ALEMTUZUMAB INJ,SOLN
Clinical Criteria Summary
Document 6: Alemtuzumab Lemtrada December 2018
Exclusion Criteria
- Secondary progressive MS with no clinical or MRI evidence of relapses
- Concurrent use of immune system modifying drugs (DMT) to treat MS (interferon beta-1B, glatiramer acetate, interferon beta 1A, natalizumab, mitoxantrone), unless the previous agent is discontinued when alemtuzumab is initiated
- Infection with Human Immunodeficiency Virus
- No documented baseline testing within 30 days prior to initiation: CBC with differential, LFT, and skin exam
- Positive test for tuberculosis
Inclusion Criteria
- Patients with relapsing MS characterized by clearly defined acute attacks with full or partial recovery
- Must be prescribed and monitored by a VA neurologist or locally designated MS Specialist
- AND meet at least one of the following conditions:
- Loss of clinical response or intolerance to at least two DMTs (injectable: interferon beta 1a, interferon beta 1b, glatiramer; oral: dimethyl fumarate, fingolimod, teriflunomide); if serum JCV Ab negative, a trial of natalizumab is required
- Currently on natalizumab therapy with development of risk factors for PML (duration > 24 months, anti JC virus antibody positive, or received immunosuppressant therapy prior to natalizumab)
- Highly aggressive disease demonstrated by heavy burden of MRI T2 lesions, presence of multiple enhancing lesions at onset, high burden of gadolinium enhancing lesions, or rapid accrual of disability
Dosage & Administration
- Recommended dosage: 12 mg/day administered by intravenous infusion for 5 consecutive days, followed by three consecutive daily infusions 1 year later
- Subsequent treatment courses: 12 mg per day on 3 consecutive days (36 mg total dose) may be administered as needed, at least 12 months after the last dose of any prior treatment course
- Must be administered in a setting with appropriate equipment and personnel to manage anaphylaxis or serious infusion reactions
- Monitor patients for 2 hours after each infusion; inform patients that serious infusion reactions can also occur after the 2-hour monitoring period
Premedication Requirements
- High dose corticosteroids (1,000 mg methylprednisolone or equivalent) immediately prior to alemtuzumab infusion and for the first 3 days of each treatment course
- Anti-viral prophylaxis for herpetic viral infections starting on the first day of each treatment course, continuing for a minimum of two months following treatment or until CD4+ lymphocyte count is > 200 cells per microliter (whichever occurs later)
Monitoring Requirements
- CBC with differential, serum creatinine levels, and urinalysis with urine cell counts and urine protein to creatinine ratio: prior to initiation and monthly until 48 months after the last infusion
- Thyroid function tests: prior to initiation and every 3 months until 48 months after the last infusion (monitoring may continue past 48 months based on clinical findings)
- Skin examination for melanoma: prior to treatment and yearly thereafter
- HPV screening for female patients: annually
- Annual brain MRI by CMSC Protocol
Safety, Black Box Warnings & REMS Restrictions
- Available only through restricted distribution under a Risk Evaluation Mitigation Strategy (REMS) program due to risks of autoimmunity, infusion reactions, and malignancies
- Black Box Warning for serious, sometimes fatal autoimmune conditions such as immune thrombocytopenia and antiglomerular basement membrane disease (anti-GBM)
- Anti-GBM disease may develop end-stage renal disease requiring dialysis or renal transplantation; alveolar hemorrhage (hemoptysis) is a common component; cases diagnosed up to 40 months after the last dose
- Associated with increased risk of malignancies, including thyroid cancer, melanoma, and lymphoproliferative disorders
Infection Risks & Clinical Considerations
- Serious and life-threatening stroke (ischemic and hemorrhagic) reported within 3 days; instruct patients to seek immediate medical attention if symptoms occur
- Evaluate for varicella zoster virus infection history or vaccination prior to initiation; if negative, vaccinate with live varicella virus product (Varivax®), wait at least six weeks after completing two doses before initiating therapy
- Do not administer live viral vaccines for at least 2 months after a course or until CD4+ lymphocyte count is > 200 cells per microliter
- Consider delaying alemtuzumab in persons with active infection until the infection is fully controlled
- Fungal infections and Listeria meningitis occur with increased frequency; counsel patients to not consume foods associated with Listeria prior to infusion
- Symptoms of Listeria infection can be difficult to distinguish from infusion reactions
Document 626: Disease Modifying Therapies in Multiple Sclerosis
Criteria for Relapsing MS & PPMS Activity Categories (General DMT Use)
- Highly active relapsing MS: Favor high efficacy DMT; moderate efficacy DMT may be considered if significant safety concerns exist regarding high efficacy options. Monitor clinical and MRI relapses at least every 6 months to determine adequacy of disease control if a low efficacy DMT is chosen. Escalate to higher efficacy DMT if ongoing/increase in disease risk within 6 months or less. De-escalation/discontinuation is inadvisable due to relapse activity.
- Minimally active relapsing MS: Favor moderate efficacy DMT; evidence supports high efficacy DMTs are more effective, though moderate efficacy DMTs tend to be safer. Monitor clinical/MRI relapses at least every 6 months if on a lesser efficacy DMT. Escalate to high efficacy DMT if ongoing/increase in disease activity within 3 months or less. De-escalation may be considered to prioritize safety; monitor with MRI every 6 months x2, then yearly x2-4, then PRN. Monitor clinically at least annually.
- Non-active relapsing MS: Monitoring without DMT ("watch and wait") may be an option. No DMT indicated for non-active MS. Favor low risk DMT if de-escalating. Consider de-escalation over stopping if no relapse activity >5 years AND >55 years, and stopping is not ideal based on prior MS activity, comorbid diseases, or current DMT evidence for elevated relapse risk after discontinuation. Consider de-escalating or stopping if no relapse activity >5 years AND >55 years. Monitor with MRI yearly x2-4, then PRN; monitor clinically at least annually.
- Clinically isolated syndrome (CIS): Favor moderate to high efficacy DMT if high risk features present (>2 brain lesions on MRI, others per Table 1). Favor low risk DMT if low-risk features (<2 brain lesions on MRI). Monitoring without DMT may be an option with brain MRI at least every 6 months to assess for development of new lesions.
- PPMS: Offer clinically appropriate DMT for <55 years and EDSS ≤6.5, or for anyone with PPMS if benefits outweigh risks. Clinical response demonstrated as slowed clinical worsening. Consider stopping if >55 years, EDSS >5.5, no MRI relapses >5 years, lack of clinical response, adverse events. No alternative DMT with a different mechanism of action for PPMS currently exists.
- General Monitoring & Vaccination: Brain MRI annually for 5 years after initiating/switching; if no relapsing activity, decrease to every 3-5 years as clinically indicated. If off DMT, monitor brain MRI annually for at least 5 years then as clinically indicated. More frequent MRIs may be needed for safety monitoring of some DMTs (e.g., natalizumab). Live/attenuated vaccines at least 4 weeks before starting; avoid during DMT. Non-live vaccines at least 2 weeks before starting.
Criteria for Alemtuzumab
- Indication/Efficacy: High efficacy DMT for refractory disease.
- 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 the first 3 days of each treatment course.
- Monitoring/Contraindications: REMS program provides lab and imaging frequency guidance. Baseline: HIV, VZV, TB, HBV, HCV, CBC w/ diff, CMP, UA w/ cell counts, adult onset Still's disease, thyroid function tests, autoimmune encephalitis, acquired hemophilia. Routine: CBC w/ diff, CMP, protein, skin exam, TSH, LFT, UA. Delay treatment if active skin infection. Give antivirals for herpes prophylaxis starting first day of treatment until 2 months or CD4+ lymphocytes >200 cells/microliter. Instruct patients to avoid potential Listeria sources and be negative for monocytegenes VZV antibodies.
- Adverse Events: Serious: Secondary autoimmune diseases, hemophagocytic lymphohistiocytosis, thrombotic thrombocytopenic purpura, serious infusion reactions, stroke/cervicocephallic arterial dissection, malignancy, 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.
- Pregnancy/Lactation: Avoid if pregnant. Use contraception during and 4 months after treatment course. Avoid breastfeeding during and at least 3 months after last dose.
Criteria for Cladribine
- Indication/Efficacy: High efficacy DMT for refractory disease.
- Administration: PO given in 2 yearly oral tablet treatment courses. Each course divided into 2 cycles. Separate from other oral medications by at least 3 hours.
- Monitoring/Contraindications: Baseline/Routine: CBC w/ diff, LFT. Screen for latent VZV, TB, Hepatitis B, Hepatitis C, indicated cancer screenings. Contraindicated if current malignancy, HIV infection, active infections, chronic infection such as TB/Hepatitis B/C. Delay treatment if active infection. Do not start second course unless lymphocytes WNL and >800 cells/microliter. Give antivirals for herpes prophylaxis if lymphocytes <200 cells/microliter. Give VZV vaccine if seronegative; give recombinant zoster vaccine if VZV positive.
- Adverse Events: Serious: Malignancies, lymphopenia, serious infections, serious skin reactions including SJS/TEN, liver injury, hypersensitivity, cardiac failure, PML, Graft-versus-host disease with blood transfusion. Common: minor infections, headache, lymphopenia, neutropenia, anemia, thrombocytopenia.
- Pregnancy/Lactation: Contraindicated during pregnancy. All patients with reproductive potential should use contraception during and for 6 months after last dose in each treatment course. Not compatible with breastfeeding.
Criteria for Fumarates (Dimethyl fumarate, Diroximel fumarate, Monomethyl fumarate)
- Indication/Efficacy: Moderate efficacy DMT. PO BID.
- Administration/Monitoring: Baseline/Routine: CBC with differential, LFT. Screen for diarrhea, nausea, infection. UA if proteinuria suspected (DMF). Monitor lymphocytes until discontinuation resolved. Limit food to 700 calories and 30g fat or less (DRF). Administer with food/healthy-fat/protein snack to decrease flushing/GI side effects. Aspirin premedication (up to 325 mg non-enteric coated 30 min prior) may reduce flushing. Temporary dose reduction possible, return to initial for up to 4 weeks then resume maintenance. Post-marketing PML cases reported with DMF; monitor all fumarates for PML risk.
- Adverse Events: Serious: Lymphopenia, PML (in context of lymphopenia), liver injury. Common: Flushing, abdominal pain, diarrhea, nausea, infection. Most common intolerances are GI related.
- Pregnancy/Lactation: DMF: Discontinue before conception, no specified washout. Active metabolite in breastmilk low and not expected to cause any AEs in breastfed infants. DRF: Acceptable to use during breastfeeding, at least after 1 month of age; monitor breastfed infants. MMF: Evolving evidence on breastfeeding (serum levels detected in infants), use with caution.
Criteria for S1PR Modulators (Fingolimod, Ozanimod, Ponesimod, Siponimod)
- Indication/Efficacy: Moderate efficacy DMT. PO daily.
- Administration/Monitoring: Baseline/Routine: EKG, LFT, CBC with differential, Varicella titer, ophthalmologic monitoring, skin exam. FDO required for all patients (at least 6 hours by healthcare professional) due to bradycardia/AV block risk. Monitor pulse, BP, ECG. Patients with preexisting conditions may require longer observation.
- 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 foods high in tyramine. Many drug interactions: CYP2C8 inducers and inhibitors.
- Ponesimod: Not recommended in severe OSA. FDO recommended if sinus bradycardia (<55bpm), first- or second-degree [Mobitz type I] atrioventricular (AV) block, or a history of MI or HF.
- Siponimod: Dose determined by CYP2C9 genotype; contraindicated in CYP2C9 3/3 genotype; caution with concomitant use with CYP2C9 or CYP3A4 inhibitors or inducers. FDO recommended if certain cardiac conditions.
- Adverse Events: Serious: AV block, PML, serious infection, liver injury, macular edema (history of diabetes or uveitis increases risk), cutaneous malignancy, PRES. Common: Headache, increased LFTs, infection, BP increase/orthostatic hypotension (ozanimod), back pain (fingolimod/ozanimod), skin exam requirements vary, nausea/diarrhea/cough/sinusitis/pain in extremity (fingolimod).
- Pregnancy/Lactation: Human evidence of fetotoxicity. Recommended to use contraception during treatment and after treatment (duration varies for each agent, refer to PI). Not compatible with breastfeeding. MS rebound after treatment discontinuation increases lymphocytes within days; return to normal lymphocyte count varies from ~2 weeks to ~2 months. Check LFT 2 months after treatment discontinuation recommended for fingolimod.
Criteria for Anti-CD20 Antibodies (Rituximab/biosimilars, Ublituximab, Ocrelizumab, Ofatumumab)
- Indication/Efficacy: High efficacy DMT.
- Administration/Monitoring:
- Rituximab/Biosimilars: IV infusion every 6 months. Off-label for MS (evidence-based indication). Pre-medicate with acetaminophen 650mg PO, diphenhydramine 50mg PO, methylprednisolone 100mg IVP over 3-5 min.
- Ublituximab: IV infusion every 24 weeks. Pre-medicate with diphenhydramine 50mg PO/IV, methylprednisolone 100mg IVP over 3-5 min +/- acetaminophen. Prevent infusion reactions; premedicate for first doses. Slower infusion rates recommended for first doses.
- Ocrelizumab: IV infusion every 6 months. Can consider using CD19 results to guide dose and/or dosing interval. Pre-medicate with acetaminophen 650mg PO, diphenhydramine 50mg PO, methylprednisolone 100mg IVP over 3-5 min.
- Ofatumumab: SubQ once monthly prefilled syringe. First dose should be given under guidance of a healthcare professional. Pre-medications showed only limited benefit in trials so are not routinely recommended. Symptomatic treatment is recommended if injection-related reactions occur. Can be stored at room temperature for up to 7 days.
- Monitoring/Contraindications: Baseline/Routine: CBC w/ diff, CMP, Immunoglobulins (IgG, IgM). Screen for hepatitis B (required), hepatitis C, TB. Delay infusion/injection if acute infection. For IV formulations: prevent infusion reactions, premedicate. Washout time from previous DMT unknown; weigh risks of longer washout against risks of another relapse. Immunoglobulins can also be used to estimate lasting immunosuppressive effect after discontinuing therapy.
- 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, minor infusion reactions.
- Pregnancy/Lactation: PIs still recommend avoiding anti-CD20 during pregnancy and that people of childbearing potential use contraception during and for at least 6 months after stopping therapy. Emerging post-marketing safety data indicate there may be the potential for safe use. For infants born to mothers who were exposed to anti-CD20 antibodies, live vaccines should not be administered until normal B-cell counts are verified. Probably compatible with breastfeeding.
Criteria for Interferons (Interferon beta-1b, Interferon beta-1a, Peginterferon beta-1a)
- Indication/Efficacy: Low efficacy DMT.
- Administration/Monitoring:
- Interferon beta-1b: IM once weekly or SubQ every other day. Some formulations contain latex; refer to agent's PI. Can be stored at room temperature for up to 7 days (AVONEX) or within 3 hours after reconstitution (EXTAVIA/BETASERON). Requires patient to reconstitute vial with a prefilled syringe of diluent.
- Interferon beta-1a: SubQ 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 30 days.
- Peginterferon beta-1a: SubQ or IM every 14 days. Can be stored at room temperature for up to 30 days.
- Monitoring/Contraindications: Baseline/Routine: CBC w/ diff, LFT, TSH. Screen for hepatitis and/or TB if high risk. Use with caution if history of seizure disorder. Pre-medicate with acetaminophen or ibuprofen to decrease flu-like symptoms. Labelling does not contraindicate use of live vaccines. Contraindicated if hypersensitivity to albumin. Use caution if severe renal impairment (pegylated interferon beta-1a).
- Adverse Events: Serious: Bone marrow suppression, depression, HF. Common: Injection site reaction, flu-like symptoms, fatigue, myalgia, abdominal pain, nausea, UTI, leukopenia, lymphadenopathy, increased LFTs.
- Pregnancy/Lactation: No washout needed; may be used up to conception. Compatible with breastfeeding. Relatively low level of immunosuppression compared to other DMTs.
Criteria for Glatiramer Acetate
- Indication/Efficacy: Low efficacy DMT. 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.
- Monitoring/Contraindications: Baseline/Routine: No specific lab monitoring indicated, can consider LFT as clinically indicated to monitor for hepatotoxicity. Labelling does not contraindicate use of live vaccines. 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.
- Adverse Events: Serious: Hepatotoxicity, skin necrosis. Common: Injection site pain or itching, lipoatrophy at injection site.
- Pregnancy/Lactation: No washout; may be used up to conception and throughout pregnancy. Compatible with breastfeeding. Relatively low level of immunosuppression compared to other DMTs.
Criteria for Teriflunomide
- Indication/Efficacy: Low efficacy DMT. PO daily.
- Administration/Monitoring: Baseline/Routine: CBC, LFT, serum phosphorus, BP. Screen patients for pregnancy (if applicable), hypophosphatemia, tuberculosis, hepatitis if high risk, lymphocytopenia. Periodically monitor LFT, CBC, BP, serum phosphorus as clinically indicated.
- Contraindications/Special: Contraindicated in pregnancy. 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, procedure should be repeated until plasma teriflunomide concentration are less than 0.02 mg/L.
- Adverse Events: Serious: Hepatotoxicity, teratogenicity, skin reactions including SJS, infection, interstitial lung disease, hematologic disorders. Common: Alopecia, diarrhea, nausea, lymphocytopenia, headache.
- Pregnancy/Lactation: Not compatible with pregnancy or breastfeeding. Very long half-life.