MULTIPLE SCLEROSIS (MS)





































  • Optic nerve lesions in a patient presenting with optic neuritis cannot be used in fulfilling the McDonald criteria. Symptomatic and asymptomatic MRI lesions can be consideredin the determination of dissemination in space or time.
  • DIS - dissemination in space
  • DIT - dissemination in time
  • Reference [2]
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:
  • DIS on MRI
  • DIS demonstrated by clinical attack implicating a different CNS site
1 ≥ 2 One of the following:
  • DIT on MRI
  • Presence of CSF-specific oligoclonal bands
1 1 DIS on MRI and one of the following:
  • DIT on MRI
  • Presence of CSF-specific oligoclonal bands

  • Symptomatic and asymptomatic MRI lesions may be considered
  • Reference [2]
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:
  • One or more T2-hyperintense lesions characteristic of MS in one or more of the following brain regions: periventricular, cortical or juxtacortical, or infratentorial
  • Two or more T2-hyperintense spinal cord lesions
  • Presence of CSF-specific oligoclonal bands




  • Reference [2]
MS differential
Condition Comment
Acute disseminated encephalomyelitis
  • Mainly seen in children; rare in adults
  • Marked by grey and white matter lesions on MRI
  • Clinical symptoms are similar to MS but also include encephalopathy (mental status changes)
Neuromyelitis optica spectrum disorder
  • Marked by optic neuritis (typically bilateral) and transverse myelitis that is longitudinally extensive (> 3 vertebral segments) involving the central cord
  • Female predisposition (9:1) and more common in Asian/African
  • 70% of affected patients are positive for aquaporin 4 antibody (AQP4-IgG)
Neurosarcoidosis
  • Marked by cranial nerve involvement (including optic nerve), myelopathy, and meningeal enhancement
  • Other findings consistent with sarcoidosis
CNS vasculitis
  • Marked by headache, mental status changes, and/or focal neurological deficits
  • Lesions of the grey and white matter often with evidence of microhemorrhage
  • May be positive for serum anti-neutrophil cytoplasmic antibodies (ANCA)
CNS hypoxic events
  • Strokes and other CNS events that lead to hypoxia/ischemia
  • Depending on the area, may cause white matter lesions
Susac's syndrome
  • Marked by vision and hearing loss and mental status changes
  • Corpus callosum (snowball lesions) and white and grey matter lesions
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
  • Marked by migraines, strokes, dementia, and psychiatric problems
  • Testing for NOTCH3 gene mutation and/or skin biopsies with distinct pathology
Connective tissue diseases
Neuro-Behcet's disease
  • Marked by large brainstem lesions in patients with a history of oral and genital ulcers and intraocular inflammation
  • HLA-B5 testing may be helpful
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS)
  • Marked by gadolinium-enhancing lesions within the brainstem and cerebellum
  • Symptoms include ataxia, double vision, and slurred speech
Fabry's disease
  • Rare genetic lipid metabolism disorder
  • Symptoms include stroke events and vertigo
  • GLA enzyme activity or gene testing




  • Reference [1,2,3,4,5,7]
Clinical Course and Prognostic Factors of MS and Related Syndromes
Radiologically isolated syndrome
  • About 34% of patients with radiologically isolated syndrome will go on to develop clinically isolated syndrome or MS (typically relapsing-remitting) over the next 5 years
  • Male sex, younger age (< 37 years), multiple CNS lesions, gadolinium-enhancing lesions, CSF-specific oligoclonal bands, abnormal visual evoked potentials, and/or presence of infratentorial/spinal cord lesions are all factors that may be associated with a higher risk of developing MS
  • Spinal cord lesions and male sex increase the risk of developing primary progressive MS
Clinically isolated syndrome
  • In studies lasting up to 20 years, 65 - 80% of patients with a clinically isolated syndrome and an abnormal baseline MRI have gone on to be diagnosed with MS
  • Male sex, younger age (< 37 years), multiple CNS lesions, gadolinium-enhancing lesions, CSF-specific oligoclonal bands, abnormal visual evoked potentials, and/or presence of infratentorial/spinal cord lesions are all factors that may be associated with a higher risk of developing MS
  • The presence of ≥ 10 brain lesions on MRI is strongly associated with progression to MS
Relapsing-remitting MS
  • Most common type of MS accounting for 85 - 90% of cases. Throughout the disease, women have higher relapse rates than men.
  • 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
  • Older age (> 37 years) at diagnosis, male sex, greater disability at baseline, and a higher degree of brain atrophy are associated with a greater risk of developing progressive disability
  • Short interval between first and second attacks and higher number of lesions at clinical onset are associated with greater risk for long-term disability
Primary progressive MS
  • Accounts for 10 - 15% of patients diagnosed with MS
  • Typically presents at an older age (mean age of onset is 40 years) and men and women are affected equally
  • Older age (> 37 years) at diagnosis, male sex, greater disability at baseline, and a higher degree of brain atrophy are associated with a greater risk of developing progressive disability
  • Motor impairment is the predominant form of progressive disability, but ataxia, visual impairment, and cognitive dysfunction may also be progressive
Secondary progressive MS
  • Typically occurs after a 10 - 15 year course of relapsing-remitting MS. Occurs more frequently in women than men.
  • 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 around11% over a ten-year period
  • Motor impairment is the predominant form of progressive disability, but ataxia, visual impairment, and/or cognitive dysfunction may also be progressive



Clinically Isolated Syndrome (CIS) Treatment Recommendations
AAN recommendations
  • Multiple trials have confirmed that treating CIS with disease-modifying therapies (DMTs) is associated with a significant delay in second clinical relapse or new brain MRI-detectedlesions in people with a first demyelinating event who are considered to be at high risk for MS on the basis of brain MRI-detected lesions
  • Clinicians should discuss the benefits and risks of treatment for people with CIS who have ≥ 2 brain lesions that have imaging characteristics consistent with MS
  • After discussing the risks and benefits, clinicians should prescribe treatment to people with a single clinical demyelinating event and two or more brain lesions characteristic of MS who decide they want this therapy. There is insufficient evidence to recommend a specific therapy.
  • For patients who are not being treated, annual imaging with close follow-up is recommended for at least 5 years [9]

EAN/ECTRIMS recommendations
  • Offer interferon or glatiramer acetate to patients with CIS and an abnormal MRI with lesions suggestive of MS who do not fulfil criteria for MS [10]

Studies in CIS

Relapsing-remitting MS Treatment Recommendations
AAN recommendations
  • Clinicians should offer disease-modifying therapies (DMTs) to people with relapsing forms of MS with recent clinical relapses or MRI activity
  • Clinicians should prescribe alemtuzumab, fingolimod, or natalizumab to people with highly active MS
  • Clinicians may recommend azathioprine or cladribine for people with relapsing forms of MS who do not have access to approved DMTs
  • Annual imaging with close follow-up for at least 5 years may be recommended for patients who are not on DMTs, have not had relapses in the preceding two years, and do not have active new MRI lesion activity on recent imaging [9]

EAN/ECTRIMS recommendations
  • Offer early treatment with DMTs in patients with active relapsing-remitting MS as defined by clinical relapses and/or MRI activity (active lesions, contrast-enhancing lesions; new or unequivocally enlarging T2 lesions assessed at least annually)
  • Choice of DMT will depend on the following factors: patient characteristics and comorbidities, disease severity/activity, drug safety profile, drug accessibility
  • Use one of the following drugs: interferon beta-1b, interferon beta-1a SQ or IM, peginterferon beta-1a, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, fingolimod, daclizumab, natalizumab, ocrelizumab and alemtuzumab [10]

Expert opinion recommendations
  • Initial therapy - patients with average-active MS
    • Dimethyl fumarate
    • Teriflunomide
    • Interferon beta
    • Glatiramer acetate
  • Initial therapy - patients with highly-active MS
    • Natalizumab
    • Fingolimod
    • Alemtuzumab
    • Daclizumab [3]

  • Definition of highly-active MS varies by trial. In one trial, the following criteria were used: ≥ 2 relapses in the prior year with ≥ 1 gadolinium-enhancing lesion on MRI. In another trial, ≥ 2 relapses in the past year or ≥ 3 relapses in the past 2 years was used. [11,12]

Primary Progressive MS Treatment Recommendations
AAN recommendations
  • Clinicians should offer ocrelizumab to people with primary progressive MS who are likely to benefit from this therapy unless there are risks of treatment that outweigh the benefits [9]

EAN/ECTRIMS recommendations
  • Consider treatment with ocrelizumab for patients with primary progressive MS [10]

Studies in primary progressive MS

Secondary Progressive MS Treatment Recommendations
AAN recommendations
  • The AAN does not make specific recommendations for secondary progressive MS [9]

EAN/ECTRIMS recommendations
  • Consider treatment with interferon beta-1a (subcutaneously) or interferon beta-1b in patients with active secondary progressive MS taking into account, in discussion with the patient, the dubious efficacy, as well as the safety and tolerability profile of these drugs
  • Consider treatment with mitoxantrone in patients with active secondary progressive MS taking into account, in discussion with the patient, the efficacy and specifically the safety and tolerability profile of this agent
  • Consider treatment with ocrelizumab or cladribine for patients with active secondary progressive MS [10]

Monitoring Therapy Recommendations
AAN recommendations
  • Patients not being treated with DMTs
    • For patients who are not being treated with DMTs, annual imaging with close follow-up is recommended for at least 5 years [9]
  • Patients being treated with DMTs
    • Clinicians should recognize that relapses or new MRI-detected lesions may develop after initiation of a DMT and before the treatment becomes effective in people with MS who are using DMTs. Consequently, many clinicians obtain new baseline MRI three to six months after initiating DMTs to monitor from a treated baseline.

EAN/ECTRIMS recommendations
  • When monitoring treatment response in patients treated with DMTs, perform a standardized reference brain MRI usually within 6 months of treatment onset and compare it with a further brain MRI performed typically 12 months after starting treatment. Adjust the timing of both MRIs, taking into account the DMTs typical onset of treatment effect and disease activity.
  • The preferred measure of treatment response to DMTs is the appearance of new or unequivocally enlarging T2 lesions supplemented by gadolinium-enhancing lesions
  • When monitoring treatment safety, perform MRI according to the following:
    • Low risk of PML: annually
    • High risk of PML (JCV+, natalizumab for ≥ 18 months): every 3 - 6 months and when switching drugs [10]

Therapy Failure / Intolerance Recommendations
AAN recommendations
  • General recommendations
    • Clinicians should discuss switching from one DMT to another in people with MS who have been using a DMT long enough for the treatment to take full effect and are adherent to their therapy when they experience one or more relapses, two or more unequivocally new MRI-detected lesions, or increased disability on examination, over a one-year period of using a DMT
    • Switching to a DMT with a different mechanism or efficacy profile may be beneficial
    • Alemtuzumab, natalizumab, fingolimod, and ocrelizumab may have higher efficacy when compared to previously approved self-injectable DMTs [9]
  • Natalizumab recommendations
    • Clinicians should discuss switching to a DMT with a lower PML risk in patients with MS taking natalizumab who are or become JCV antibody positive, especially with an index of above 0.9 while on therapy
    • Clinicians should check for natalizumab antibodies in people with MS who have infusion reactions before subsequent infusions, or in people with MS who experience breakthrough disease activity with natalizumab use. Clinicians should switch DMTs in people with MS who have persistent natalizumab antibodies.
    • Physicians must counsel people with MS considering natalizumab discontinuation that there is an increased risk of MS relapse or MRI-detected disease activity within six months of discontinuation
    • Physicians and people with MS choosing to switch from natalizumab to fingolimod should initiate treatment within eight to 12 weeks after natalizumab discontinuation (for reasons other than pregnancy or pregnancy planning) to diminish the return of disease activity [9]
  • Cancer while receiving DMTs
    • If a patient with MS develops a malignancy while using a DMT, clinicians should promptly discuss switching to an alternate DMT, especially for people with MS using azathioprine, methotrexate, mycophenolate, cyclophosphamide, fingolimod, teriflunomide, alemtuzumab, or dimethyl fumarate [9]
  • Serious infections while receiving DMTs
    • People with MS who develop serious infections potentially linked to their DMT should switch DMTs (does not pertain to PML management in people with MS using DMT [9]

EAN/ECTRIMS recommendations
  • Offer a more efficacious drug to patients treated with interferon or glatiramer acetate who show evidence of treatment failure
  • When treatment with a highly efficacious drug is stopped, either due to inefficacy or safety concerns, consider starting another highly efficacious drug
  • In treatment decisions, consider the possibility of resumed disease activity or even rebound when stopping treatment, particularly with natalizumab

Expert opinion recommendations for relapsing-remitting MS
  • Step 1
    • For patients who do not achieve therapeutic goals on their initial therapy, consider switching to one of the following:
      • Natalizumab
      • Fingolimod
      • Alemtuzumab
      • Mitoxantrone - due to side effects, should only be used as a last resort
  • Step 2
    • For patients who fail Step 1, consider the following:
      • Rituximab
      • Ofatumumab
      • Stem cell transplant [3]

Stopping Therapy Recommendations
AAN recommendations
  • Clinically-isolated syndrome
    • There is insufficient evidence to make a recommendation in regards to the risk/benefit of stopping therapy in patients with CIS who are being treated with DMTs [9]
    • In CIS treatment studies (see CIS treatment above), patients were typically treated for 2 - 3 years
  • Relapsing-remitting MS
    • No randomized controlled trials have directly addressed the question of whether, when, or why to discontinue DMTs in an individual with relapsing-remitting MS who has no evidence of relapses or disability progression and has stable brain imaging. The natural history of untreated relapsing-remitting MS is for relapses and disability accumulation to occur.
    • In a randomized controlled trial of 175 individuals taking natalizumab who had been relapse free for one year and had no gadolinium-enhanced lesions on MRI, participants were randomized to continue natalizumab use, switch to placebo, or switch to other therapies. Relapses occurred in 4% of those continuing natalizumab use and in 15 - 29% of those in other treatment arms over 24 weeks. An observational study comparing outcomes in individuals who did or did not stop DMT after a period of at least five years without relapses found a similar risk of relapses between the groups but an increased risk of disability progression among those who stopped DMT. Younger age and lower Expanded Disability Status Scale (EDSS) scores were significant predictors of relapse (clinical or MRI) after treatment discontinuation.
    • Clinicians should advocate that people with MS who are stable (that is, no relapses, no disability progression, stable imaging) on DMT should continue their current DMT unless the patient and physician decide a trial off therapy is warranted [9]
  • Secondary progressive MS
    • People with secondary progressive MS who have relapses or active MRI-detected new lesion formation benefit from DMT
    • No randomized controlled trials have directly addressed the question of whether or when to discontinue DMTs in people with secondary progressive MS. Clinical trials have not evaluated the benefits of DMT in individuals with secondary progressive MS who are nonambulatory with respect to other clinically relevant domains, including vision, cognition, and upper limb function
    • Among individuals with secondary progressive MS (those with and those without clinical relapses) for at least two years at the time of treatment withdrawal, an EDSS ≥ 6 was associated with a 50% lower risk of relapses or MRI-detected activity after treatment discontinuation
    • Clinicians should assess the likelihood of future relapse in individuals with secondary progressive MS by assessing patient age, disease duration, relapse history, and MRI-detected activity (e.g., frequency, severity, time since most recent relapse or gadolinium-enhanced lesion).
    • Clinicians may advise discontinuation of DMT in people with secondary progressive MS who do not have ongoing relapses (or gadolinium-enhanced lesions on MRI activity) and have not been ambulatory (EDSS ≥ 7) for at least two years [9]

EAN/ECTRIMS recommendations
  • Consider continuing a DMT if a patient is stable (clinically and on MRI) and shows no safety or tolerability issues [10]

Pregnancy Recommendations
AAN recommendations
  • Relapse risk is reduced during pregnancy and increases in the postpartum period (3 - 6 months)
  • Clinicians should counsel women to stop their DMT before conception for planned pregnancies unless the risk of MS activity during pregnancy outweighs the risk associated with the specific DMT during pregnancy
  • Clinicians should discontinue DMTs during pregnancy if accidental exposure occurs, unless the risk of MS activity during pregnancy outweighs the risk associated with the specificDMT during pregnancy
  • Clinicians should not initiate DMTs during pregnancy unless the risk of MS activity during pregnancy outweighs the risk associated with the specific DMT during pregnancy [9]

EAN/ECTRIMS recommendations
  • Advise all women of childbearing potential that the only DMT that has an FDA pregnancy category rating of "B" is glatiramer acetate
  • For women planning a pregnancy, if there is a high risk of disease reactivation, consider using interferon or glatiramer acetate until pregnancy is confirmed. In some very specific (active) cases, continuing this treatment during pregnancy could also be considered.
  • For women with persistent high disease activity, it would generally be advised to delay pregnancy. For those who, despite this advice, still decide to become pregnant or have an unplanned pregnancy, consider the following:
    • Treatment with natalizumab throughout pregnancy may be considered after full discussion of potential implications
    • Treatment with alemtuzumab could be an alternative therapeutic option for planned pregnancy in very active cases, provided that a 4-month interval is strictly observed from the latest infusion until conception [10]



Fatigue
Overview
  • Fatigue, which is often severe, affects up to 80% of patients with MS. It may be precipitated by heat, overexertion, and stress. It may also be related to the time of day. [8,13]
Treatment
  • Amantadine
    • Starting: 100 mg twice daily
    • Max: 400 - 600 mg/day [13]
    • Efficacy: mostly unproven [PMID 17253480]
  • Exercise - aerobic, strength training, stretching and yoga; has shown benefit in trials [PMID 26358158]
  • Modafinil (Provigil®)
  • L-Carnitine
    • Dosing: 1000 mg twice daily [13]
    • Efficacy: mostly unproven in trials [PMID 22592719]
Studies
  • A crossover study (N=141) published in 2021 that compared amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), and methylphenidate (up to 10 mg twice daily) to placebo for MS fatigue found that none of the drugs were superior to placebo [PMID 33242419]
Spasticity
Overview
  • Spasticity is common in MS affecting up to 80% of patients
  • Spasticity can range from a sense of tightness, especially in the legs, to prolonged muscle contraction that can lead to contractures and an inability to walk [8]
  • The efficacy of recommended treatments has not been well-studied [PMID 23450612, PMID 14583932]
Treatment
  • First-line
  • Second-line
    • Diazepam
    • Clonazepam
    • Dantrolene
      • Dosing: titrate as follows:
        • 25 mg once daily for seven days, then
        • 25 mg three times a day for seven days, then if necessary
        • 50 mg three times a day for seven days, then if necessary
        • 100 mg three times a day
        • Use lowest effective dose
        • Do not exceed 100 mg four times a day
  • Other
    • Exercise
    • Cannabidiol or tetrahydrocannabinol
    • Botulinum injections
    • Phenol injections
Oscillopsia
Overview
  • Oscillopsia is a condition where objects in the visual field appear to oscillate
  • Patients with MS who have brainstem and/or cerebellar lesions may develop oscillopsia
  • Only a few small trials have looked at the efficacy of gabapentin and memantine in treating oscillopsia [PMID 20437565, PMID 19756822]
Treatment
  • First-line
    • Gabapentin - in trials, doses of 1200 mg/day have been used
  • Second-line
    • Memantine (Namenda®) - in trials, doses of 40 - 60 mg/day have been used
Gait disturbance
Overview
  • Gait disturbance is a common problem in MS affecting up to 85% of patients
  • Mobility issues are often multifactorial with lesion pathology, fatigue, spasticity, and muscle weakness/deconditioning all playing a role
Treatment
  • First-line
    • Exercise and physical therapy
  • Second-line
    • Dalfampridine (Ampyra®)
      • Dosing: 10 mg every 12 hours
      • May increase risk of seizures. FDA-approved to improve walking in adults with MS.
      • Efficacy: [PMID 19249634]
Tremor
Overview
  • Tremor is a common condition in MS affecting 25 - 60% of patients
  • MS-associated tremor can be severe and disabling. The most common types of tremor in MS are postural tremor (tremor while maintaining stationary position against gravity) and intention tremor (tremor occurring with target-directed movement that increases in amplitude as the movement gets closer to the target).
  • Medications are mostly ineffective at treating tremor while surgery may be indicated in severe cases [14]
Treatment
  • Medications
  • Surgery
    • Thalamotomy
    • Deep brain stimulation
Bladder dysfunction
Overview
  • As MS progresses, the prevalence of bladder dysfunction symptoms approaches 100%. Initial symptoms typically appear around 8 years after diagnosis with about 10% of patients having symptoms at the time of diagnosis.
  • Urinary storage symptoms (e.g. urgency, frequency, incontinence) and voiding symptoms (e.g. hesitancy, weak/interrupted stream, straining, incomplete emptying sensation) may occur depending on the location of MS lesions [15]
Treatment
  • Medications
    • Antimuscarinic agents (e.g. oxybutynin, tolterodine, solifenacin, darifenacin) - for storage symptoms
    • Mirabegron (Myrbetriq®) - for storage symptoms
    • Alpha-1 blockers - for voiding symptoms
    • Desmopressin (DDAVP) - for storage symptoms
      • Dosing (tablet): 0.1 - 0.6 mg once daily. Restrict fluid intake one hour before and up to 8 hours after taking. Use lowest effective dose.
      • Contraindicated in hyponatremia (Na ≤ 135 mmol/L) and CrCl < 50 ml/min
      • After initiating or changing therapy, monitor for hyponatremia at 1 week, 1 month, and every 6 months thereafter depending on risk
      • Risk factors for hyponatremia include elderly, female sex, decreased renal function, and concomitant drugs that lower sodium [15,16,17]
    • PDE-5 inhibitors (e.g. tadalafil) - may be beneficial for storage and voiding symptoms
    • Cannabinoids - may help storage symptoms
  • Other
    • Intravesical botulinum toxin
    • Urinary catheterization - permanent and intermittent
    • Pelvic floor exercises
    • Sacral neuromodulation [15]
Sexual dysfunction
Overview
  • Sexual dysfunction is common in both women and men with MS. In studies of men with MS, the following issues have been reported: erectile dysfunction (50% – 75%), ejaculatory dysfunction and/or orgasmic dysfunction (50%), reduced libido (39%), anorgasmia (37%). In women, the following has been reported:anorgasmia or hyporgasmia (37%), decreased vaginal lubrication (36%) and reduced libido (31%).
  • Sexual dysfunction in MS is often multifactorial and includes lesion pathology (e.g. genital numbness/paresthesia, erectile dysfunction), hormone dysregulation, psychological factors (depression, etc.), fatigue/weakness, and medication side effects
  • PDE-5 inhibitors have been shown to be effective in men, but treatment options in women are limited [18]
Treatment
Bowel dysfunction
Overview
  • Bowel dysfunction affects up to 70% of patients with MS and symptoms can range from chronic constipation to fecal incontinence
  • Bowel dysfunction is often multifactorial, and in the case of constipation includes lesion pathology (e.g. anorectal hyposensitivity, pelvic floor dyssynergia, loss of supraspinal modulation), and medication side effects (particularly anticholinergics). Factors that may contribute to fecal incontinence include lesion pathology (e.g. anorectal hyposensitivity, anal sphincter weakness, loss of voluntary control of defecation), and uncontrolled colonic peristalsis. [5,19]
Treatment
  • Constipation
    • Exercise and diet
    • Abdominal massage
    • Biofeedback
    • Laxatives - psyllium fiber, polyethylene glycol (Miralax®), lactulose, bisacodyl
    • Serotonin agonists - prucalopride (Motegrity®)
    • Chloride channel activators - lubiprostone (Amitiza®)
    • Guanylate cyclase agonists - linaclotide (Linzess®)
    • Transanal irrigation and enemas
  • Fecal incontinence
    • Pelvic floor exercises
    • Periodic evacuation of the rectum using enemas or suppositories
    • Injectable anal bulking agents
    • Sphincteroplasty
    • Sacral nerve stimulator
    • Colostomy or ileostomy in refractory cases [5,19]
Mood and cognition
Overview
  • Mood and cognitive disorders are common in patients with MS. Treatment is generally the same as in patients without MS.
Treatment
  • Mood disorders
    • Antidepressants - depression and anxiety
    • Exercise - depression and anxiety
  • Cognitive impairment
  • Pseudobulbar affect - sudden inappropriate laughing or crying
    • Dextromethorphan/quinidine - available as Nuedexta®, or much cheaper as individual components [PMID 16634036]
Pain
Overview
  • Pain is common in patients with MS affecting up to 60% of patients at some point during the course of their disease
  • MS lesions can produce pain both directly and indirectly. Neuropathic pain in MS may include paresthesias in affected distributions, optic neuritis, and trigeminal neuralgia (affects up to 4% of MS patients). Musculoskeletal pain is common and may occur from spasticity, contractures, and mobility/posture issues. [5,8,20]
Treatment



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
During therapy and for 48 months after the last dose
  • 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



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 and thrombotic thrombocytopenic purpura (TTP) 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.
  • 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.
  • 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 - vaccinate patients who are nonimmune before therapy
  • Baseline MRI (within 3 months prior to treatment)
During therapy
  • 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



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. Test for varicella immunity before starting therapy and vaccinate nonimmune patients. Administer live-attenuated or live vaccines (e.g. Zostavax®) at least 4 to 6 weeks prior to starting therapy. 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 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®)

Dosage forms | Dosing

  • Tecfidera® (dimethyl fumarate) - 120 mg and 240 mg capsule | 120 mg twice daily for 7 days then 240 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

  • 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


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


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 by 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. Four weeks after stopping therapy, lymphocyte counts still did not return to baseline. Consider stopping or changing 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
  • PML - rare cases of PML 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


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


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 by 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. Four weeks after stopping therapy, lymphocyte counts still did not return to baseline. 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.
  • PML - rare cases of PML 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®)

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: Glutopa®

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


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 | 125 mcg SQ 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


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


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.
  • Injection site reactions - in trials, injection site reactions were reported in 78% of interferon beta-treated patients and included inflammation (42%), pain (16%), hypersensitivity (4%), necrosis (4%), mass (2%), and edema (2%). Reactions tended to decrease over time.
  • 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 that occurred 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
Before each dose
  • CBC and liver function tests
  • Pregnancy test
  • ECG and cardiac ECHO
After therapy
  • 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


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
Crohn's disease

Efficacy


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


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.

  • Estimates are for patients with no prior immunosuppressant use
  • Reference [9]
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
  • Imm = immunosuppressants
  • Examples of immunosuppressants include mitoxantrone, azathioprine, methotrexate, cyclophosphamide, and mycophenolate mofetil
  • Reference [Manufacturer's PI]
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 decreases in hemoglobin levels (mean decrease of 0.6 g/dl) that are frequently transient
  • 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

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


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.
  • 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) - no cases of PML were identified in ocrelizumab clinical trials, but JC virus infection resulting in PML has been observed in patients treated with other anti-CD20 antibodies
  • Vaccines - do not administer live vaccines during therapy and until B-cell repletion. 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).
  • 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


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.
  • 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 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. 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.

Fingolimod (Gilenya®)

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))

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



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 (≥ 500 msec) - DO NOT USE
  • Concomitant Class Ia or Class III antiarrhythmic drugs - DO NOT USE
  • Bradycardia - fingolimod may slow the heart rate. 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.
  • 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 was seen in 4% of patients. The conduction abnormalities were usually transient and asymptomatic, and resolved 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 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.
  • 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. The increases generally occurred within 12 weeks of stopping therapy.
  • 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

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


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



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 have been reported with S1P receptor modulators and other MS and UC 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 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 - not recommended

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



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 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



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 cell carcinomas was 1% in siponimod-treated patients. Cases of melanoma and squamous cell carcinoma have also been reported in siponimod-treated patients. Patients receiving siponimod should have regular skin cancer screenings and take preventive measures (e.g. protective clothing, sunscreen) to reduce their risk of skin cancer. 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. 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 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

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