms | Maintenance dosing
- 10 mg tablet | 3.5 mg/kg administered orally and divided into 2 yearly treatment courses (1.75 mg/kg per treatment course). See Mavenclad PI for specific instructions.
FDA-approved indications
MS in adults with:
- Relapsing-remitting disease
- Active secondary progressive disease
- Because of its safety profile, use of cladribine is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS
Efficacy
Lab / other monitoring
Before therapy
- Pregnancy test
- CBC - lymphocytes should be in normal range before initiating first course of therapy
- Liver function tests
- HIV
- TB screening
- Hepatitis C screening
- Hepatitis B screening - see interpreting HBV screening results
- Varicella immunity - administer live-attenuated varicella vaccine (e.g. Zostavax®) at least 4 to 6 weeks prior to starting cladribine. Vaccination with zoster vaccine recombinant, adjuvanted (Shingrix®) is recommended for patients who are seropositive to varicella zoster, either prior to or during cladribine treatment, including when their lymphocyte counts are less than or equal to 500 cells/mcL.
- Baseline MRI (within 3 months prior to treatment)
- CBC - check 2 and 6 months after the start of treatment in each treatment course and before the second treatment course. If the lymphocyte count at month 2 is below 200 cells/mcL, monitor monthly until month 6. Hold cladribine therapy if the lymphocyte count is below 200 cells/mcL. Lymphocyte count should be ≥ 800 cells/mcL before starting second course of therapy. Treatment course may be delayed up to 6 months to allow lymphocytes to recover. In patients with lymphocyte counts < 200 cells/mcL, administer prophylactic antiviral therapy.
- Liver function tests - perform before each treatment course
- TB screening - perform before each treatment course
- Hepatitis B and C - perform before each treatment course
Mechanism of action
- The mechanism by which cladribine exerts its therapeutic effects in patients with multiple sclerosis has not been fully elucidated but is thought to involve cytotoxic effects on B and T lymphocytes through impairment of DNA synthesis, resulting in depletion of lymphocytes
Side effects
- NOTE: Only side effects that had an incidence of at least 5% and higher than placebo are listed
Side effect | Cladribine (N=440) | Placebo (N=435) |
---|---|---|
Upper respiratory tract infection | 38% | 32% |
Headache | 25% | 19% |
Lymphopenia | 24% | 2% |
Nausea | 10% | 9% |
Back pain | 8% | 6% |
Arthralgia and arthritis | 7% | 5% |
Insomnia | 6% | 4% |
Bronchitis | 5% | 3% |
Hypertension | 5% | 3% |
Fever | 5% | 3% |
Depression | 5% | 3% |
Drug interactions
- Antiviral and antiretroviral drugs - compounds that require intracellular phosphorylation to become active (e.g., lamivudine, zalcitabine, ribavirin, stavudine, and zidovudine) could interfere with the intracellular phosphorylation and activity of cladribine. Avoid concomitant use.
- Hematotoxic drugs - cladribine may lower hemoglobin, platelets, and neutrophils. Use with other hematotoxic drugs may potentiate these effects. Use caution.
- Immunosuppressants - concomitant immunosuppressive drugs may increase the risk of adverse events. Combined use is not recommended. Acute short-term therapy with corticosteroids can be administered.
- Interferon beta - concomitant interferon beta may increase the risk of lymphopenia. Avoid concomitant use.
- Oral contraceptives - it's unknown if cladribine reduces the effects of oral contraceptives. Addition of a barrier method during cladribine dosing and for at least 4 weeks after the last dose in each treatment course is recommended.
- Potent ENT, CNT and BCRP Transporter Inhibitors - cladribine is a substrate of breast cancer resistance protein (BCRP), equilibrative nucleoside (ENT1), and concentrative nucleoside (CNT3) transport proteins. The bioavailability, intracellular distribution, and renal elimination of cladribine may be altered by potent ENT1, CNT3, and BCRP transporter inhibitors. Avoid co-administration of potent ENT1, CNT3, or BCRP transporter inhibitors (e.g., ritonavir, eltrombopag, curcumin, cyclosporine, dilazep, nifedipine, nimodipine, cilostazol, sulindac, dipyridamole, or reserpine) during the 4 to 5 day cladribine treatment cycles. If this is not possible, consider selection of alternative concomitant drugs with no or minimal ENT1, CNT3, or BCRP transporter inhibiting properties. If this is not possible, dose reduction to the minimum mandatory dose of drugs containing these compounds, separation in the timing of administration, and careful patient monitoring is recommended.
- BCRP potent inducers - cladribine is a BCRP substrate. Potent BCRP inducers (e.g. corticosteroids) may reduce exposure to cladribine.
- P-glycoprotein potent inducers - cladribine is a P-glycoprotein substrate. Potent P-glycoprotein inducers (e.g. rifampicin, St. John's Wort) may reduce exposure to cladribine.
Contraindications / Precautions
- Pregnancy - DO NOT USE. Cladribine is teratogenic. Advise females and males of reproductive potential to use effective contraception during cladribine dosing and for 6 months after the last dose in each treatment course. It's unknown if cladribine reduces the effects of oral contraceptives. Addition of a barrier method during cladribine dosing and for at least 4 weeks after the last dose in each treatment course is recommended.
- Breastfeeding - do not breastfeed during dosing with cladribine and for 10 days after the last dose
- Current malignancy - DO NOT USE
- HIV infection - DO NOT USE
- Hepatitis B or C - DO NOT USE in patients with active infection. Treat infections before initiating therapy.
- Tuberculosis - DO NOT USE in patients with active infection. Treat latent infections before initiating therapy.
- Herpes virus infection - in trials, 6% of cladribine-treated patients developed herpes infections compared to 2% of placebo-treated patients. The most frequent infections were herpes zoster and herpes labialis. Administer live-attenuated varicella vaccine (e.g. Zostavax®) at least 4 to 6 weeks prior to starting cladribine. Vaccination with zoster vaccine recombinant, adjuvanted (Shingrix®) is recommended for patients who are seropositive to varicella zoster, either prior to or during cladribine treatment, including when their lymphocyte counts are less than or equal to 500 cells/mcL. In patients with lymphocyte counts < 200 cells/mcL, administer prophylactic antiviral therapy.
- Cancer risk - cladribine increases the risk of cancer. In studies, the risk of cancer was 0.27 events per 100 patient-years in cladribine-treated patients compared to 0.13 events per 100 patient-years in placebo-treated patients. After the completion of 2 treatment courses, do not administer additional cladribine treatment during the next 2 years, because studies have shown this further increases cancer risk. The risk of malignancy with reinitiating cladribine more than 2 years after the completion of 2 treatment courses has not been studied.
- Lymphopenia - cladribine reduces the lymphocyte count. In trials, 87% of cladribine-treated patients experienced lymphopenia. The lowest counts occurred around 2 - 3 months after each treatment course and were lower with each subsequent treatment. In patients receiving cumulative doses of 3.5 mg/kg over 2 courses, 26% experienced lymphocyte counts < 500 cells/mcL. It can take ≥ 7 months for lymphocyte counts to return to normal.
- Infections - cladribine may increase the risk of infection. In trials, infections occurred in 49% of cladribine-treated patients compared to 44% of placebo-treated patients. Herpes zoster and pyelonephritis were the most frequent serious infections.
- Progressive multifocal leukoencephalopathy (PML) - no cases of PML, a serious neurologic disease caused by the JC virus, have been identified in MS patients treated with cladribine, but cases have occurred in patients treated with parenteral cladribine for oncologic indications. Symptoms of PML 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.
- Vaccines - administer vaccines prior to starting therapy. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting cladribine (see list of live/killed vaccines). Do not give live vaccines during treatment with cladribine or while leukopenia is present.
- Neutrophil decrease - cladribine may lower neutrophil counts. In trials, neutrophil counts between 1000 cells/mcL and the lower limits of normal were observed in 27% of cladribine-treated patients compared to 13% of placebo-treated patients. Counts < 1000 cells/mcL were observed in 3.6% of cladribine-treated patients.
- Hemoglobin decrease - cladribine may lower RBC counts. In trials, hemoglobin levels between 8 g/dl and the lower limits of normal were observed in 26% of cladribine-treated patients compared to 19% of placebo-treated patients.
- Platelet reduction - cladribine may lower platelet counts. In trials, platelet counts between 75,000 and the lower limits of normal were observed in 11% of cladribine-treated patients compared to 4% of placebo-treated patients.
- Blood transfusion - transfusion-associated graft-versus-host disease has been observed rarely after transfusion of nonirradiated blood in patients treated with cladribine for non-MS treatment indications. In patients requiring blood transfusions, irradiation of cellular blood components is recommended prior to administration.
- Hypersensitivity reactions - in trials, hypersensitivity reactions occurred in 11% of cladribine-treated patients compared to 7% of placebo-treated patients. Hypersensitivity reactions that were serious and/or led to discontinuation (e.g., dermatitis, pruritus) occurred in 0.5% of cladribine-treated patients.
- Liver toxicity - in trials, serious liver toxicity was observed in 0.3% of cladribine-treated patients and no placebo-treated patients. Liver function returned to normal upon discontinuation.
- Heart failure - one case of heart failure with myocarditis has been reported in MS patients treated with cladribine.
- Kidney disease
- CrCl ≥ 60 ml/min: no dose adjustment necessary
- CrCl < 60 ml/min: DO NOT USE
- Liver disease
- Child-Pugh A: no dose adjustment necessary
- Child-Pugh B and C: DO NOT USE
Dimethyl Fumarate (Tecfidera®) | Monomethyl Fumarate (Bafiertam®)
Dosage forms | Dosing
- Tecfidera® (dimethyl fumarate) - 120 mg and 240 mg capsule | 120 mg twice daily for 7 days then 240 mg twice daily
- Generic available | $$$ for 60 capsules
- Bafiertam® (monomethyl fumarate) - 95 mg capsule | 95 mg mg twice daily for 7 days then 190 mg twice daily
- No generic | $$$$ for 120 capsules
- Tecfidera® (dimethyl fumarate) is the prodrug of Bafiertam® (monomethyl fumarate), and they share the same prescribing information
FDA-approved indications
MS in adults with:
- Clinically isolated syndrome
- Relapsing-remitting disease
- Active secondary progressive disease
Efficacy
Pediatric-onset MS
Relapsing-remitting MS
Radiologically isolated syndrome
Lab monitoring
- CBC before therapy, 6 months after starting therapy, every 6 - 12 months during therapy, and as clinically indicated
- Liver function tests before starting therapy and during therapy as clinically indicated
Mechanism of action
- Dimethyl fumarate and diroximel fumarate (Vumerity®) both undergo rapid presystemic hydrolysis by esterases and are converted to the active metabolite, monomethyl fumarate (MMF)
- MMF activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. Nrf2 activation leads to a reduction in the release of inflammatory cytokines, and it also has antioxidant effects.
Side effects
- NOTE: Only side effects that occurred at an incidence ≥ 2% higher than placebo are listed
Side effect | Tecfidera (N=769) |
Placebo (N=771) |
---|---|---|
Flushing | 40% | 6% |
Abdominal pain | 18% | 10% |
Diarrhea | 14% | 11% |
Nausea | 12% | 9% |
Vomiting | 9% | 5% |
Pruritus | 8% | 4% |
Rash | 8% | 3% |
Albumin urine present | 6% | 4% |
Erythema | 5% | 1% |
Dyspepsia | 5% | 3% |
ALT increased | 4% | 2% |
Lymphopenia | 2% | <1 |
Drug interactions
- Diroximel fumarate (Vumerity®) - diroximel fumarate and dimethyl fumarate are converted to the same active metabolite. Do not combine.
Contraindications / Precautions
- Pregnancy - risk unknown. In animal studies, diroximel fumarate resulted in adverse effects on embryofetal and offspring development (increased incidences of skeletal abnormalities, increased mortality, decreased body weights, neurobehavioral impairment) at clinically relevant drug exposures.
- Hypersensitivity reactions - anaphylaxis, angioedema, urticaria, and dyspnea have occurred after the first dose and at any time during therapy
- Flushing - in trials, 40% of dimethyl fumarate-treated patients experienced flushing (e.g. warmth, redness, itching, and/or burning sensation). Symptoms typically occurred soon after starting treatment and improved or resolved over time. Taking diroximel fumarate with food, and/or taking a non-enteric coated aspirin 30 minutes prior to dosing may help to reduce flushing.
- Lymphopenia - in trials, mean lymphocyte counts decreased an average of 30% during the first year of therapy. Lymphocyte counts < 0.5x109/L occurred in 6% of dimethyl fumarate-treated patients and < 1% of placebo-treated patients. Severe lymphopenia (< 0.5x109/L) lasting more than 6 months occurred in 2% of patients, and it took a median of 96 weeks after drug discontinuation for counts to return to normal in these patients. In other patients, median times to recovery were 4 to 17 weeks depending on the degree of lymphopenia. Consider changing or stopping therapy for lymphopenia (< 0.5x109/L) lasting ≥ 6 months.
- Infections - serious infections including viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections have occurred in patients treated with dimethyl fumarate. In trials, the incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with dimethyl fumarate or placebo, respectively.
- Herpes zoster infections - serious cases of herpes zoster including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster meningomyelitis have occurred in patients receiving dimethyl fumarate
- Progressive multifocal leukoencephalopathy (PML) - rare cases of PML, a serious neurologic disease caused by the JC virus, have been reported, particularly in patients with lymphopenia (< 0.8x10⁹/L) for > 6 months. Symptoms of PML 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.
- Liver toxicity - serious cases of liver injury have been reported in patients receiving dimethyl fumarate. The onset occurred from a few days to several months after starting therapy. Liver abnormalities resolved after discontinuing treatment. In trials, liver enzyme elevations ≥ 3 X ULN were similar between dimethyl fumarate and placebo. Check liver function tests before starting therapy and as clinically indicated.
- Kidney disease - has not been studied. The PI states that kidney disease would not be expected to affect MMF exposure and therefore, dose adjustments are not necessary.
- Liver disease - has not been studied. The PI states that liver disease would not be expected to affect MMF exposure and therefore, dose adjustments are not necessary.
Diroximel Fumarate (Vumerity®)
Dosage forms | Dosing
- Vumerity® (diroximel fumarate) - 231 mg delayed-release capsule | 231 mg twice daily for 7 days then 462 mg twice daily
FDA-approved indications
MS in adults with:
- Clinically isolated syndrome
- Relapsing-remitting disease
- Active secondary progressive disease
Efficacy
Lab monitoring
- CBC before therapy, 6 months after starting therapy, every 6 - 12 months during therapy, and as clinically indicated
- Liver function tests before starting therapy and during therapy as clinically indicated
Mechanism of action
- Diroximel fumarate and dimethyl fumarate (Tecfidera®) both undergo rapid presystemic hydrolysis by esterases and are converted to the active metabolite, monomethyl fumarate (MMF)
- MMF activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. Nrf2 activation leads to a reduction in the release of inflammatory cytokines, and it also has antioxidant effects.
Side effects
- NOTE: Diroximel fumarate was approved based on bioavailability studies showing it was comparable to dimethyl fumarate for absorption of the active metabolite, MMF. The Vumerity PI presents information from dimethyl fumarate studies. Only side effects that occurred at an incidence ≥ 2% higher than placebo are listed
Side effect | Dimethyl fumarate (N=769) |
Placebo (N=771) |
---|---|---|
Flushing | 40% | 6% |
Abdominal pain | 18% | 10% |
Diarrhea | 14% | 11% |
Nausea | 12% | 9% |
Vomiting | 9% | 5% |
Pruritus | 8% | 4% |
Rash | 8% | 3% |
Albumin urine present | 6% | 4% |
Erythema | 5% | 1% |
Dyspepsia | 5% | 3% |
ALT increased | 4% | 2% |
Lymphopenia | 2% | <1 |
Drug interactions
- Dimethyl fumarate (Tecfidera®) - diroximel fumarate and dimethyl fumarate are converted to the same active metabolite. Do not combine.
Contraindications / Precautions
NOTE: The Vumerity PI refers to dimethyl fumarate in many of the precautions. Dimethyl fumarate (Tecfidera®) and diroximel fumarate (Vumerity®) are both rapidly metabolized to the same active metabolite, monomethyl fumarate (MMF).
- Pregnancy - risk unknown. In animal studies, diroximel fumarate resulted in adverse effects on embryofetal and offspring development (increased incidences of skeletal abnormalities, increased mortality, decreased body weights, neurobehavioral impairment) at clinically relevant drug exposures.
- Flushing - in trials, 40% of dimethyl fumarate-treated patients experienced flushing (e.g. warmth, redness, itching, and/or burning sensation). Symptoms typically occurred soon after starting treatment and improved or resolved over time. Taking diroximel fumarate with food, and/or taking a non-enteric coated aspirin 30 minutes prior to dosing may help to reduce flushing.
- Hypersensitivity reactions - anaphylaxis, angioedema, urticaria, and dyspnea have occurred after the first dose and at any time during therapy
- Lymphopenia - in trials, mean lymphocyte counts decreased an average of 30% during the first year of therapy. Lymphocyte counts < 0.5x109/L occurred in 6% of dimethyl fumarate-treated patients and < 1% of placebo-treated patients. Severe lymphopenia (< 0.5x109/L) lasting more than 6 months occurred in 2% of patients, and it took a median of 96 weeks after drug discontinuation for counts to return to normal in these patients. In other patients, median times to recovery were 4 to 17 weeks depending on the degree of lymphopenia. Consider changing or stopping therapy for lymphopenia (< 0.5x109/L) lasting ≥ 6 months.
- Infections - serious infections including viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections have occurred in patients treated with dimethyl fumarate. In trials, the incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar between patients treated with dimethyl fumarate and placebo, respectively.
- Herpes zoster infections - serious cases of herpes zoster including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster meningomyelitis have occurred in patients receiving dimethyl fumarate.
- Progressive multifocal leukoencephalopathy (PML) - rare cases of PML, a serious neurologic disease caused by the JC virus, have been reported, particularly in patients with lymphopenia (< 0.8x10⁹/L) for > 6 months. Symptoms of PML 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.
- Liver toxicity - serious cases of liver injury have been reported in patients receiving dimethyl fumarate. The onset occurred from a few days to several months after starting therapy. Liver abnormalities resolved after discontinuing treatment. In trials, liver enzyme elevations ≥ 3 X ULN were similar between dimethyl fumarate and placebo. Check liver function tests before starting therapy and as clinically indicated.
- Kidney disease
- CrCl ≥ 60 ml/min: no dose adjustment necessary
- CrCl < 60 ml/min: not recommended
- Liver disease - has not been studied. The PI states that liver disease would not be expected to affect MMF exposure and therefore, dose adjustments are not necessary.
Glatiramer Acetate | Copaxone® | Glatopa®
Dosage forms | Dosing
- Copaxone® (glatiramer acetate) - 20 mg and 40 mg prefilled syringe | 20 mg SQ once daily or 40 mg SQ three times a week
- Generic called Glutopa® is available | $$$$ for 30 syringes
FDA-approved indications
MS in adults with:
- Clinically isolated syndrome
- Relapsing-remitting disease
- Active secondary progressive disease
Efficacy
Lab monitoring
- None
Mechanism of action
- The mechanism by which glatiramer acetate treats MS is not completely understood. Studies in animals and in vitro studies suggest that glatiramer acetate activates certain suppressor T-cells in the periphery.
Side effects
- NOTE: Only side effects that occurred at an incidence of ≥ 10% are listed
Side effect | Copaxone 20 mg/mL (N=563) |
Placebo (N=564) |
---|---|---|
Injection Site Erythema | 43% | 10% |
Injection Site Pain | 40% | 20% |
Infection | 30% | 28% |
Injection Site Pruritus | 27% | 4% |
Injection Site Mass | 26% | 6% |
Asthenia | 22% | 21% |
Pain | 20% | 17% |
Vasodilatation | 20% | 5% |
Injection Site Edema | 19% | 4% |
Rash | 19% | 11% |
Nausea | 15% | 11% |
Influenza | 14% | 13% |
Dyspnea | 14% | 4% |
Chest Pain | 13% | 6% |
Anxiety | 13% | 10% |
Back Pain | 12% | 10% |
Contraindications / Precautions
- Pregnancy - available human data on the use of glatiramer acetate in pregnant women are not sufficient to support conclusions about drug-associated risk for major birth defects and miscarriage. In animal studies, glatiramer acetate had no adverse embryonic or developmental effects when given to pregnant rats and rabbits.
- Immediate injection reactions - glatiramer acetate may cause reactions immediately (within seconds and up to 1 hour) after an injection. Reactions reported include flushing, chest pain, palpitations, tachycardia, anxiety, dyspnea, constriction of the throat, and urticaria. In studies, the 20 mg daily dose had a higher incidence than the 40 mg thrice weekly dose (16% vs 2%).
- Chest pain - in studies, approximately 13% of patients treated with 20 mg of glatiramer acetate and 2% of patients treated with 40 mg experienced transient chest pain. The chest pain did not always occur immediately after dosing. The clinical significance and etiology of the pain is unknown.
- Lipoatrophy - in trials, lipoatrophy occurred in 2% of patients treated with 20 mg of glatiramer acetate and 0.5% of patients treated with 40 mg. Lipoatrophy may occur at any time during treatment and is thought to be permanent. Patients should rotate injection sites to help prevent.
- Skin necrosis - rare cases of skin necrosis have been reported in the postmarketing setting
- Immunosuppression - the effects of glatiramer acetate on the immune system have not been completely elucidated. It may potentially suppress and/or alter the immune response.
- Glatiramer acetate antibodies - antibodies to glatiramer acetate form in most patients, and studies in both rats and monkeys have suggested that immune complexes are deposited in the renal glomeruli
- Elevated IgG levels - in a trial where patients were given glatiramer acetate 20 mg once daily for 2 years, serum IgG levels reached at least 3 times baseline values in 80% of patients after 3 months of treatment. By 12 months, 30% of patients still had IgG levels at least 3 times baseline values, and 90% had levels above baseline. The antibodies were exclusively of the IgG subtype and predominantly of the IgG-1 subtype. Whether these effects are associated with a greater risk of adverse events is unknown.
- Liver toxicity - cases of hepatic toxicity including liver failure and hepatitis have been reported in patients receiving glatiramer acetate. Cases have occurred within days of starting treatment and after years of continuous treatment. Consider stopping therapy if signs of liver toxicity develop.
- Kidney disease - has not been studied
- Liver disease - manufacturer makes no recommendation
Interferon Beta | Betaseron® | Avonex® | Plegridy® | Rebif® | Extavia®
Dosage forms | Maintenance dosing
- Avonex® (interferon beta-1a) - prefilled syringe | 30 mcg IM once weekly
- Plegridy® (peginterferon beta-1a) - prefilled pen and syringe | 125 mcg SQ or IM every 14 days
- Rebif® (interferon beta-1a) - prefilled syringe | 22 - 44 mcg SQ three times a week
- Betaseron® (interferon beta-1b) - injection kit | 0.25 mg SQ every other day
- Extavia® (interferon beta-1b) - injection kit | 0.25 mg SQ every other day
FDA-approved indications
MS in adults with:
- Clinically isolated syndrome
- Relapsing-remitting disease
- Active secondary progressive disease
Efficacy
Avonex®
- Dimethyl fumarate vs Interferon β-1a in Patients With Pediatric-Onset MS, JAMA Netw Open (2022)
- Avonex® vs Placebo in CIS, NEJM (2000)
- Avonex® vs Placebo in MS, Ann Neurol (1996)
Lab monitoring
- Monitor CBC and blood chemistries including liver function tests (CMP) at 1, 3, and 6 months following initiation of therapy and periodically thereafter
Mechanism of action
- Interferon beta is a naturally occurring protein that binds to receptors on human cells. Receptor binding induces the expression of a number of proteins that lead to the enhancement of suppressor T-cell activity, reduction of pro-inflammatory cytokine production, down-regulation of antigen presentation, and inhibition of lymphocyte trafficking into the central nervous system.
Side effects
- NOTE: Data is from the Betaseron PI. Only side effects that occurred at an incidence ≥ 10% are listed.
Side effect | Placebo (N=965) |
Betaseron (N=1407) |
---|---|---|
Lymphocytes count decreased (<1500/mm3) | 66% | 86% |
Injection site reaction | 26% | 78% |
Flu-like symptoms (complex) | 37% | 57% |
Asthenia | 48% | 53% |
Headache | 43% | 50% |
Pain | 35% | 42% |
Hypertonia | 33% | 40% |
Fever | 19% | 31% |
Myalgia | 14% | 23% |
Insomnia | 16% | 21% |
Rash | 15% | 21% |
Chills | 9% | 21% |
Incoordination | 15% | 17% |
Abdominal pain | 11% | 16% |
Absolute neutrophil count decreased (< 1500/mm3) | 5% | 13% |
White blood cell count decreased (<3000/mm3) | 4% | 13% |
ALT increased (SGPT > 5 times baseline) |
4% | 12% |
Peripheral edema | 10% | 12% |
Urinary urgency | 8% | 11% |
Skin disorder | 8% | 10% |
Contraindications / Precautions
NOTE: Information is from Betaseron PI. Precautions may differ for other interferon beta products.
- Pregnancy - Data from a large population-based cohort study, as well as other published studies over several decades, have not identified a drug-associated risk of major birth defects with the use of interferon beta products during early pregnancy. Findings regarding a potential risk for low birth weight or miscarriage with the use of interferon beta products in pregnancy have been inconsistent.
- Hepatic injury - severe cases of hepatic toxicity including liver failure and autoimmune liver disease have been reported in patients receiving beta interferon. In trials, ALT elevations > 5 X baseline value were reported in 12% of interferon-treated patients and 4% of placebo-treated patients. AST elevations > 5 X baseline value were reported in 4% of interferon-treated patients and 1% of placebo-treated patients. Monitor liver function tests regularly, and use caution when combining with other hepatotoxic drugs.
- Anaphylaxis and allergic reactions - rare cases of anaphylaxis have been reported with interferon-beta administration. Other allergic reactions including dyspnea, bronchospasm, tongue edema, skin rash and urticaria have been reported.
- Depression - interferon beta products have been associated with an increased risk of depression and suicide. Patients should be advised to report symptoms of depression to their healthcare provider and discontinuation of therapy should be considered.
- Congestive heart failure (CHF) - cases of CHF, cardiomyopathy, and cardiomyopathy with CHF have been reported in patients receiving interferon beta who did not have risk factors for these conditions. A temporal relationship between interferon beta and these events was noted in some cases. Use caution in patients with pre-existing CHF and monitor other patients for signs of heart failure. Consider discontinuing interferon beta for new or worsening CHF.
- Pulmonary arterial hypertension (PAH) - cases of PAH have been reported in patients receiving interferon beta products, including those without predisposing factors. PAH may develop at any time during therapy, with some cases occurring years after initiation. Consider PAH in patients with unexplained symptoms of heart failure (e.g. dyspnea, fatigue).
- Injection site reactions - in trials, injection site reactions were reported in 78% of interferon beta-treated patients. Reactions included inflammation (42%), pain (16%), hypersensitivity (4%), necrosis (4%), mass (2%), and edema (2%). Reactions tended to decrease over time. In the postmarketing setting, cases of injection site abscess and cellulitis have been reported, some requiring surgical drainage and IV antibiotics.
- Injection site necrosis - in trials, injection site necrosis occurred in 4% of interferon beta-treated patients. Injection site necrosis typically occurs within the first 4 months of initiating therapy, but cases have been reported more than a year after the start of therapy. Vasculitis was noted in some lesions that were biopsied. Healed lesions typically leave scarring, and some have required skin grafts.
- Decreased white blood cells - in trials, leukopenia occurred in 18% of interferon beta-treated patients and 6% of placebo-treated patients. Monitor CBCs at 1, 3, and 6 months following initiation of therapy and periodically thereafter. Dosage reductions or discontinuation may be necessary in affected patients.
- Thrombotic microangiopathy - cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome have been reported with interferon beta products. Cases occurred several weeks to years after starting interferon beta products.
- Flu-like symptoms - in trials, flu-like symptoms were reported in 57% of interferon beta-treated patients. Symptoms had a median duration of 7.5 days, and their incidence decreased over time.
- Seizures - seizures have been temporally associated with the use of beta interferon products in clinical trials and postmarketing safety surveillance. A causal relationship has not been established.
- Drug-induced lupus - cases of drug-induced lupus have been reported in some patients receiving interferon beta products. Signs and symptoms of drug-induced lupus include rash, serositis, polyarthritis, nephritis, and Raynaud’s phenomenon. Anti-nuclear and/or anti-double-stranded DNA antibodies have been identified in some cases.
- Liver disease - interferon beta may cause liver toxicity. Use caution and monitor liver function tests.
- Kidney disease - manufacturer makes no recommendation
Mitoxantrone
Dosage forms | Maintenance dosing
- Mitoxantrone - 2 mg/ml vial | 12 mg/m² given as a short (approximately 5 to 15 minutes) intravenous infusion every 3 months
FDA-approved indications
- Adults with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis
Efficacy
Lab / other monitoring
Before therapy
- CBC and liver function tests
- Pregnancy test
- ECG and cardiac ECHO
- CBC and liver function tests
- Pregnancy test
- ECG and cardiac ECHO
- Cardiac ECHO annually
Mechanism of action
- Mitoxantrone intercalates into DNA through hydrogen bonding causing crosslinks and strand breaks. Mitoxantrone also interferes with RNA and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. It has a cytocidal effect on both proliferating and nonproliferating cultured human cells, suggesting lack of cell cycle phase specificity.
- Mitoxantrone has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, TNFα, and IL-2
Side effects
- NOTE: Only side effects with an overall incidence ≥ 5% and more than placebo are listed
Side effect | Placebo (N=64) |
Mitoxantrone 12 mg/m² (N=62) |
---|---|---|
Nausea | 20% | 76% |
Alopecia | 31% | 61% |
Menstrual disorder | 26% | 61% |
Amenorrhea | 3% | 43% |
Upper respiratory tract infection | 52% | 53% |
Urinary tract infection | 13% | 32% |
Stomatitis | 8% | 19% |
Leukopenia | 0% | 19% |
Arrhythmia | 8% | 18% |
Diarrhea | 11% | 16% |
Gamma-GT increased | 3% | 15% |
Urine abnormal | 6% | 11% |
ECG abnormal | 3% | 11% |
Constipation | 6% | 10% |
Back pain | 5% | 8% |
SGOT increased | 8% | 8% |
Sinusitis | 2% | 6% |
Low granulocytes | 2% | 6% |
Anemia | 2% | 6% |
SGPT increased | 3% | 5% |
Headache | 5% | 6% |
Contraindications / Precautions
- Pregnancy - DO NOT USE. Category D. Teratogenic.
- Cardiotoxicity - Congestive heart failure (CHF), potentially fatal, may occur either during therapy with mitoxantrone or months to years after termination of therapy. Cardiotoxicity risk increases with cumulative mitoxantrone dose and may occur whether or not cardiac risk factors are present. Presence or history of cardiovascular disease, radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenedione, or use of other cardiotoxic drugs may increase this risk. MS patients with a baseline LVEF below the lower limit of normal should not be treated with mitoxantrone. MS patients should be assessed for cardiac signs and symptoms by history, physical examination and ECG prior to each dose. Additional doses of mitoxantrone should not be administered to MS patients who have experienced either a drop in LVEF to below the lower limit of normal or a clinically significant reduction in LVEF during mitoxantrone therapy. MS patients should not receive a cumulative mitoxantrone dose greater than 140 mg/m². MS patients should undergo yearly quantitative LVEF evaluation after stopping mitoxantrone to monitor for late occurring cardiotoxicity. In cancer patients, the risk of symptomatic CHF was estimated to be 2.6% for patients receiving up to a cumulative dose of 140 mg/m²
- Secondary leukemia - mitoxantrone therapy in patients with MS and in patients with cancer increases the risk of developing secondary acute myeloid leukemia. Publications describe leukemia risks of 0.25% to 2.8% in cohorts of patients with MS treated with mitoxantrone and followed for varying periods of time. This leukemia risk exceeds the risk of leukemia in the general population. The most commonly reported types were acute promyelocytic leukemia and acute myelocytic leukemia
- Liver disease - patients who have hepatic impairment should ordinarily not be treated with mitoxantrone. In patients with severe hepatic impairment, the AUC is more than three times greater than the value observed in patients with normal hepatic function.
- Kidney disease - mitoxantrone pharmacokinetics in patients with renal impairment are unknown
Natalizumab (Tysabri®)
Dosage forms | Maintenance dosing
- Tysabri® (natalizumab) - 300 mg vial | 300 mg IV every 4 weeks
FDA-approved indications
MS in adults with:
- Clinically isolated syndrome
- Relapsing-remitting disease
- Active secondary progressive disease
- See biologicals
Efficacy
Multiple sclerosis
6-week dosing
Lab monitoring
- John Cunningham virus (JCV) antibody testing to help determine the risk of PML
- Liver function tests and CBC when indicated
Mechanism of action
- Tysabri is a recombinant humanized IgG4ϰ monoclonal antibody that binds to the α4-subunit of α4β1 and α4β7 integrins expressed on the surface of all leukocytes except neutrophils.Tysabri inhibits the α4-mediated adhesion of leukocytes to their counter-receptor(s). Inhibiting this interaction prevents transmigration of leukocytes across the endothelium into inflamed parenchymal tissue. The therapeutic mechanism of Tysabri in MS may be through the inhibition of leukocyte migration across the blood-brain-barrier.
Side effects
- NOTE: Only side effects occurring at an overall incidence ≥ 5% are listed
Side effect | Natalizumab (N=627) |
Placebo (N=312) |
---|---|---|
Headache | 38% | 33% |
Fatigue | 27% | 21% |
Urinary tract infection | 21% | 17% |
Arthralgia | 19% | 14% |
Depression | 19% | 16% |
Lower respiratory tract infection | 17% | 16% |
Pain in extremity | 16% | 14% |
Rash | 12% | 9% |
Gastroenteritis | 11% | 9% |
Abdominal discomfort | 11% | 10% |
Diarrhea | 10% | 9% |
Vaginitis | 10% | 6% |
Tooth infections | 9% | 7% |
Urinary frequency | 9% | 7% |
Herpes | 8% | 7% |
Tonsillitis | 7% | 5% |
Dermatitis | 7% | 4% |
Vertigo | 6% | 5% |
Chest discomfort | 5% | 3% |
Other hypersensitivity reactions | 5% | 2% |
Muscle cramps | 5% | 3% |
Irregular menstruation | 5% | 4% |
Contraindications / Precautions
- Pregnancy - risk unknown
- Concomitant immunosuppressants or immunomodulators - DO NOT COMBINE
- Progressive multifocal leukoencephalopathy (PML) - Tysabri increases the risk of PML which has a mortality rate of > 20%. Symptoms of PML 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. Risk is increased by longer duration of therapy (especially > 2 years), prior treatment with immunosuppressants, and the presence of anti-JCV antibodies. Risk of PML by JC antibody index and length of therapy are presented in the tables below. Providers must be enrolled in the Tysabri CD TOUCH program in order to prescribe Tysabri.
Risk of PML in patients using natalizumab for 25 - 36 months✝ | |
---|---|
anti-JCV index | PML risk |
< 0.9 | 0.2/1000 |
0.9 - 1.5 | 0.3/1000 |
> 1.5 | 3/1000 |
Risk of PML in patients who are anti-JCV antibody positive | ||
---|---|---|
Length of Tysabri exposure | No prior Imm | Prior Imm use |
1 - 24 months | < 1/1000 | 1/1000 |
25 - 48 months | 3/1000 | 12/1000 |
49 - 72 months | 6/1000 | 13/1000 |
- Stopping therapy - for patients who stop natalizumab, there is an increased risk of MS relapse in the first 6 months. Initiating fingolimod within 8 - 12 weeks may reduce risk.
- Herpes infections - Tysabri increases the risk of herpes encephalitis, meningitis, and retinitis. The duration of treatment with Tysabri prior to onset ranged from a few months to several years. Monitor patients receiving Tysabri for signs and symptoms of meningitis, encephalitis, and retinitis. Retinitis may present with decreased visual acuity, eye pain, and/or redness.
- Hepatotoxicity - cases of acute hepatitis and liver failure have occurred
- Hypersensitivity reactions - hypersensitivity reactions including urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea, chest pain, and anaphylaxis have occurred. Reactions typically occur within 2 hours of starting an infusion. Reactions are more common in patients who develop natalizumab antibodies. Check for natalizumab antibodies in patients who have infusion reactions or experience decreased efficacy. Natalizumab should be discontinued in patients with persistent antibodies.
- Tysabri antibodies - in MS trials, anti-Tysabri antibodies were detected in up to 9% of patients. Antibody development was associated with reduced efficacy and an increase in hypersensitivity reactions. Patients who receive 1 - 2 infusions of Tysabri followed by an extended period without exposure are at greater risk of developing antibodies and experiencing hypersensitivity reactions. Before restarting therapy, antibody testing may be appropriate.
- Serious infections - Tysabri may increase the risk of serious infections including invasive fungal infections, bacterial infections, viral infections, and others. In MS trials, the rate of serious infections was 3% in both Tysabri-treated patients and placebo-treated patients.
- Increase in blood counts - Tysabri increases circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Levels return to normal when Tysabri is discontinued.
- Decrease in hemoglobin - Tysabri induces mild reductions in hemoglobin levels (mean decrease of 0.6 g/dl) that are frequently transient
- Thrombocytopenia - cases of thrombocytopenia, including immune thrombocytopenic (ITP), have been reported in the postmarketing setting. If symptoms of thrombocytopenia develop (e.g. bleeding, easy bruising), a platelet count should be checked promptly. Cases of neonatal thrombocytopenia, at times associated with anemia, have been reported in newborns with in utero exposure to Tysabri. Check a CBC in newborns who were exposed to Tysabri in utero.
- Vaccines - patients may receive non-live vaccines. Do not give live or attenuated vaccines.
- Liver disease - has not been studied
- Kidney disease - has not been studied
Ocrelizumab (Ocrevus®)
Dosage forms | Maintenance dosing
- Ocrevus® (ocrelizumab) - 300 mg vial | First dose: 300 mg IV; Second dose: 300 mg IV 2 weeks later; Subsequent doses: 600 mg IV every 6 months
FDA-approved indications
MS in adults with:
- Primary progressive disease
- Clinically isolated syndrome
- Relapsing-remitting disease
- Active secondary progressive disease
Efficacy
Lab monitoring
Before therapy
- Hepatitis B screening - see interpreting HBV screening results
Mechanism of action
- Ocrelizumab is a recombinant humanized monoclonal antibody directed against CD20-expressing B-cells. Ocrelizumab is a glycosylated immunoglobulin G1 (IgG1).
- The precise mechanism by which ocrelizumab exerts its therapeutic effects in multiple sclerosis is unknown, but is presumed to involve binding to CD20, a cell surface antigen present on pre-B and mature B lymphocytes. Following cell surface binding to B lymphocytes, ocrelizumab results in antibody-dependent cellular cytolysis and complement-mediated lysis.
Side effects
- NOTE: Only side effects that occurred at an incidence ≥ 5% and more than Rebif are listed
Side effect | Ocrevus 600 mg IV every 24 weeks (N=825) |
Rebif 44 mcg SQ 3 times a week (N=826) |
---|---|---|
Upper respiratory tract infections | 40% | 33% |
Infusion reactions | 34% | 10% |
Depression | 8% | 7% |
Lower respiratory tract infections | 8% | 5% |
Back pain | 6% | 5% |
Herpes virus- associated infections | 6% | 4% |
Pain in extremity | 5% | 4% |
Drug interactions
- Immunosuppressive drugs - concomitant immunosuppressive drugs including corticosteroids may increase the risk of infection. When switching from other immunosuppressants, the duration of effect of these drugs should be taken into account because of potential additive immunosuppressive effects when initiating ocrelizumab.
Contraindications / Precautions
- Pregnancy - risk unknown
- Hepatitis B infection - DO NOT GIVE. Ocrelizumab is contraindicated in patients with active HBV confirmed by positive results for HBsAg and anti-HBV tests. For patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment. See interpreting HBV screening results.
- Infusion reactions - In trials, up to 40% of ocrelizumab-treated patients experienced infusion reactions including pruritus, rash, urticaria, erythema, bronchospasm, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, nausea, tachycardia, and anaphylaxis. Observe patients for at least 1 hour after infusion. Reactions may occur up to 24 hours after infusion. Premedicate with an antihistamine and 100 mg of methylprednisolone (or an equivalent corticosteroid) IV 30 minutes prior to each infusion to reduce the frequency and severity of infusion reactions
- Infections - In RR MS trials, 58% of ocrelizumab-treated patients experienced one or more infections compared to 52% of interferon beta-treated patients. Ocrelizumab increased the risk for upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes-related infections. Ocrelizumab was not associated with an increased risk of serious infections in MS patients.
- Herpes infections - In trials, a slightly higher incidence of herpes infections was seen in ocrelizumab-treated patients when compared to interferon beta-treated patients, including herpes zoster (2.1% vs 1.0%), herpes simplex (0.7% vs 0.1%), oral herpes (3.0% vs 2.2%), and genital herpes (0.1% vs 0%). Serious herpes infections including encephalitis, meningitis, intraocular infections, and disseminated skin and soft tissue infections have occurred in the postmarketing setting.
- Progressive multifocal leukoencephalopathy (PML) - cases of PML have been reported in ocrelizumab-treated patients in the postmarketing setting. PML is an opportunistic viral infection of the brain caused by the JC virus that typically only occurs in immunocompromised patients and usually leads to death or severe disability. Symptoms of PML develop over days to weeks and include progressive weakness on one side of the body, clumsiness of limbs, vision disturbances, disorientation, memory loss, and personality changes. Ocrelizumab should be stopped immediately if signs of PML occur. MRI findings consistent with PML have been observed in asymptomatic patients who went on to develop symptomatic PML. Monitoring patients for PML with MRI may help prevent mortality and morbidity if detected early.
- Vaccines - do not administer live vaccines during therapy and until B-cell repletion occurs after discontinuation. Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of ocrelizumab for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of ocrelizumab for non-live vaccines. In infants of mothers exposed to ocrelizumab during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts as measured by CD19+ B-cells. You may administer non-live vaccines, as indicated, prior to recovery from B-cell depletion, but should consider assessing vaccine immune responses. A study that looked specifically at vaccine responses in patients treated with ocrelizumab found that responses to tetanus, Pneumovax, and influenza were attenuated but still expected to be protective in many patients. [PMID 32727835]
- Malignancies - ocrelizumab may increase the risk of malignancy. In trials, breast cancer occurred more frequently in ocrelizumab-treated patients (6 of 781) than in interferon beta- and placebo-treated patients (0 of 668).
- Immune-mediated colitis (IMC) - cases of IMC, occurring weeks to years after ocrelizumab initiation, have been reported in the postmarketing setting. Symptoms of IMC include sudden onset of persistent diarrhea, abdominal pain, fever, and rectal bleeding. IMC is treated with corticosteroids, supportive therapy, and in severe cases, colectomy.
- Decreased immunoglobulins - ocrelizumab may decrease total immunoglobulins with the greatest decline seen in IgM levels. Following treatment, the proportion of ocrelizumab-treated patients reporting IgG, IgA, and IgM levels below the LLN at 96 weeks was 1.5%, 2.4%, and 16.5%, respectively.
- Decreased neutrophils - In a PP MS clinical trial, decreased neutrophil counts occurred in 13% of ocrelizumab-treated patients compared to 10% in placebo-treated patients.
- Ocrelizumab antibodies - in trials, anti-ocrelizumab antibodies developed in ∼ 1% of patients. It is unknown if antibody production is associated with adverse events or decreased efficacy.
- Liver disease - contraindicated in hepatitis B infection. Patients with mild hepatic impairment were included in clinical trials. No significant change in the pharmacokinetics was observed.
- Kidney disease - patients with mild renal impairment were included in clinical trials. No significant change in the pharmacokinetics was observed.
Ofatumumab (Kesimpta®)
Dosage forms
Sensoready Pen
- 20 mg
- Store refrigerated
Prefilled syringe
- 20 mg
- Store refrigerated
Dosing
- Initial dosing of 20 mg by subcutaneous injection at Weeks 0, 1, and 2, followed by subsequent dosing of 20 mg by subcutaneous injection once monthly starting at Week 4
- If an injection of ofatumumab is missed, it should be administered as soon as possible without waiting until the next scheduled dose. Subsequent doses should be administered at the recommended intervals.
FDA-approved indications
MS in adults with:
- Clinically isolated syndrome
- Relapsing-remitting disease
- Active secondary progressive disease
Efficacy
Lab monitoring
Before therapy
- Hepatitis B screening - see interpreting HBV screening results
- Serum Immunoglobulins - prior to initiating ofatumumab, perform testing for quantitative serum immunoglobulins. For patients with low serum immunoglobulins, consult immunology experts before initiating treatment with ofatumumab.
Mechanism of action
- Ofatumumab is a recombinant human monoclonal immunoglobulin G1 (IgG1) antibody that binds to human CD20 expressed on B-cells
- The precise mechanism by which ofatumumab exerts its therapeutic effects in multiple sclerosis is unknown, but is presumed to involve binding to CD20, a cell surface antigen present on pre-B and mature B lymphocytes. Following cell surface binding to B lymphocytes, ofatumumab results in antibody-dependent cellular cytolysis and complement-mediated lysis.
Side effects
- NOTE: Only side effects that occurred at an incidence ≥ 5% and more than teriflunomide are listed
Side effect | Ofatumumab 20 mg (N=946) |
Teriflunomide 14 mg (N=936) |
---|---|---|
Upper respiratory tract infections | 39% | 38% |
Injection-related reactions (systemic) | 21% | 15% |
Headache | 13% | 12% |
Injection-site reactions (local) | 11% | 6% |
Urinary tract infection | 10% | 8% |
Back pain | 8% | 6% |
Blood IgM decreased | 6% | 2% |
Drug interactions
- Immunosuppressive drugs - concomitant immunosuppressive drugs including corticosteroids may increase the risk of infection. When switching from other immunosuppressants, the duration of effect of these drugs should be taken into account because of potential additive immunosuppressive effects when initiating ofatumumab.
Contraindications / Precautions
- Pregnancy - risk to fetus is unknown, but B-cell lymphopenia and reduced antibody response in offspring exposed to ofatumumab in utero may occur. Females of reproductive potential should use effective contraception while receiving ofatumumab and for at least 6 months after the last dose.
- Hepatitis B infection - DO NOT GIVE. Ofatumumab is contraindicated in patients with active HBV confirmed by positive results for HBsAg and anti-HBV tests. For patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment. See interpreting HBV screening results.
- Infections - ofatumumab may increase the risk of infections. In trials where ofatumumab was compared to teriflunomide, the overall rate of infections and serious infections was similar between groups (51.6% vs 52.7%, and 2.5% vs 1.8%, respectively). The most common types of infections seen in ofatumumab-treated patients were upper respiratory tract infections (39%) and urinary tract infections (10%). Ofatumumab initiation should be delayed in patients with an active infection, and the potential lingering immunosuppressive effects of other drugs should be considered when switching to ofatumumab.
- Progressive multifocal leukoencephalopathy (PML) - no cases of PML, a serious neurologic disease caused by the JC virus, were identified in ofatumumab trials that involved MS patients, but PML resulting in death has occurred in CLL patients receiving intravenous ofatumumab at higher doses. Symptoms of PML 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.
- Injection-related reactions - in trials, up to 21% of ofatumumab-treated patients reported injection-related reactions. Systemic reactions typically occurred within 24 hours of the first injection and included fever, headache, myalgia, chills, and fatigue. Injection site reactions included erythema, swelling, itching, and pain. The first injection of ofatumumab should occur under supervision of a healthcare provider.
- Vaccines - do not administer live vaccines during therapy and until B-cell repletion occurs after discontinuation. Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of ofatumumab for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of ofatumumab for non-live vaccines. In infants of mothers exposed to ofatumumab during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts. Inactivated vaccines may be administered, as indicated, prior to recovery from B-cell depletion, but an assessment of vaccine immune responses, including consultation with a qualified specialist, should be considered to determine whether a protective immune response was mounted.
- Reduction in immunoglobulins - ofatumumab causes a reduction in immunoglobulins. In trials, decreases in immunoglobulin M (IgM) were reported in 7.7% of patients treated with ofatumumab. Immunoglobulin reductions led to discontinuation of treatment in 3.4% of patients. Immunoglobulin G (IgG) levels declined an average of 4.3% at 48 weeks but returned to baseline by 96 weeks. Monitor the levels of quantitative serum immunoglobulins during treatment, especially in patients with opportunistic or recurrent infections, and after discontinuation of therapy until B-cell repletion. Consider discontinuing ofatumumab therapy if a patient with low immunoglobulins develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.
- Ofatumumab antibodies - in trials, anti-ofatumumab antibodies were seen in 0.2% (2/914) of patients. Antibody production was not associated with decreased efficacy or adverse events, however, with such few cases it is not possible to adequately assess the effect of these antibodies.
- Liver disease - contraindicated in hepatitis B infection. Has not been studied in patients with hepatic impairment. Manufacturer makes no recommendation.
- Kidney disease - has not been studied. Manufacturer makes no recommendation.
Ublituximab (Briumvi®)
Dosage forms
Vial
- 150 mg/6 ml (25 mg/ml)
- Store refrigerated
Dosing
- First infusion: 150 mg IV
- Second infusion: 450 mg IV administered two weeks after the first infusion
- Subsequent infusions: 450 mg IV administered 24 weeks after the first infusion and every 24 weeks thereafter
FDA-approved indications
MS in adults with:
- Clinically isolated syndrome
- Relapsing-remitting disease
- Active secondary progressive disease
Efficacy
Lab monitoring
Before therapy
- Hepatitis B screening - see interpreting HBV screening results
- Serum Immunoglobulins - prior to initiating ublituximab, perform testing for quantitative serum immunoglobulins. For patients with low serum immunoglobulins, consult immunology experts before initiating treatment with ofatumumab.
- Pregnancy testing
Mechanism of action
- The precise mechanism by which ublituximab-xiiy exerts its therapeutic effects in multiple sclerosis is unknown, but is presumed to involve binding to CD20, a cell surface antigen present on pre-B and mature B lymphocytes. Following cell surface binding to B lymphocytes, ublituximab-xiiy results in cell lysis through mechanisms including antibody-dependent cellular cytolysis and complement-dependent cytolysis.
Side effects
- NOTE: Only side effects that occurred at an incidence ≥ 5% and more than Teriflunomide are listed
Side effect | Ublituximab IV (N=545) |
Teriflunomide 14 mg (N=548) |
---|---|---|
Infusion reactions | 48% | 12% |
Upper respiratory tract infections | 45% | 41% |
Lower respiratory tract infections | 9% | 7% |
Herpes infections | 6% | 5% |
Pain in extremity | 6% | 4% |
Insomnia | 6% | 3% |
Fatigue | 5% | 4% |
Drug interactions
- Immunosuppressive drugs - concomitant immunosuppressive drugs, including corticosteroids, may increase the risk of infection. When switching from other immunosuppressants, the duration of effect of these drugs should be taken into account because of potential additive immunosuppressive effects when initiating ublituximab.
Contraindications / Precautions
- Pregnancy - ublituximab may cause transient peripheral B-cell depletion and lymphocytopenia in newborns exposed in utero. Pregnancy testing should be performed before therapy and prior to each infusion. Contraception is recommended during treatment and for 6 months after the last dose.
- Hepatitis B infection - DO NOT GIVE. Ublituximab is contraindicated in patients with active HBV confirmed by positive results for HBsAg and anti-HBV tests. For patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment. See interpreting HBV screening results.
- Infusion reactions - in trials, 48% of ublituximab-treated patients experienced infusion reactions, including pyrexia, chills, headache, influenza-like illness, tachycardia, nausea, throat irritation, erythema, and anaphylaxis. Most reactions occurred within 24 hours of the first infusion, and 0.6% were considered serious. Patients should be premedicated with corticosteroids and antihistamines prior to infusion. Monitor patients for at least 1 hour after the first 2 infusions and permanently discontinue ublituximab in patients who experience life-threatening reactions.
- Infections - immunosuppressants like ublituximab can increase the risk of infection. In trials, 56% of ublituximab-treated patients experienced an infection compared to 54% of teriflunomide-treated patients. The incidence of serious infections was 5% and 3%, respectively. The most common infections were upper respiratory tract infections (45%) and UTIs (10%). Ublituximab should be delayed in patients with active infections.
- Progressive multifocal leukoencephalopathy (PML) - cases of PML, a life-threatening opportunistic viral infection of the brain caused by the JC virus, have been reported with other anti-CD20 antibody treatments. Symptoms of PML develop over days to weeks and include progressive weakness on one side of the body, clumsiness of limbs, vision disturbances, disorientation, memory loss, and personality changes. Ublituximab should be stopped immediately if signs of PML occur. MRI findings consistent with PML have been observed in asymptomatic patients who went on to develop symptomatic PML. Monitoring patients for PML with MRI may help prevent mortality and morbidity if detected early.
- Vaccines - do not administer live attenuated vaccines during ublituximab therapy and until B-cell repletion occurs after discontinuation. Live attenuated vaccines should be given at least 4 weeks before initiation, and non-live vaccines should be given at least 2 weeks before initiation when possible. In infants of mothers exposed to ublituximab during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts as measured by CD19+ B-cells. Non-live vaccines may be administered, as indicated, prior to B-cell recovery, but an assessment of vaccine response should be considered.
- Reduction in immunoglobulins - B-cell-depleting agents like ublituximab can cause a reduction in immunoglobulins, particularly IgM. In trials, 21% of ublituximab-treated patients had IgM levels below the lower limits of normal after 96 weeks of therapy. Low immunoglobulin levels have been associated with an increased risk of serious infections in trials involving other anti-CD20 therapies. Monitor antibody levels during treatment and consider stopping therapy if a serious infection develops or hypogammaglobulinemia requiring treatment occurs.
- Decreased neutrophil levels - in studies, neutrophil counts below the lower limit of normal occurred in 15% of ublituximab-treated patients, and most of these counts were between 1000 and 1500 cells/μl. Overall, 1% of patients had counts below 500 cells/μl.
- Anti-ublituximab antibodies - in studies, 81% of ublituximab-treated patients tested positive for anti-ublituximab antibodies, and 6.4% were neutralizing antibodies. Antibodies had no observable effect on the safety or efficacy of ublituximab.
- Kidney disease - mild renal impairment has no meaningful effect on ublituximab pharmacokinetics. Ublituximab has not been studied in patients with moderate-to-severe kidney disease.
- Liver disease - mild hepatic impairment has no meaningful effect on ublituximab pharmacokinetics. Ublituximab has not been studied in patients with moderate-to-severe liver disease.
Fingolimod | Gilenya® | Tascenso®
Dosage forms | Maintenance dosing
- Gilenya® (fingolimod) - 0.25 mg and 0.5 mg capsule | 0.5 mg once daily (adults and children ≥ 88 lbs (40kg)) | 0.25 mg once daily (children < 88 lbs (40kg))
- Tascenso® ODT (fingolimod) - 0.25 mg and 0.5 mg orally disintegrating tablet | 0.5 mg once daily (adults and children ≥ 88 lbs (40kg)) | 0.25 mg once daily (children < 88 lbs (40kg))
FDA-approved indications
MS in patients ≥ 10 years old with:
- Clinically isolated syndrome
- Relapsing-remitting disease
- Active secondary progressive disease
Efficacy
Lab / other monitoring
- Obtain baseline ECG
- CBC before starting therapy and as clinically indicated
- Liver function tests before starting therapy and as clinically indicated. Most increases in liver enzymes occur within 9 months of starting therapy.
- Pregnancy test
- Eye exam at baseline, 3 - 4 months after starting therapy, and as clinically indicated for visual changes
- Patients without a healthcare professional confirmed history of chickenpox or without documentation of a full course of vaccination against varicella should be tested for antibodies to varicella before initiating therapy. For non-immune patients, Varicella vaccine should be given and treatment postponed 1 month.
Mechanism of action
- Fingolimod is metabolized by sphingosine kinase to the active metabolite, fingolimod-phosphate. Fingolimod-phosphate is a sphingosine 1-phosphate receptor modulator, and binds with high affinity to sphingosine 1-phosphate receptors 1, 3, 4, and 5. Fingolimod-phosphate blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood.
Side effects
- NOTE: Only side effects with an overall incidence ≥ 3% and more than placebo are listed
Side effect | Fingolimod 0.5 mg (N=783) |
Placebo (N=773) |
---|---|---|
Headache | 25% | 24% |
Liver transaminase elevations | 15% | 4% |
Nausea | 13% | 12% |
Diarrhea | 13% | 10% |
Cough | 12% | 11% |
Influenza | 11% | 8% |
Sinusitis | 11% | 8% |
Abdominal pain | 11% | 10% |
Back pain | 10% | 9% |
Pain in extremity | 10% | 7% |
Dyspnea | 9% | 7% |
Bronchitis | 8% | 5% |
Hypertension | 8% | 4% |
Lymphopenia | 7% | < 1% |
Migraine | 6% | 4% |
Vision blurred | 4% | 2% |
Bradycardia | 3% | 1% |
Alopecia | 3% | 2% |
Blood triglycerides increased | 3% | 1% |
Skin papilloma | 3% | 2% |
Drug interactions
- QT-prolonging drugs - use caution when combining
- Ketoconazole - ketoconazole increases fingolimod levels 1.7-fold. Use caution.
- Immunosuppressants including steroids - consider risk of immunosuppression/infection when combining, and the overlap of effects that may occur when changing therapies
- Drugs that slow the heart rate - use caution and monitor effects when combining with other drugs that slow the heart rate (e.g. beta blockers, diltiazem, verapamil, clonidine, digoxin)
Contraindications / Precautions
- Pregnancy - fingolimod may cause fetal harm. In rat and rabbit studies, developmental toxicity was observed at doses that were less than what is recommended in humans. After stopping therapy, it takes approximately 2 months for fingolimod to be eliminated from the body. Women of childbearing potential should avoid pregnancy during this time.
- Recent (within 6 months) cardiovascular disease (CVD) - DO NOT USE. CVD includes myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III/IV heart failure.
- Heart block - do not use unless patient has a functioning pacemaker. Heart block includes Mobitz Type II second-degree block, third-degree AV block, and sick sinus syndrome.
- Prolonged QTc interval - fingolimod is contraindicated in patients with a QTc interval ≥ 500 msec. Patients with prolonged QTc intervals (> 450 msec adult and pediatric males, > 470 msec adult females, or > 460 msec pediatric females) before dosing or during 6-hour observation or QT-prolonging risk factors (e.g., hypokalemia, concomitant QT-prolonging drugs) should be monitored overnight with continuous ECG in a medical facility.
- Concomitant Class Ia or Class III antiarrhythmic drugs - DO NOT USE
- Bradycardia - fingolimod may slow the heart rate. After the first dose, maximum reductions typically occur within 6 hours, but a second decrease within 24 hours due to diurnal variation may be seen. Heart rates less than 40 bpm in adults and 50 bpm in children are rare. In adult trials, symptomatic bradycardia following the first dose was reported in 0.6% of patients. Heart rate monitoring for 6 hours after the first dose is recommended in all patients. Continued monitoring is recommended when indicated. In most patients, heart rates return to baseline within a month.
- Liver injury - fingolimod may cause an increase in liver enzymes. In adult trials lasting up to 2 years, increases in liver enzymes > 3 X ULN occurred in 14% of fingolimod-treated patients and 3% of placebo-treated patients. Most elevations occurred within 9 months of starting therapy.
- AV block - fingolimod may cause AV conduction delays. In adult trials, first-degree AV block was seen in 5% of patients and second-degree (Mobitz Type I) AV block in 4%. The conduction abnormalities were usually transient and asymptomatic, resolving within the first 24 hours of treatment.
- Infections - fingolimod may increase risk of infections. In trials, serious infections occurred in 2.3% of fingolimod-treated patients and 1.6% of placebo-treated patients.
- Herpes infections - in trials, herpes infections occurred in 9% of fingolimod-treated patients (0.5 mg) compared to 7% of placebo-treated patients. Serious, life-threatening events of disseminated varicella zoster and herpes simplex infections, including cases of encephalitis and multiorgan failure, have occurred with fingolimod in the postmarketing setting. Varicella titers should be checked before therapy, and nonimmune patients should be vaccinated. Therapy should be delayed for at least 1 month after vaccination.
- Cryptococcal infections - Cryptococcal infections, including cases of fatal cryptococcal meningitis and disseminated cryptococcal infections, have been reported with fingolimod in the postmarketing setting. Cryptococcal infections have generally occurred after approximately 2 years of fingolimod treatment, but may occur earlier.
- HPV infections - Human papillomavirus (HPV) infections, including papilloma, dysplasia, warts, and HPV-related cancer, have been reported in patients treated with fingolimod in the postmarketing setting. Consider giving the HPV vaccine prior to treatment.
- Progressive multifocal leukoencephalopathy (PML) - cases of PML, a serious neurologic disease caused by the JC virus, have been reported in patients receiving fingolimod. Symptoms of PML 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. A condition called immune reconstitution inflammatory syndrome (IRIS) has been reported in patients who stopped fingolimod after PML diagnosis. IRIS typically occurs within a few months of fingolimod discontinuation and often presents as a rapid decline in the patient's neurologic status with characteristic changes on MRI.
- Tumefactive multiple sclerosis - tumefactive MS is a rare form of MS that is marked by large tumor-like demyelinating lesions on MRI. Cases of tumefactive MS have been reported with fingolimod. Most cases occurred within the first 9 months of treatment, but cases have been reported for up to 4 months after therapy cessation.
- Macular edema - fingolimod may cause macular edema. Obtain an eye exam at baseline, 3 - 4 months after starting therapy, and as clinically indicated. In trials, macular edema occurred in 0.5% of fingolimod-treated patients and 0.4% of placebo-treated patients. Most cases occurred within 4 months of starting therapy. Patients with a history of uveitis and/or diabetes have a higher risk.
- Posterior Reversible Encephalopathy Syndrome (PRES) - rare cases of PRES have been reported in fingolimod-treated patients. Symptoms of PRES include sudden onset of severe headache, altered mental status, visual disturbances, and seizures.
- Respiratory effects - fingolimod may cause a slight decrease in respiratory function. In adult trials lasting up to 2 years, the reduction from baseline inFEV₁(% predicted) was 2.8% in fingolimod-treated patients and 1.0% in placebo-treated patients.
- Severe increase in disability upon discontinuation - severe increases in disability upon discontinuing fingolimod have been reported. Most cases occurred within 12 weeks of stopping therapy, but some have been reported up to 24 weeks.
- Blood pressure increase - in adult trials, fingolimod caused an average increase in SBP/DBP of 3 mmHg/2 mmHg
- Skin cancer - in adult trials, the risk of basal cell carcinoma (2% vs 1% for placebo) and melanoma was increased in fingolimod-treated patients
- Lymphoma - cases of lymphoma have been reported in patients receiving fingolimod. The reporting rate of non-Hodgkin lymphoma with fingolimod is greater than that expected in the general population adjusted by age, gender, and region.
- Effect after stopping therapy - fingolimod remains in the system for up to 2 months upon discontinuation. Consider risks of starting new therapy and continued side effects/precautions when stopping.
- Hypersensitivity reactions - hypersensitivity reactions, including rash, urticaria, and angioedema have been reported
- Leukopenia - fingolimod causes a dose-dependent reduction in peripheral lymphocyte count to 20 – 30% of baseline values
- Vaccines - response to all vaccines will be attenuated. Do not give live or attenuated vaccines during and for up to 2 months after discontinuation of therapy.
- Kidney disease - exposure to drug and metabolites is increased. No dosage adjustment is recommended, although it has not been studied extensively.
- Liver disease
- Mild to moderate (Child-Pugh A/B) - no dose adjustment
- Severe (Child-Pugh C) - use caution. Monitor closely.
Ozanimod (Zeposia®)
Dosage forms
Capsule
- 0.23 mg
- 0.46 mg
- 0.92 mg
7-day starter pack
- 4 X 0.23 mg capsules
- 3 X 0.46 mg capsules
37-day starter pack
- 4 X 0.23 mg capsules
- 3 X 0.46 mg capsules
- 30 X 0.92 mg capsules
Dosing
Multiple sclerosis and ulcerative colitis
- Days 1 - 4: 0.23 mg once daily
- Days 5 - 7: 0.46 mg once daily
- Day 8 and on: 0.92 mg once daily
- May take without regard to food
- Swallow capsules whole
- If a dose is missed during the first 2 weeks of treatment, reinitiate treatment using the titration regimen
- If a dose is missed after the first 2 weeks of treatment, continue with the treatment as planned
Liver disease
- Child-Pugh A and B
- Days 1 - 4: 0.23 mg once daily
- Days 5 - 7: 0.46 mg once daily
- Day 8 and on: 0.92 mg every other day
- Child-Pugh C: not recommended
FDA-approved indications
- MS in adults with:
- Clinically isolated syndrome
- Relapsing-remitting disease
- Active secondary progressive disease
- Moderately to severely active ulcerative colitis in adults
Efficacy
Multiple Sclerosis
Ulcerative colitis
Lab / other monitoring
Before starting therapy
- CBC
- Liver function tests (within the last 6 months)
- Varicella zoster antibody titers. If negative, vaccination is recommended before starting therapy. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ozanimod.
- ECG
- Eye exam (evaluation of the fundus, including the macula)
Mechanism of action
- Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1 and 5. Ozanimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis is unknown but may involve the reduction of lymphocyte migration into the central nervous system.
Side effects
- NOTE: Only side effects with an overall incidence ≥ 2% and at least 1% higher than INF beta-1a are listed
Side effect | Ozanimod 0.92 mg (N=882) |
IFN beta-1a 30 mcg once weekly (N=885) |
---|---|---|
Upper respiratory infection | 26% | 23% |
Hepatic transaminase increase | 10% | 5% |
Orthostatic hypotension | 4% | 3% |
Urinary tract infection | 4% | 3% |
Back pain | 4% | 3% |
Hypertension | 4% | 2% |
Upper abdominal pain | 2% | 1% |
Drug interactions
- Monoamine Oxidase (MAO) Inhibitors - DO NOT COMBINE. Co-administration of ozanimod with MAO-B inhibitors may decrease exposure of the active metabolites of ozanimod. In addition, metabolites of ozanimod may inhibit MAO. Co-administration of ozanimod with MAO inhibitors (e.g., selegiline, phenelzine, linezolid) is contraindicated, and at least 14 days should elapse between discontinuation of ozanimod and initiation of treatment with MAO inhibitors.
- CYP2C8 strong inhibitors - DO NOT COMBINE. Ozanimod is a CYP2C8 substrate and CYP2C8 inhibitors may increase its exposure and the risk for adverse events.
- CYP2C8 strong inducers - DO NOT COMBINE. Ozanimod is a CYP2C8 substrate and CYP2C8 inducers may decrease its exposure and efficacy.
- BCRP inhibitors - DO NOT COMBINE. Ozanimod is a BCRP substrate and BRCP inhibitors may increase its exposure and risk for adverse events.
- Adrenergic and Serotonergic Drugs - an active metabolite of ozanimod inhibits MAO-B and may increase the risk for hypertensive crisis when administered with serotonergic or adrenergic drugs (e.g. opioid drugs, SSRIs, SNRIs, tricyclics, tyramine, pseudoephedrine ). Concomitant use of these drugs with ozanimod is not recommended, but if it cannot be avoided, blood pressure should be closely monitored during combined use.
- Immunosuppressive agents (e.g. anti-neoplastic agents, immunomodulators) - ozanimod has not been studied with other non-corticosteroid immunosuppressive drugs. Consider risk of immunosuppression/infection when combining, and the overlap of effects that may occur when changing therapies. Ozanimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.
- Alemtuzumab (Lemtrada®) - because of the prolonged immune-suppressing effects of alemtuzumab, initiating ozanimod after alemtuzumab is not recommended
- Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic drugs - these drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. If treatment with ozanimod is considered, advice from a cardiologist should be sought.
- Combination beta blocker and calcium channel blocker - ozanimod has not been studied in patients who are taking a beta blocker with a heart rate-lowering calcium channel blocker (e.g. verapamil, diltiazem). Ozanimod may potentiate the decrease in heart rate that is seen with these drugs. If concomitant therapy is necessary, a cardiologist should be consulted.
- QT-prolonging drugs - ozanimod has not been studied in combination with QT-prolonging drugs. Do not use with QT-prolonging drugs that have known arrhythmogenic properties. Use caution when combining with others.
Food interactions
- Tyramine - MAO in the gastrointestinal tract and liver (primarily type A) provides protection from exogenous amines (e.g., tyramine). Ozanimod inhibits MAO and could lead to the absorption of intact tyramine which can cause severe hypertension. Aged, fermented, cured, smoked, and pickled foods containing large amounts of exogenous amines (e.g., aged cheese, pickled herring) may cause release of norepinephrine resulting in a rise in blood pressure (tyramine reaction). Patients should be advised to avoid foods containing a large amount of tyramine when taking ozanimod.
Contraindications / Precautions
- Pregnancy - based on animal data, ozanimod may cause fetal harm. Women of childbearing potential should use effective contraception to avoid pregnancy during ozanimod therapy and for 3 months after stopping therapy.
- Cardiovascular disease (CVD) - patients with a history of CVD should consult a cardiologist before using ozanimod, and patients with a history of a CVD event within the last 6 months should not use ozanimod. CVD events include myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III or IV heart failure.
- Heart block - do not use unless the patient has a functioning pacemaker. Heart block includes Mobitz Type II second-degree block, third-degree AV block, sick sinus syndrome, and sino-atrial block.
- Severe untreated sleep apnea - DO NOT USE
- Infections - ozanimod is an immunosuppressant and therefore it may increase the risk of fungal, viral, and bacterial infections. In MS studies lasting up to 2 years, rates of infections and serious infections were similar between ozanimod-treated patients and interferon beta-1a-treated patients (35% vs 34% and 1% vs 0.8%, respectively). In two ulcerative colitis (UC) trials lasting up to 10 weeks, rates of infections and serious infections were similar between ozanimod-treated patients and placebo-treated patients (9.9% vs 10.7% and 0.8% vs 0.4%, respectively). In a third UC trial that lasted 52 weeks, the overall rate of infections was higher in ozanimod-treated patients than placebo-treated patients (23% vs 12%), and the rate of serious infections was similar (0.9% vs 1.8%).
- Herpes viral infections - ozanimod may increase the risk of herpes infections. In MS studies lasting up to 2 years, herpes zoster occurred in 0.6% of ozanimod-treated patients and 0.2% of interferon beta-1a-treated patients. In a UC study lasting 52 weeks, herpes zoster was reported in 2.2% of ozanimod-treated patients and 0.4% of placebo-treated patients. Varicella titers should be measured before therapy and non-immune patients should be vaccinated. Ozanimod should be postponed until at least 4 weeks after vaccination.
- Progressive multifocal leukoencephalopathy (PML) - cases of PML, a serious neurologic disease caused by the JC virus, have been reported with S1P receptor modulators, including ozanimod. Symptoms of PML 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. Patients with suspected PML should be evaluated promptly, and ozanimod should be discontinued.
- Decrease in lymphocytes - due to its mechanism of action (reversible sequestration of lymphocytes in lymphoid tissues) ozanimod causes an average reduction in the peripheral lymphocyte count to 45% of baseline values. In MS trials, lymphocyte counts less than 0.2 X 109 occurred in up to 3.3% of patients. In UC trials, counts less than 0.2 X 109 occurred in up to 2.3% of patients. Counts typically rose above this level while patients remained on treatment. After ozanimod discontinuation, the median time for peripheral blood lymphocytes to return to the normal range was 30 days with approximately 90% of patients returning to the normal range within 3 months. If other immunosuppressants are to be initiated during this time, caution should be used.
- Vaccines - response to all vaccines may be attenuated in patients receiving ozanimod. Do not give live or attenuated vaccines during therapy and for up to 3 months after discontinuation of therapy. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ozanimod.
- Bradycardia - ozanimod may cause a transient decrease in heart rate. In MS trials, the greatest mean decrease in heart rate from baseline was 1.2 bpm and it occurred 5 hours after dosing on Day 1. The maximal heart rate effect occurred on Day 8 of titration. The incidence of bradycardia was 0.8% in ozanimod-treated patients and 0.7% in interferon beta-1a-treated patients. In UC trials, bradycardia was reported in 0.2% of ozanimod-treated patients and 0% of placebo-treated patients.
- Prolonged QTc interval - consult a cardiologist before using
- Atrioventricular (AV) conduction delay - initiation of ozanimod may result in transient AV conduction delays. First- and second-degree type 1 AV blocks were observed in healthy volunteers treated with ozanimod; however, in studies lasting up to 2 years, second- or third-degree AV blocks were not reported in patients treated with ozanimod.
- Liver injury - in MS trials, ALT elevations > 3 X ULN occurred in 5.5% of ozanimod-treated patients compared to 3.1% of interferon beta-1a-treated patients. The median time to elevations was 6 months, and 79% of patients continued treatment with levels returning to < 3 X ULN within 2 - 4 weeks. Ozanimod was discontinued in 1.1% of patients for ALT elevations > 5 X ULN. In UC trials, ALT elevations > 3 X ULN occurred in 2.6% of ozanimod-treated patients. The majority of these patients continued treatment with values returning to < 3 X ULN within 2 - 4 weeks. Patients who develop symptoms of liver injury (e.g. nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice and/or dark urine) should be evaluated for hepatotoxicity.
- Blood pressure increases - in MS studies, systolic blood pressure increased slightly (1 - 2 mmHg) in patients treated with ozanimod when compared to interferon beta-1a-treated patients. There was no effect on diastolic blood pressure. In UC trials, SBP increased by 3.7 - 5.1 mmHg over baseline. There was no effect on DBP. Foods high in tyramine (> 150 mg) may increase the risk. See Food interactions above.
- Respiratory effects - ozanimod may cause a dose-dependent decrease in respiratory function. In MS trials, the reduction from baseline in FEV1 was 60 ml at 1 year in ozanimod-treated patients when compared to interferon beta-1a-treated patients, and the mean difference in percent predicted FEV1 was 1.9%. Dose-dependent reductions in forced vital capacity (average 60 ml) were also seen after 3 months of treatment. In a UC trial, ozanimod-treated patients had a decrease in FEV1 of 22 ml at 10 weeks when compared to placebo-treated patients. There is insufficient information to determine the reversibility of the decrease in FEV1 or FVC after drug discontinuation.
- Macular edema - S1P modulators, including ozanimod, have been associated with an increased risk of macular edema. In MS studies, macular edema occurred in 0.3% of ozanimod-treated patients and 0.3% of interferon beta-1a-treated patients. In UC trials, macular edema was reported in 0.2 - 0.4% of ozanimod-treated patients and 0% of placebo-treated patients. Patients with diabetes and/or a history of uveitis are at greater risk. Patients should have a full eye exam before starting therapy and if they experience any vision changes during therapy. Higher risk patients should have regular eye exams.
- Posterior Reversible Encephalopathy Syndrome (PRES) - in trials, one case of PRES was reported in patients taking ozanimod. Symptoms of PRES include sudden onset of severe headache, altered mental status, visual disturbances, and seizures. PRES is usually reversible, but it may evolve into ischemic stroke or cerebral hemorrhage in some patients. If PRES is not identified promptly, permanent sequelae may occur.
- Severe increase in disability upon discontinuation - in rare cases, severe increases in disability have occurred upon discontinuing S1P receptor modulators. The increases generally occurred within 12 weeks of stopping therapy.
- Immunosuppression after stopping therapy - when switching between immunosuppressants, it is important to consider the prolonged immunosuppressive effects of the therapy that is being discontinued so that excessive, overlapping immunosuppression does not occur. Ozanimod remains in the blood for up to 3 months after discontinuation, and lymphocytes counts may be suppressed during this same period.
- Kidney disease - no dose adjustment necessary
- Liver disease - see Dosing above
Ponesimod (Ponvory®)
Dosage forms
Tablet
- 20 mg
Starter pack (tablets)
- 2 mg X 2
- 3 mg X 2
- 4 mg X 2
- 5 mg
- 6 mg
- 7 mg
- 8 mg
- 9 mg
- 10 mg X 3
Dosing
Multiple sclerosis
- Days 1 and 2: 2 mg once daily
- Days 3 and 4: 3 mg once daily
- Day 5 and 6: 4 mg once daily
- Day 7: 5 mg once daily
- Day 8: 6 mg once daily
- Day 9: 7 mg once daily
- Day 10: 8 mg once daily
- Day 11: 9 mg once daily
- Days 12,13,14: 10 mg once daily
- Day 15 and on: 20 mg once daily
- May take without regard to food
- Swallow tablet whole
- Missed doses: if fewer than 4 consecutive doses are missed, resume titration or maintenance dosing where it was left off. If 4 or more consecutive doses are missed during titration or maintenance, treatment should be reinitiated with a new starter pack.
First dose monitoring
- Because ponesimod can cause bradycardia upon initiation, it is recommended that patients with the following conditions be monitored for 4 hours after receiving the first dose:
- Resting heart rate < 55 bpm
- First- or second-degree (Mobitz type I) AV block
- History of myocardial infarction or heart failure occurring more than 6 months prior to treatment initiation and in stable condition
- An ECG should be obtained at the beginning and end of the 4-hour period. If any of the following are present after 4 hours, continued monitoring is recommended:
- The heart rate 4 hours post-dose is less than 45 bpm
- The heart rate 4 hours post-dose is at the lowest value post-dose, suggesting that the maximum pharmacodynamic effect on the heart may not have occurred
- The ECG 4 hours post-dose shows new onset second-degree or higher AV block
- If post-dose symptomatic bradycardia, bradyarrhythmia, or conduction related symptoms occur, or if ECG 4 hours post-dose shows new onset second degree or higher AV block or QTc ≥ 500 msec, appropriate management should be started
FDA-approved indications
MS in adults with:
- Clinically isolated syndrome
- Relapsing-remitting disease
- Active secondary progressive disease
Efficacy
Lab / other monitoring
Before starting therapy
- CBC (within last 6 months)
- Liver function tests (within the last 6 months)
- Varicella zoster antibody titers. If negative, vaccination is recommended before starting therapy. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ponesimod.
- ECG
- Eye exam (evaluation of the fundus, including the macula)
Mechanism of action
- Ponesimod is a sphingosine 1-phosphate (S1P) receptor 1 modulator that binds with high affinity to S1P receptor 1. Ponesimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which ponesimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.
Side effects
- NOTE: Only side effects with an overall incidence ≥ 2% and at least 1% higher than teriflunomide are listed
Side effect | Ponesimod 20 mg once daily (N=565) |
Teriflunomide 14 mg once daily (N=566) |
---|---|---|
Upper respiratory infection | 37% | 34% |
Hepatic transaminase increase | 23% | 12% |
Hypertension | 10% | 9% |
Urinary tract infection | 6% | 5% |
Dyspnea | 5% | 1% |
Dizziness | 5% | 3% |
Cough | 4% | 2% |
Pain in extremity | 4% | 3% |
Somnolence | 3% | 2% |
Pyrexia | 2% | 1% |
C-reactive protein increase | 2% | 1% |
High cholesterol | 2% | 1% |
Vertigo | 2% | 1% |
Drug interactions
- CYP3A4 strong inducers - DO NOT COMBINE. Ponesimod is a CYP3A4 substrate and CYP3A4 inducers may decrease its exposure and efficacy.
- UGT1A1 inducers - DO NOT COMBINE. Ponesimod is a UGT1A1 substrate and UGT1A1 inducers (e.g. rifampin, phenytoin, carbamazepine) may decrease its exposure and efficacy.
- Immunosuppressive agents (e.g. anti-neoplastic agents, immunomodulators) - ponesimod has not been studied with other immunosuppressive drugs. Consider risk of immunosuppression/infection when combining, and the overlap of effects that may occur when changing therapies. Ponesimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.
- Alemtuzumab (Lemtrada®) - because of the prolonged immune-suppressing effects of alemtuzumab, initiating ponesimod after alemtuzumab is not recommended
- Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic drugs - these drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. If treatment with ponesimod is considered, advice from a cardiologist should be sought.
- Verapamil and diltiazem - ponesimod should not be combined with verapamil or diltiazem because of the potential for significant bradycardia. If concomitant therapy is considered, advice from a cardiologist should be sought.
- Beta blockers - because of the potential for significant bradycardia, caution should be used when combining beta blockers with ponesimod. If the resting heart rate is > 55 bpm under chronic beta blocker therapy, ponesimod may be started. If the heart rate is ≤ 55 bpm, beta blocker therapy should be stopped before initiating ponesimod. Beta blockers can be restarted after ponesimod has been titrated and the resting heart rate is > 55 bpm. Beta blockers can be initiated in patients receiving stable doses of ponesimod.
- Digoxin - ponesimod should not be combined with digoxin because of the potential for significant bradycardia. If concomitant therapy is considered, advice from a cardiologist should be sought.
- QT-prolonging drugs - ponesimod has not been studied in combination with QT-prolonging drugs. Do not use with QT-prolonging drugs that have known arrhythmogenic properties. Use caution when combining with others.
Contraindications / Precautions
- Pregnancy - based on animal data, ponesimod may cause fetal harm. Women of childbearing potential should use effective contraception to avoid pregnancy during ponesimod therapy and for 1 week after stopping therapy.
- Cardiovascular disease (CVD) - patients with a history of a CVD event within the last 6 months should not use ponesimod, and patients with a history of stable CVD should consult a cardiologist before using ponesimod. CVD events include myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III or IV heart failure.
- Heart block - do not use unless the patient has a functioning pacemaker. Heart block includes Mobitz Type II second-degree block, third-degree AV block, sick sinus syndrome, and sino-atrial block.
- Severe untreated sleep apnea - use is not recommended since significant bradycardia may be poorly tolerated in these patients. If treatment is considered, advice from a cardiologist should be sought.
- Uncontrolled hypertension - use is not recommended since significant bradycardia may be poorly tolerated in these patients. If treatment is considered, advice from a cardiologist should be sought.
- Infections - ponesimod is an immunosuppressant and therefore it may increase the risk of fungal, viral, and bacterial infections. In an MS trial lasting 2 years, rates of infections and serious infections were similar between ponesimod-treated patients and teriflunomide-treated patients (54% vs 52% and 1.6% vs 0.9%, respectively). Initiation of ponesimod should be delayed in patients with active infections.
- Herpes viral infections - ponesimod may increase the risk of herpes infections. In an MS trial lasting 2 years, herpetic infections occurred in 4.8% of ponesimod-treated patients and 4.8% of teriflunomide-treated patients. Varicella titers should be measured before therapy and non-immune patients should be vaccinated. Initiation of ponesimod should be postponed for at least 1 month after vaccination.
- Cryptococcal infections - cases of cryptococcal meningitis and disseminated cryptococcal infections have been reported with other S1P receptor modulators. If symptoms of infection occur, patients should stop ponesimod and be evaluated immediately.
- Progressive multifocal leukoencephalopathy (PML) - cases of PML, a serious neurologic disease caused by the JC virus, have been reported with S1P receptor modulators and other MS therapies. Symptoms of PML 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. Patients with suspected PML should be evaluated promptly and ponesimod should be discontinued.
- Decrease in lymphocytes - due to its mechanism of action (reversible sequestration of lymphocytes in lymphoid tissues) ponesimod causes an average reduction in the peripheral lymphocyte count to 30 - 40% of baseline values. In an MS trial lasting 2 years, lymphocyte counts less than 0.2 X 109 occurred in 3.2% of patients. After ponesimod discontinuation, lymphocyte counts returned to normal within 2 weeks. If other immunosuppressants are to be initiated during this time, caution should be used.
- Vaccines - response to all vaccines may be attenuated during ponesimod therapy and for 1 - 2 weeks after discontinuation. Do not give live or attenuated vaccines during therapy and for 1 - 2 weeks after discontinuation of therapy. If live vaccines are given before therapy, they should be given at least 1 month prior to starting ponesimod.
- Bradycardia - ponesimod may cause a transient decrease in heart rate. In an MS trial lasting 2 years, the mean decrease in heart rate on Day 1 of dosing was 6 bpm. The greatest effect occurred 2 - 4 hours after dosing, and heart rate typically returned to baseline 4 - 5 hours after dosing. Bradycardia (< 50 bpm) occurred in 5.8% of patients over the course of the trial. It is recommended that some patients be monitored after receiving the first dose of ponesimod. See Dosing above.
- Atrioventricular (AV) conduction delay - initiation of ponesimod may result in transient AV conduction delays. In one study, first-degree AV block occurred in 3.4% of ponesimod-treated patients. The conduction abnormalities were typically transient, asymptomatic, and resolved within 24 hours.
- Prolonged QTc interval - consult a cardiologist before using
- Atrial fibrillation / flutter - consult a cardiologist before using
- Liver injury - in an MS trial lasting 2 years, ALT elevations > 3 X ULN occurred in 17.3% of ponesimod-treated patients compared to 8.3% of teriflunomide-treated patients. The median time to elevations was 3 months, and 89% of patients continued treatment with levels returning to < 3 X ULN within 2 - 4 weeks. Patients who develop symptoms of liver injury (e.g. nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice and/or dark urine) should be evaluated for hepatotoxicity.
- Blood pressure increases - in an MS trial lasting 2 years, ponesimod-treated patients had an average increase in SBP and DBP of 2.9 mmHg and 2.8 mmHg, respectively. Blood pressure increases were first detected 1 month after starting therapy.
- Skin cancers - skin cancers have been reported in patients receiving S1P receptor modulators including ponesimod. Periodic skin examinations are recommended for all patients.
- Respiratory effects - ponesimod may cause a dose-dependent decrease in respiratory function. In an MS trial lasting 2 years, the reduction from baseline in FEV1 was 8.3% at 2 years in ponesimod-treated patients and 4.4% in teriflunomide-treated patients. There is insufficient information to determine the reversibility of the decrease in FEV1 after drug discontinuation. Use caution in patients with respiratory disease.
- Macular edema - S1P modulators, including ponesimod, have been associated with an increased risk of macular edema. In an MS study lasting 2 years, macular edema occurred in 1.1% of ponesimod-treated patients and 0% of teriflunomide-treated patients. Patients with diabetes and/or a history of uveitis are at greater risk. Patients should have a full eye exam before starting therapy and if they experience any vision changes during therapy. Higher risk patients should have regular eye exams.
- Posterior Reversible Encephalopathy Syndrome (PRES) - cases of PRES have been reported in patients who were treated with other S1P receptor modulators. In premarketing trials, no cases of PRES were identified in ponesimod-treated patients. Symptoms of PRES include sudden onset of severe headache, altered mental status, visual disturbances, and seizures. PRES is usually reversible, but it may evolve into ischemic stroke or cerebral hemorrhage in some patients. If PRES is not identified promptly, permanent sequelae may occur.
- Severe increase in disability upon discontinuation - in rare cases, severe increases in disability have occurred upon discontinuing S1P receptor modulators. The increases generally occurred within 12 weeks of stopping therapy.
- Immunosuppression after stopping therapy - when switching between immunosuppressants, it is important to consider the prolonged immunosuppressive effects of the therapy that is being discontinued so that excessive, overlapping immunosuppression does not occur. Ponesimod remains in the blood for up to 1 week after discontinuation, and lymphocytes counts may be suppressed for up to 2 weeks.
- Kidney disease - no dose adjustment necessary
- Liver disease
- Child-Pugh A: no dose adjustment necessary
- Child-Pugh B and C: do not use
Siponimod (Mayzent®)
Dosage forms
Tablet
- 0.25 mg
- 2 mg
- Also comes in a starter pack with 12 X 0.25 mg tablets
Dosing
MS and CIS
- Siponimod dosing is based on CYP2C9 genotype. See Mayzent PI for complete dosing instructions and titration schedules.
- Typical maintenance dose: 1 - 2 mg once daily
- Do not cut, crush, or chew tablets
- May take without regard to food
FDA-approved indications
MS in adults with:
- Clinically isolated syndrome
- Relapsing-remitting disease
- Active secondary progressive disease
Efficacy
Lab / other monitoring
Before starting therapy
- Obtain CYP2C9 genotype. Dosing recommendations are based on this.
- CBC
- Liver function tests
- Varicella zoster antibody titers. If negative, vaccination is recommended before starting therapy. Siponimod should be postponed until at least 4 weeks after vaccination.
- ECG
- Eye exam (evaluation of the fundus, including the macula)
Mechanism of action
- Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod binds with high affinity to S1P receptors 1 and 5. Siponimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which siponimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.
Side effects
- NOTE: Only side effects with an overall incidence ≥ 5% and at least 1% higher than placebo are listed
Side effect | Siponimod 2 mg (N=1099) |
Placebo (N=546) |
---|---|---|
Headache | 15% | 14% |
Hypertension | 13% | 9% |
Transaminase increase | 11% | 3% |
Falls | 11% | 10% |
Peripheral edema | 8% | 4% |
Nausea | 7% | 4% |
Dizziness | 7% | 5% |
Diarrhea | 6% | 4% |
Bradycardia | 6% | 3% |
Pain in extremity | 6% | 4% |
Drug interactions
- Alemtuzumab (Lemtrada®) - because of the prolonged immune-suppressing effects of alemtuzumab, initiating treatment with siponimod after alemtuzumab is not recommended
- Beta blockers - use caution when initiating siponimod in patients receiving beta blockers because of the additive effects on lowering heart rate. Temporary interruption of the beta blocker may be needed prior to initiation of siponimod. Beta blocker treatment can be initiated in patients receiving stable doses of siponimod.
- Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic drugs - these drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. If treatment with siponimod is considered, advice from a cardiologist should be sought.
- CYP2C9 moderate inducers - siponimod is a CYP2C9 substrate and CYP2C9 inducers decrease its exposure. Use caution when combining siponimod with moderate CYP2C9 inducers.
- CYP3A4 moderate or strong inducers + CYP2C9*1/*3 and*2/*3 genotype - concomitant use of siponimod and moderate (e.g., modafinil, efavirenz) or strong CYP3A4 inducers is not recommended for patients with CYP2C9*1/*3 and*2/*3 genotype. See CYP3A4 for more.
- Drugs that slow the heart rate - siponimod should generally not be initiated in patients who are taking medications that can slow the heart rate. Examples of these drugs include verapamil and diltiazem, ivabradine, and digoxin.
- Immunosuppressive agents (e.g. anti-neoplastic agents, immunomodulators, corticosteroids) - siponimod has not been studied with other immunosuppressive drugs. Consider risk of immunosuppression/infection when combining, and the overlap of effects that may occur when changing therapies. Siponimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate
- QT-prolonging drugs - siponimod has not been studied in combination with QT-prolonging drugs. Do not use with QT-prolonging drugs that have known arrhythmogenic properties. Use caution when combining with others.
- With moderate CYP2C9 inhibitors + moderate or strong CYP3A4 inhibitors - siponimod is a CYP2C9 and CYP3A4 substrate. Individual drugs (e.g. fluconazole) or drug combinations that involve both moderate CYP2C9 inhibition and moderate or strong CYP3A4 inhibition increase exposure to siponimod and should not be taken with it. See CYP2C9 and CYP3A4 for more.
- With moderate CYP2C9 inducers + strong CYP3A4 inducers - siponimod is a CYP2C9 and CYP3A4 substrate. Individual drugs (e.g. rifampin) or drug combinations that involve both moderate CYP2C9 induction and strong CYP3A4 induction decrease exposure to siponimod and should not be taken with it. See CYP2C9 and CYP3A4 for more.
Contraindications / Precautions
- Pregnancy - based on animal data, siponimod may cause fetal harm and is not recommended. Women of childbearing potential should use effective contraception to avoid pregnancy during and for 10 days after stopping siponimod.
- CYP2C9*3/*3 genotype - siponimod exposure is increased in patients homozygous for CYP2C9*3 (i.e., CYP2C9*3/*3 genotype) which occurs in approximately 0.4% - 0.5% of Caucasians and less in others. Siponimod should not be given to these patients.
- Cardiovascular disease (CVD) - for patients with a history of a CVD event within the last 6 months, do not use siponimod. CVD events include myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III or IV heart failure. For patients with a history of CVD, consult a cardiologist before using.
- Heart block - do not use unless patient has a functioning pacemaker. Heart block includes Mobitz Type II second-degree block, third-degree AV block, and sick sinus syndrome.
- Bradycardia - siponimod may slow the heart rate. Heart rate decreases reach an average maximum of 5 - 6 bpm within 3 - 4 hours after the first dose. With up-titration, continued smaller decreases occur with maximum decreases from baseline peaking on day 5 - 6. After day 6, heart rates start to increase and reach placebo levels by day 10. In one study (N=1651) lasting a median of 21 months, bradycardia occurred in 4.4% of siponimod-treated patients and 2.9% of placebo-treated patients. First dose monitoring for 6 hours or longer is recommended for patients with sinus bradycardia (< 55 bpm), first- or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure with onset > 6 months. See Mayzent PI [sec 2.4] for recommendations on monitoring.
- Atrioventricular (AV) conduction delay - initiation of siponimod results in transient AV conduction delays which typically manifest as first-degree AV block. In trials, first-degree AV block was seen in 5.1% of siponimod-treated patients and 1.9% of placebo-treated patients. Second-degree AV blocks, usually Mobitz type I (Wenckebach), were observed in 1.7% of siponimod-treated patients. Most conduction delays resolved within 24 hours after initial dosing.
- Infections - siponimod is an immunosuppressant and therefore it may increase the risk of fungal, viral, and bacterial infections. In one study (N=1651) lasting a median of 21 months, serious infections occurred in 2.9% of siponimod-treated patients and 2.5% of placebo-treated patients.
- Decrease in lymphocytes - siponimod causes a dose-dependent reduction in the peripheral lymphocyte count of 20 - 30% of baseline. Lymphocyte counts return to normal within 10 days of stopping therapy in 90% of patients but may remain suppressed for 3 - 4 weeks. These effects should be considered when stopping siponimod and before starting other therapies.
- Macular edema - in trials, macular edema occurred in 1.8% of siponimod-treated patients and 0.2% of placebo-treated patients. Patients with diabetes and/or a history of uveitis are at greater risk with an incidence of about 10% in these patients. Patients should have a full eye exam before starting therapy and at any time there is a change in vision. Higher risk patients should have regular eye exams.
- Prolonged QTc interval - consult a cardiologist before using
- Respiratory effects - siponimod may cause a slight decrease in respiratory function. In trials, the reduction from baseline in FEV1 was 88 ml at 2 years in siponimod-treated patients and the mean difference in percent predicted FEV1 between siponimod-treated patients and placebo-treated patients was 2.8%.
- Liver injury - in trials, transaminase and bilirubin elevations occurred in 10.1% of siponimod-treated patients and 3.7% of placebo-treated patients with ALT increases 3 - 5 X ULN occurring in 5.6% of siponimod-treated patients. Most elevations occurred within 6 months of starting therapy. ALT levels returned to normal within 1 month of stopping therapy. In trials, siponimod was discontinued if elevations exceeded a 3-fold increase and the patient showed symptoms related to hepatic dysfunction.
- Skin cancers - siponimod may increase the risk of skin cancers. In one study, the incidence of basal and squamous cell carcinomas in siponimod-treated patients was 1% and 0.2%, respectively. Cases of melanoma have also been reported. Patients receiving siponimod should have regular skin cancer screenings and take preventive measures (e.g. protective clothing, sunscreen) to reduce their risk. Phototherapy with UV radiation (e.g psoriasis) is not recommended during siponimod therapy.
- Blood pressure elevations - siponimod may raise blood pressure levels. In one study (N=1651) lasting a median of 21 months, siponimod-treated patients had an average increase over placebo of approximately 3 mmHg in systolic pressure and 1.2 mmHg in diastolic pressure.
- Herpes viral infections - siponimod may increase the risk of herpes infections, including meningitis or meningoencephalitis. In one study (N=1651) lasting a median of 21 months, herpes infections occurred in 4.6% of siponimod-treated patients and 3% of placebo-treated patients. Herpes zoster was reported in 2.5% of siponimod-treated patients and 0.7% of placebo-treated patients. Varicella titers should be measured before therapy and non-immune patients should be vaccinated. Siponimod should be postponed until at least 4 weeks after vaccination.
- Progressive multifocal leukoencephalopathy (PML) - cases of PML, a serious neurologic disease caused by the JC virus, have not been reported with siponimod, but they have been reported with fingolimod, another S1P receptor modulator. Symptoms of PML 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.
- Vaccines - response to all vaccines will be attenuated. Do not give live or attenuated vaccines during and for up to 4 weeks after discontinuation of therapy. Siponimod therapy should be interrupted 1 week prior and for 4 weeks after other vaccinations.
- Posterior Reversible Encephalopathy Syndrome (PRES) - no cases of PRES have been reported with siponimod, but rare cases have been seen with fingolimod, another S1P receptor modulator. Symptoms of PRES include sudden onset of severe headache, altered mental status, visual disturbances, and seizures.
- Severe increase in disability upon discontinuation - in rare cases, severe increases in disability have occurred upon discontinuing S1P receptor modulators. The increases generally occurred within 12 weeks of stopping therapy.
- Kidney disease - no dose adjustment necessary
- Liver disease - no dose adjustment necessary
Teriflunomide (Aubagio®)
Dosage forms
Tablet
- 7 mg
- 14 mg
- Generic available
Dosing
- Dosing: 7 - 14 mg once daily
- May take without regard to food
FDA-approved indications
MS in adults with:
- Clinically isolated syndrome
- Relapsing-remitting disease
- Active secondary progressive disease
Efficacy
Lab monitoring
- Liver function tests before starting therapy. Monitor ALT at least monthly for 6 months after starting therapy and as clinically indicated thereafter.
- CBC before starting therapy and as clinically indicated
- Pregnancy test before starting therapy. Teriflunomide is contraindicated in pregnancy.
- TB testing before starting therapy. For patients testing positive, treat prior to therapy.
Mechanism of action
- Teriflunomide inhibits dihydroorotate dehydrogenase (DD), a mitochondrial enzyme involved in de novo pyrimidine synthesis. DD inhibition suppresses the proliferation of autoreactive B and T cells and promotes a shift towards anti-inflammatory cytokines. Teriflunomide is an active metabolite of the drug leflunomide that is used to treat rheumatoid arthritis.
Side effects
Side effect | Aubagio 14 mg (N=1002) |
Placebo (N=997) |
---|---|---|
Headache | 16% | 15% |
Increase in ALT | 15% | 9% |
Diarrhea | 14% | 8% |
Alopecia | 13% | 5% |
Nausea | 11% | 7% |
Paresthesia | 9% | 7% |
Arthralgia | 6% | 5% |
Neutropenia | 6% | 2% |
Hypertension | 4% | 2% |
Drug interactions
- BCRP substrates - teriflunomide is a BCRP inhibitor and it may increase exposure to BCRP substrates
- CYP1A2 substrates - teriflunomide is a CYP1A2 weak inducer and it may decrease exposure to CYP1A2 substrates
- CYP2C8 substrates - teriflunomide is a CYP2C8 inhibitor and it may increase exposure to CYP2C8 substrates. Use caution when combining.
- Immunosuppressant drugs - teriflunomide has not been studied long term with other immunosuppressant medications. When switching from teriflunomide to other immunosuppressants, consider the long half-life of teriflunomide and possible overlapping effects.
- Leflunomide - DO NOT COMBINE. Teriflunomide is the principal active metabolite of leflunomide.
- OAT3 substrates - teriflunomide is an OAT3 inhibitor and it may increase exposure to OAT3 substrates
- OATP1B1/1B3 substrates - teriflunomide is an OATP1B1/1B3 inhibitor and it may increase exposure to OATP1B1/1B3 substrates. Consider dose adjustments when necessary.
- Oral contraceptives - teriflunomide may increase exposure to ethinyl estradiol and levonorgestrel by 1.3 - 1.6 fold
- Rosuvastatin (Crestor®) - rosuvastatin doses should not exceed 10 mg when given with teriflunomide
- Warfarin (coumadin®) - peak INR levels may be decreased by 25% when warfarin is combined with teriflunomide. Monitor INR levels closely.
Contraindications / Precautions
- Pregnancy - DO NOT USE. May cause fetal harm or death.
- Severe liver disease - DO NOT USE
- Coadministration with leflunomide - DO NOT COMBINE. Teriflunomide is the principal active metabolite of leflunomide.
- History of a hypersensitivity reaction to leflunomide - DO NOT USE. Teriflunomide is the principal active metabolite of leflunomide.
- Hepatotoxicity - acute liver failure requiring transplantation has been reported in patients taking teriflunomide in the postmarketing setting. The risk may be higher in patients with preexisting liver disease and in those who are taking other hepatotoxic medications. In trials, ALT > 3 X ULN occurred in 6.2% of patients (14 mg dose). Elevations occurred mostly during the first year of treatment, and half returned to normal without discontinuation. Consider stopping therapy for ALT > 3 X ULN.
- Rapid elimination protocol - teriflunomide is eliminated slowly from plasma. It takes an average of 8 months after discontinuation for levels to decline below 0.02 mg/L, and in some people, it can take as long as 2 years. Accelerated elimination can be achieved with one of the two following procedures: (1) Administration of cholestyramine 8 g every 8 hours for 11 days. If cholestyramine 8 g three times a day is not well tolerated, cholestyramine 4 g three times a day can be used; (2) administration of 50 g oral activated charcoal powder every 12 hours for 11 days. With either regimen, teriflunomide levels have been shown to decrease by > 98% after 11 days.
- Bone marrow suppression - in trials, WBCs decreased by an average of 15% and platelets decreased by an average of 10%. The decrease in WBCs occurred during the first 6 weeks of treatment and persisted during therapy.
- Serious infections - teriflunomide is an immunosuppressant, and therefore, it may increase the risk of infection. In studies, the incidence of serious infections in teriflunomide-treated patients was similar to what was seen in placebo-treated patients (7 mg - 2.2% | 14 mg - 2.7% | placebo - 2.2%)
- Tuberculosis (TB) - test for TB before starting therapy. If positive, treat before starting therapy.
- Vaccines - do not give live or attenuated vaccines during therapy. Consider the long half-life of teriflunomide when giving vaccines after stopping therapy.
- Malignancy - teriflunomide may increase the risk of malignancy, particularly lymphoproliferative disorders. In trials, no increased risk of malignancy was observed.
- Hypersensitivity - teriflunomide can cause anaphylaxis and severe allergic reactions including dyspnea, urticaria, and angioedema including lips, eyes, throat, and tongue
- Serious skin reactions - serious skin reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving teriflunomide
- Drug reaction with eosinophilia and systemic symptoms (DRESS) - DRESS, including one fatal case, has been reported in patients receiving teriflunomide. DRESS typically presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement including hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately.
- Peripheral neuropathy - in trials, peripheral neuropathy was seen in 1.4% (7 mg) and 1.9% (14 mg) of teriflunomide-treated patients compared to 0.4% of placebo-treated patients. Not all cases of peripheral neuropathy resolved after treatment discontinuation. Age > 60 years, concomitant neurotoxic medications, and diabetes may increase the risk. If a patient taking teriflunomide develops symptoms consistent with peripheral neuropathy, such as bilateral numbness or tingling of hands or feet, consider discontinuing teriflunomide therapy and performing an accelerated elimination procedure (see above).
- Pancreatitis in pediatric patients - in a pediatric MS trial, pancreatitis occurred in 1.8% of teriflunomide-treated patients and 0% of placebo-treated patients. Cases of pancreatitis in adults have been reported in the postmarketing setting. Teriflunomide is not approved for use in children. If pancreatitis is suspected, discontinue teriflunomide and start an accelerated elimination procedure.
- Increase in blood pressure - in trials, average SBP increased by 2.3 mmHg (7 mg) and 2.7 mmHg (14 mg) in teriflunomide-treated patients compared to a decrease of 0.6 mmHg in placebo-treated patients. Hypertension was reported as an adverse reaction in 3 - 4% of teriflunomide-treated patients. Check blood pressure before therapy and periodically thereafter.
- Interstitial lung disease - cases of interstitial lung disease have been reported in the postmarketing setting
- Liver disease
- Mild to moderate (Child-Pugh A/B) - no dose adjustment
- Severe (Child-Pugh C) - DO NOT USE
- Kidney disease - no dose adjustment necessary
- OTHER TREATMENTS
- Haematopoietic stem cell transplant
- Haematopoietic stem cell transplants (HSCT) have been used to treat refractory MS. During a HSCT, stem cells are obtained from a donor (allogeneic) or the patient (autologous). The cells are typically taken from the bone marrow or peripheral blood. To obtain cells from the peripheral blood, a procedure called "mobilization" must be performed. During mobilization, the patient receives granulocyte colony-stimulating factor (G-CSF) +/- cytotoxic chemotherapy in order to increase the number of circulating stem cells.
- Before transplantation, ablative conditioning is performed where the patient is given high-dose chemotherapy and/or total body radiation in order to ablate the native immune system. Stem cells are then infused into the patient where they restore the bone marrow and reconstitute the immune system. To reduce the risks of ablative conditioning, lower intensity regimens called "nonmyeloablative regimens" have been developed. These regimens use lower doses of chemotherapy in order to reduce overall immune suppression.
- The best candidates for HSCT are patients who are young (≤ 50 years), ambulatory, have active relapsing–remitting MS, short disease duration (≤ 5 years), and ongoing relapses despite treatment
- In trials lasting up to 5 years, 70 - 80% of MS patients who have undergone HSCT have achieved complete suppression of disease activity
- See HSCT studies below for more [5,21]
- Exercise
- Exercise has been shown to be beneficial in the treatment of MS. It has also been shown to be beneficial for a number of MS symptoms including gait disturbance, fatigue, mood, cognition, and quality of life.
- All patients with MS should be encouraged to engage in regular exercise that includes both strength and endurance training. They should also be aware that exercise does not have any harmful effects on their condition. [22]
- Rituximab
- Rituximab is a B-cell depleting agent that is FDA-approved to treat rheumatoid arthritis and polyangiitis. Rituximab is similar to ocrelizumab in that they are both monoclonal antibodies that target CD20-expressing B-cells.
- Several studies have looked at the efficacy of rituximab in treating RR MS (PMID 18272891, PMID 27038238) and PP MS (PMID 19847908)
- Smoking
- Smoking is a strong risk factor for MS, and continued smoking after diagnosis is associated with increased progression to disability
- All patients with MS should be strongly advised to quit smoking [5,8]
- STUDIES
- Head-to-head drug trials
- Fingolimod vs Interferon Beta-1a in Pediatric MS, NEJM (2018)
- Ocrelizumab vs Interferon Beta-1a in RR MS (2017), NEJM (2017)
- Alemtuzumab vs Interferon Beta in Treatment-resistant RR MS, Lancet (2012)
- Alemtuzumab vs Interferon Beta as First-line Treatment for RR MS, Lancet (2012)
- Fingolimod vs interferon beta for RR MS, NEJM (2010)
- Glatiramer Acetate vs Interferon Beta-1b in RR MS, Lancet Neurol (2009)
- Alemtuzumab vs Interferon Beta in RR MS, NEJM (2008)
- Natalizumab + Interferon beta vs Interferon beta in RR MS, NEJM (2006)
- Haematopoietic stem cell transplant (HSCT) trials
- PRICE ($) INFO
Pricing legend
- $ = 0 - $50
- $$ = $51 - $100
- $$$ = $101 - $150
- $$$$ = > $150
- Pricing based on one month of therapy at standard dosing in an adult
- Pricing based on information from GoodRX.com®
- Pricing may vary by region and availability
- BIBLIOGRAPHY
- 1 - PMID 27889190 - Diagnosis of multiple sclerosis: progress and challenges, Lancet (2017)
- 2 - PMID 29275977 - Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria, Lancet (2017)
- 3 - PMID 27889192 - Evolving concepts in the treatment of relapsing multiple sclerosis, Lancet (2017)
- 4 - PMID 27889191 - Progressive multiple sclerosis: prospects for disease therapy, repair, and restoration of function, Lancet (2017)
- 5 - PMID 29576504 - Multiple sclerosis, Lancet (2018)
- 6 - PMID 29320652 - Multiple sclerosis, NEJM (2018)
- 7 - PMID 30094157 - Multi-component relaxation in clinically isolated syndrome: Lesion myelination may predict multiple sclerosis conversion, Neuroimage Clin (2018)
- 8 - Multiple sclerosis in adults: management, NICE clinical guidelines (2014)
- 9 - PMID 29686116 - AAN Summary of Practice Guideline for Clinicians: Practice Guideline: Disease-modifying Therapies for Adults with Multiple Sclerosis (2018)
- 10 - PMID 29352526 - ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis (2018)
- 11 - PMID 24728334 - Recurrence or rebound of clinical relapses after discontinuation of natalizumab therapy in highly active MS patients, J Neurol (2014)
- 12 - PMID 19308305 - The efficacy of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL, J Neurol (2009)
- 13 - PMID 27087457 - Fatigue Management in Multiple Sclerosis, Curr Treat Options Neurol (2016)
- 14 - PMID 17318714 - Tremor in multiple sclerosis, J Neurol (2007)
- 15 - PMID 29956001 - The Management of Lower Urinary Tract Dysfunction in Multiple Sclerosis, Curr Neurol Neurosci Rep (2018)
- 16 - PMID 27862898 - Low-dose desmopressin combined with serum sodium monitoring can prevent clinically significant hyponatremia in patients treated for nocturia, BJU Int (2017)
- 17 - DDAVP tablet PI
- 18 - PMID 22447199 - Multiple sclerosis and sexual dysfunction, Asian J Androl (2012)
- 19 - PMID 30584387 - Neurogenic bowel dysfunction in patients with multiple sclerosis: prevalence, impact, and management strategies, Degener Neurol Neuromuscul Dis (2018)
- 20 - PMID 29070964 - Trigeminal Neuralgia Commonly Precedes the Diagnosis of Multiple Sclerosis, Int J MS Care (2017)
- 21 - PMID 28621766 - Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis, Nature Reviews (2017)
- 22 - PMID 30637728 - Rehabilitation for people with multiple sclerosis: an overview of Cochrane Reviews, Cochrane Database Syst Rev. (2019)
- 23 - PMID 35025605 - Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis, Science (2022)
- 24 - PMID 37184850 - Population-Based Estimates for the Prevalence of Multiple Sclerosis in the United States by Race, Ethnicity, Age, Sex, and Geographic Region, JAMA Neurology (2023)