FINGOLIMOD CAP,ORAL
Clinical Criteria Summary
Criteria for MS Disease Activity Categories & General DMT Selection
- • Highly active relapsing MS: >1 clinical and/or 1-2 radiographic relapses per year while on low- to moderate-efficacy DMT; OR presenting within 5 years since disease onset with initial high-risk features (myelopathic relapses, infratentorial signs, incomplete recovery from initial relapses within 6 months, >1 clinical and/or radiographic relapse per year, high burden brain/spinal cord T2 lesions at disease onset, high accumulation of brain/spinal T2 lesions over first year or ≥5 over 2 years).
- • Minimally to non-active relapsing MS: Does not meet criteria for highly active; overlap exists; no clinical or radiographic relapses >5 years.
- • Clinically isolated syndrome (CIS): Favor moderate to high efficacy DMT if high-risk features present (>2 brain lesions on MRI); favor low risk DMT if low-risk features (<2 brain lesions on MRI, no high-risk features); monitoring without DMT may be an option with brain MRI at least every 6 months.
- • Primary progressive multiple sclerosis (PPMS): Offer clinically appropriate DMT for <55 years and EDSS ≤6.5, or for anyone if benefits outweigh risks; consider stopping if >55 years, EDSS >5.5, no relapses >5 years, lack of clinical response, or adverse events.
- • General Selection Principles: Efficacy is prioritized for highly active (favor high efficacy DMT) and minimally active (favor moderate efficacy DMT; escalate to high efficacy if ongoing/increase in disease activity in 3 months or less). Safety is prioritized for non-active (monitoring with no DMT may be an option; favor low risk DMT if de-escalating). Most DMTs have a positive correlation between efficacy and risk.
Criteria for De-escalation and Discontinuation of DMT
- • Age & Stability Considerations: MS relapses tend to become less frequent with age; de-escalation/discontinuation may reduce side effect risk for older patients. It may be reasonable to discontinue DMT in patients older than 55 years with stable MS, or consider early discontinuation in patients older than 50 years on lower efficacy DMT (interferons or glatiramer).
- • Relapse Risk Factors After Discontinuation: Increased risk associated with age under 55 years, history of disease activity or disability progression within 3 years prior to stopping, moderate disability (EDSS 4-5.5), and being on a higher potency DMT immediately prior to discontinuation.
- • De-escalation vs. Discontinuation: De-escalation may include evidence-based dose reduction, extending dosing interval, or switching to a higher safety DMT. Patients on natalizumab or S1PR modulators should be considered for de-escalation rather than discontinuation due to relapse risk after stopping.
- • Post-Discontinuation Monitoring: Monitor with MRI annually for first two years after stopping, then yearly x2-4, then PRN; monitor clinically at least annually. If stable, transition to annual clinical visits with intermittent MRIs.
Criteria for Alemtuzumab (LEMTRADA)
- • Administration: IV infusion daily for 5 days then 1 year later, IV infusion daily for 3 days. Repeat 3-day courses if clinically indicated and at least 12 months after last dose. Typical pre-medication: high dose corticosteroid as methylprednisolone 1000mg immediately prior to first dose and for first 3 days of each course.
- • Contraindications & Special Considerations: Has a REMS program providing lab and imaging frequency guidance. Contraindicated if active infection. Delay treatment if active skin infusion reactions, stroke or cervicocephallic arterial dissection, malignancy, PML.
- • Monitoring: Baseline: HIV, VZV, TB, HBV, CBC w/ diff, CMP, UA w/ cell counts, thyroid function tests, autoimmune encephalitis, acquired hemophilia. Routine: CBC w/ diff, CMP, TSH, LFT, UA w/ cell counts, protein, skin exam.
- • Adverse Events: Serious: Secondary autoimmune diseases (including autoimmune hepatitis, thyroid disorders, hemophagocytic lymphohistiocytosis, adult onset Still’s disease, thrombotic microangiopathy, thrombotic thrombocytopenic purpura, acquired hemophilia), serious infusion reactions, PML. Common: rash, headache, pyrexia, nasopharyngitis, nausea/vomiting, minor infections, fatigue, insomnia, urticaria, pruritus, thyroid disorders, arthralgia, pain in extremity, back pain, diarrhea, sinusitis, oropharyngeal pain, paresthesia, dizziness, abdominal pain, flushing.
- • Vaccines: Give antivirals for herpes prophylaxis starting day 1 of treatment until CD4+ lymphocytes >200 cells/microliter or 2 months. Consider giving VZV vaccine if patient has not been vaccinated and is negative for monocytegenes VZV antibodies. Instruct patients to avoid potential sources of Listeria.
- • Washout: Unknown appropriate washout time from previous DMT; weigh risks of longer washout against relapse risk. Additive immunosuppression risk assessed via lymphocyte counts when switching.
- • Pregnancy & Lactation: Avoid if pregnant; use contraception during and for 4 months after treatment course. Avoid breastfeeding during treatment and at least 3 months after last dose.
Criteria for Anti-CD20 Antibodies (Rituximab, Ublituximab, Ocrelizumab, Ofatumumab)
- • Administration: Rituximab/biosimilars: IV infusion every 6 months; typical pre-medications: acetaminophen 650mg PO, diphenhydramine 50mg PO, methylprednisolone 100mg IVP over 3-5 minutes. Ublituximab: IV infusion every 24 weeks; typical pre-medications: diphenhydramine 50mg PO/IV, methylprednisolone 100 mg IVP over 3-5 minutes +/- acetaminophen; slower infusion rates recommended for first doses. Ocrelizumab: IV infusion every 6 months; typical pre-medications: acetaminophen 650mg PO, diphenhydramine 50mg PO, methylprednisolone 100mg IVP over 3-5 minutes. Ofatumumab: SubQ once monthly; first dose under healthcare professional guidance; can be stored at room temperature for up to 7 days.
- • Contraindications & Special Considerations: Contraindicated if active HBV infection. Delay infusion/injection if acute infection. For IV formulations, prevent infusion reactions with premedication and slower rates. Rituximab/biosimilars: MS is off-label indication but evidence-based. Ocrelizumab: only anti-CD20 antibody FDA approved for PPMS. Can consider using CD19 results to guide dose/dosing interval.
- • Monitoring: Baseline/Routine: CBC w/ diff, CMP, immunoglobulins (IgG, IgM). Screen for hepatitis B (required), hepatitis C, TB, pregnancy.
- • Adverse Events: Serious: HBV reactivation, serious infusion/injection-related reactions (most common with initial dose), serious infections, PML, malignancy, immune-mediated colitis (ocrelizumab), hypoglobulinemia. Common: minor infusion/injection-related reactions, infections, CV events (rituximab).
- • Washout: Unknown appropriate washout time from previous DMT; weigh risks of longer washout against relapse risk. Immunoglobulins can estimate lasting immunosuppressive effect after discontinuation. Lymphocyte counts help assess magnitude of immunosuppression and additive risks when switching.
- • Pregnancy & Lactation: PIs recommend avoiding anti-CD20 during pregnancy and people of childbearing potential should use contraception during and for at least 6 months after stopping therapy. Emerging post-marketing safety data indicate potential for safe use. For infants born to mothers exposed, live vaccines should not be administered until normal B-cell counts are verified. Probably compatible with breastfeeding.
Criteria for Cladribine (MAVENCLAD)
- • Administration: PO given in 2 yearly treatment courses. Each course divided into 2 treatment cycles. Separate from other oral medications by at least 3 hours.
- • Contraindications & Special Considerations: Contraindicated if current malignancy, HIV infection, active infections, chronic hepatitis or TB, Hepatitis B, Hepatitis C, and indicated cancer screenings. Delay treatment if active infection. Do not start unless lymphocytes are WNL and >800 cells/microliter before starting second course.
- • Monitoring: Baseline/Routine: CBC w/ diff, LFT. Screen for latent infections, VZV failure, PML potential. Give VZV vaccine if seronegative prior to starting another cladribine course; give recombinant zoster vaccine if VZV positive. Give antivirals for herpes prophylaxis if lymphocytes<200 cells/microliter.
- • Adverse Events: Serious: malignancies, lymphopenia, serious infections, serious skin reactions including SJS and TEN, liver injury, hypersensitivity, cardiac failure, PML potential, Graft-versus-host disease with blood transfusion. Common: minor infections, headache, lymphopenia, neutropenia, anemia, thrombocytopenia.
- • Washout: 4-month washout; intermediate half-life but prolonged biologic activity; no human evidence of fetotoxicity. Unknown appropriate washout time from previous DMT; weigh risks of longer washout against relapse risk. Additive immunosuppression risk assessed via lymphocyte counts when switching.
- • Pregnancy & Lactation: Contraindicated during pregnancy. All patients with reproductive potential (regardless of gender) should use contraception during and for 6 months after the last dose in each treatment course. Not compatible with breastfeeding.
Criteria for Fumarates (Dimethyl fumarate, Diroximel fumarate, Monomethyl fumarate)
- • Administration: PO BID. Administer with food; can administer meals or snack to decrease flushing and GI side effects. Healthy-fat or protein containing food (e.g., yogurt, peanut butter) may help for DMF and MMF. Limit food to 700 calories and 30g fat or less for DRF. Aspirin can premedicate with non-enteric coated aspirin (up to 325 mg) 30 minutes prior to dose to reduce flushing. Temporary dose reduction may be used for up to 4 weeks then resume maintenance dose.
- • Contraindications & Special Considerations: Most common intolerances are GI related and flushing. DRF associated with lower GI intolerances; flushing incidence not significantly different from other fumarates. Post-marketing cases of PML reported with DMF; all fumarates should be monitored for PML risk.
- • Monitoring: Baseline/Routine: CBC with differential, LFT. Screen for hepatitis and/or TB if high risk. UA if proteinuria suspected (DMF). Discontinue if lymphocytes <500 for >6 months; monitor lymphocytes until discontinuation which may be resolved. Lymphocyte counts help assess magnitude of immunosuppression and additive risks after discontinuation or switching to higher efficacy DMT.
- • Adverse Events: Common: flushing, abdominal pain, diarrhea, nausea, infection.
- • Washout: Unknown appropriate washout time from previous DMT; weigh risks of longer washout against relapse risk.
- • Pregnancy & Lactation: Should be discontinued before conception; no specified washout required. DMF: Active metabolite in breastmilk low and not expected to cause AEs in breastfed infants; exposed infants should be monitored for adequate weight gain and development, especially younger exclusively breastfed infants. DRF: Acceptable to use during breastfeeding at least after 1 month of age; breastfed infants should be monitored, especially younger exclusively breastfed infants.
Criteria for Glatiramer acetate (COPAXONE, GLATOPA, other generics)
- • Administration: SubQ daily OR 3 times weekly. Doses should be at least 48 hours apart. Can inject with or without autoinjector. Can be stored at room temperature for up to one month.
- • Contraindications & Special Considerations: Contraindicated if hypersensitivity to mannitol. Idiosyncratic post-injection reactions may include chest pain, flushing, dyspnea, palpitations and/or anxiety that tends to subside within 30 minutes; can occur at any point during treatment.
- • Monitoring: Baseline/Routine: No specific lab monitoring indicated; can consider LFT as clinically indicated to monitor for hepatotoxicity. Lymphocyte counts can help assess magnitude of immunosuppression and additive risks after discontinuation or switching.
- • Adverse Events: Serious: hepatotoxicity, skin necrosis. Common: injection site pain or itching, lipoatrophy at injection site.
- • Washout: Unknown appropriate washout time from previous DMT; weigh risks of longer washout against relapse risk. Glatiramer has a relatively low level of immunosuppression compared to other DMTs.
- • Pregnancy & Lactation: No washout, may be used up to conception and throughout pregnancy. Compatible with breastfeeding. Labelling does not contraindicate use of live vaccines; consider risk vs benefit.
Criteria for Interferons (Interferon beta-1b, Interferon beta-1a, Peginterferon beta-1a)
- • Administration: Interferon beta-1b: IM once weekly or SubQ every other day. Can be stored at room temperature for up to 7 days. Some formulations contain latex. Requires patient to reconstitute vial with prefilled syringe of diluent; use within 3 hours after reconstitution. Interferon beta-1a: SubQ 3 times weekly. Doses should be at least 48 hours apart. Can be stored at room temperature for up to 30 days. Peginterferon beta-1a: SubQ or IM every 14 days. Can be stored at room temperature for up to 30 days. Can pre-medicate with acetaminophen or ibuprofen to decrease flu-like symptoms.
- • Contraindications & Special Considerations: Contraindicated if hypersensitivity to albumin (beta-1b) or latex agent. Use with caution if history of seizure disorder; severe renal impairment for pegylated interferon beta-1a.
- • Monitoring: Baseline/Routine: CBC w/ diff, LFT, thyroid function/TSH. Screen for hepatitis and/or TB if high risk. Lymphocyte counts can help assess magnitude of immunosuppression and additive risks after discontinuation or switching.
- • Adverse Events: Serious: bone marrow suppression, depression, HF, liver injury, hypersensitivity formation, melanoma. Common: injection site reaction, flu-like symptoms, fatigue, myalgia, abdominal pain, nausea, UTI, leukopenia, lymphadenopathy, increased LFTs.
- • Washout: Unknown appropriate washout time from previous DMT; weigh risks of longer washout against relapse risk. Interferons have a relatively low level of immunosuppression compared to other DMTs. Labelling does not contraindicate use of live vaccines; consider risk vs benefit.
- • Pregnancy & Lactation: No washout needed, may be used up to conception. Compatible with breastfeeding.
Criteria for Natalizumab (TYSABRI)
- • Administration: IV infusion every 4 weeks. Has a REMS program to help monitor for and assess risk for antibody development of PML. Three baseline risk factors associated with increased PML risk: presence of JCV index value antibodies (higher index = higher risk), longer treatment duration, prior treatment with an immunosuppressant.
- • Contraindications & Special Considerations: Hold natalizumab if any sign or symptom of PML until appropriate evaluation and risk ruling out PML has occurred. 2018 AAN guidelines recommend switching to an alternative DMT during treatment within 8-12 weeks to decrease rebound risk.
- • Monitoring: Baseline: CBC, LFT, JCV antibody index value. Routine: CBC and LFTs found with natalizumab. MS rebound after treatment discontinuation increases if found; consider additive risk of PML if switched to another DMT with PML evaluation.
- • Adverse Events: Serious: PML, other infections, formation, melanoma, anemia and thrombocytopenia. Common: Infusion reactions, headache, diarrhea, arthralgia, depression, pain in extremity, rash, vaginitis.
- • Washout: MS rebound after treatment discontinuation increases if found with natalizumab. 2018 AAN guidelines recommend switching to an alternative DMT within 8-12 weeks to decrease rebound risk. In considering risks of additive immunosuppression, consider additive risk of PML if switched to another DMT with appropriate evaluation and risk ruling out PML has occurred.
- • Pregnancy & Lactation: PI still recommends avoiding during pregnancy and people of childbearing potential use contraception during and for at least 3 months after stopping therapy. Emerging post-marketing safety data indicate potential for safe use. For infants born to mothers exposed during third trimester, live vaccines should be postponed. Probably compatible with breastfeeding.
Criteria for S1PR Modulators (Fingolimod, Ozanimod, Ponesimod, Siponimod)
- • Administration: PO daily. Fingolimod: Missed doses require First Dose Observation (FDO) if treatment interrupted ≥1 day during first 2 weeks, >7 days during weeks 3 to 4, or >14 days after 1 month of treatment. Ozanimod: Reduce dose in mild or moderate hepatic impairment; use in severe severe hepatic impairment not recommended. Active metabolite inhibits MAO-B, so serotonergic medications should be avoided. MAO-Is are contraindicated. Avoid concomitant medications that decrease heart rate or prolong QT, CYP2C8 inducers and inhibitors. Avoid foods high in tyramine. Ponesimod: Missed doses ≤3 consecutive during titration resume with first missed dose; if ≥4 consecutive doses missed reinitiate treatment with day 1 of initial titration regimen including FDO if applicable. Siponimod: Dose determined by CYP2C9 genotype. Restart titration if any dose missed more than 24 hours during initial titration or if 4 or more consecutive days after titration including first-dose monitoring when appropriate.
- • Contraindications & Special Considerations: Many cardiac contraindications for all agents. Avoid concurrent therapy with medications that decrease heart rate or prolong QT. Fingolimod: FDO required for all patients due to risk of bradycardia and AV block; observation of pulse, BP, and ECG by healthcare professional for at least 6 hours. Patients who experience abnormalities or with other preexisting conditions may require longer observation. Ozanimod: Many drug interactions; Strong CYP3A4 and UGT1A1 inducers medications that decrease heart rate or prolong QT are not recommended. Assess for concomitant meds that might lower HR. FDO recommended if sinus bradycardia (<55bpm), first- or second-degree [Mobitz type I] atrioventricular block, or a history of MI or HF. Ponesimod: Not recommended in severe OSA. Many drug interactions; Strong CYP3A4 and UGT1A1 inducers medications that decrease heart rate or prolong QT are not recommended. Assess for concomitant meds that might lower HR. FDO recommended if sinus bradycardia (<55bpm), first- or second-degree [Mobitz type I] atrioventricular block, or a history of MI or HF. Siponimod: Additional contraindications: CYP2C9 3/3 genotype, concomitant use with CYP2C9 or CYP3A4 inhibitors or inducers (caution with drug interaction with moderate inhibitors and inducers). FDO recommended if certain cardiac conditions; monitoring of pulse, BP, and ECG by healthcare professional for at least 6 hours. Patients who experience abnormalities or with other preexisting conditions may require longer observation.
- • Monitoring: Baseline: EKG, LFT, CBC with differential, ophthalmologic and skin exam frequencies vary between agents - refer to PI. Screen for hepatitis and/or TB if high risk. Routine: BP, CBC with differential, LFT found with fingolimod. Other S1PR modulators carry this warning as well. In considering risks of additive immunosuppression, consider additive risk of PML if switched to another DMT with appropriate evaluation and risk ruling out PML has occurred. Check LFT 2 months after treatment discontinuation recommended for fingolimod.
- • Adverse Events: Serious: AV block, PML, serious infection, liver injury, macular edema (history of diabetes or uveitis increases risk), cutaneous malignancy, posterior reversible encephalopathy syndrome (PRES). Common: headache, bradycardia, increased LFTs infection, BP increase, orthostatic hypotension (ozanimod), back pain (fingolimod and ozanimod), skin requirements vary (fingolimod), nausea (fingolimod), diarrhea (fingolimod), sinusitis (fingolimod), abdominal pain (fingolimod), cough (fingolimod), pain in extremity (fingolimod).
- • Vaccines: Give VZV vaccine if no confirmed history of chickenpox and/or antibody negative.
- • Washout: MS rebound after treatment discontinuation increases; return to normal lymphocyte count varies from ~2 weeks to ~2 months, refer to individual agent’s PI. This may be an especially relevant concern if switching to a higher efficacy DMT with PML risk. Check LFT 2 months after treatment discontinuation recommended for fingolimod.
- • Pregnancy & Lactation: Human evidence of fetotoxicity. Recommended to use contraception during treatment and after treatment (duration varies for each agent, refer to PI). The latter duration can also be considered as the recommended washout period prior to planning pregnancy. See MS rebound information below for additional considerations. Not compatible with breastfeeding.
Criteria for Teriflunomide (AUBAGIO)
- • Administration: PO daily. All patients with reproductive potential should use contraception (regardless of gender). If liver injury or other serious reaction, pregnancy, or if pregnancy is desired stop teriflunomide and start drug accelerated elimination procedure with cholestyramine or activated charcoal. Especially in pregnancy or planning pregnancy (for either gender), procedure should be repeated until plasma teriflunomide concentration are less than 0.02 mg/L (0.02 mcg/mL).
- • Contraindications & Special Considerations: Contraindicated in pregnancy. Screen patients for: pregnancy (if applicable), hypophosphatemia, tuberculosis, lymphocytopenia, hepatitis if high risk.
- • Monitoring: Baseline/Routine: CBC, LFT, serum phosphorus, BP. Periodically as teriflunomide has a relatively low level of immunosuppression compared to other DMTs.
- • Adverse Events: Serious: hepatotoxicity, teratogenicity, skin reactions including SJS, infection, interstitial lung disease, hematologic disorders. Common: alopecia, diarrhea, nausea, headache.
- • Washout: Unknown appropriate washout time from previous DMT; weigh risks of longer washout against relapse risk. In considering risks of additive immunosuppression, teriflunomide has a relatively low level of immunosuppression compared to other DMTs.
- • Pregnancy & Lactation: Not compatible with pregnancy. Very long half-life, see Contraindications/Special Considerations for washout and elimination protocol. Not compatible with breastfeeding.