Pharmacologic Therapies for Multiple Sclerosis: From injectable to oral agents

Transcription

1 Pharmacologic Therapies for Multiple Sclerosis: From injectable to oral agents KIRANPAL SINGH SANGHA, PHARM.D. CLINICAL PHARMACY SPECIALIST CNS THE UNIVERSITY OF CINCINNATI MEDICAL CENTER

2 Objectives List three oral therapies for Multiple Sclerosis (MS) Describe dosing of common injectable therapies for MS List a common adverse effect for the interferon products Describe storage of common agents for MS I have no conflicts of interest related to this presentation

3 What is Multiple Sclerosis? Most common disabling neurological disease of young adults Characterized by areas of inflammation, demyelination, axonal loss & gliosis in the CNS The cause is unknown, but immune mediated physiology is widely accepted

4 Potential Triggers - Multiple Sclerosis Genetic predisposition Infectious agent Abnormal immunologic response Environmental factors MS

5 Multiple Sclerosis Age of onset: 15 to 45 years Gender: 70% women Prevalence: 350,000 in the USA, about 2.5 million people worldwide Geography: incidence increases with distance from equator Quality of life disease Immunotherapies do not treat symptoms Many MS patients feel their symptoms are neglected by their physicians

6 Common Symptoms Spasticity Bladder symp. Incontinence Fatigue Visual symp. Optic neuritis, diplopia Bowel symp. Incontinence, constipation Cognitive symp. Depression & mood symp. Sexual dysfunction Pain

7 Why do we treat MS? Disease modifying therapies (DMT) have been shown to reduce rate of relapse & there is evidence of reduction of long term disability Studies with interferon-beta 1a IM, interferon-beta 1b, interferon beta 1a SQ and glatiramer acetate have shown that treating early (CIS) has been shown to delay progression to clinically definite MS MS is the most common cause of non traumatic neurologic disability in adults

8 Time line for Multiple Sclerosis 1986 Consortium of MS Centers founded (CMSC) Injectable DMT s: 1993 IFN-1b Betaseron 1995 IFN-1a Avonex 1996 Glatiramer 2002 IFN-1a Rebif Oral DMT s: 2010 Dalfampridine 2010 Fingolimod 2012 Teriflunomide 2013 Dimethyl fumarate 1950 s Interferons 1 st identified Future? MS Named 1916 James Dawson describes pathology MS 1970 s ACTH replaced by IV steriods Other DMT s: 2014 Alemtuzumab

9 Clinically Isolated Syndrome (CIS) CIS is a first episode of neurologic symptoms that lasts at least 24 hrs & is caused by inflammation or demyelination in the CNS Drug Interferon beta-1b Interferon beta 1a IM Glatiramer acetate Reduction in conversion to clinically definite MS at 3 or 5 yr follow-up 37% 35% 45%

10 MS Treatment -Acute Relapses IV Methylprednisolone 1 gm/day x 3-5 days Recent trials show equal efficacy of IV & PO dosage forms. Some Clinicians are using PO prednisone for relapses Clinical Pearl - PO Prednisone 1000 mg/day x 3-5 days if IV therapy is not an option If steroids fail plasmapheresis is an option

11 MS -Choosing initial DMT No consensus on initial therapy CMSC 2014 consensus statement says to initiate treatment with an FDA approved DMT Availability of oral agents presents alternatives to injectable agents Some suggest efficacy of the meds decreases if adherence is < 80% Risks of certain adverse effects increase with comorbidities The only drug that should not be used 1 st line is alemtuzumab.

12 Treatment DMT s 1 st generation -injectable: Beta interferon-1a (Avonex), beta interferon-1b (Betaseron), beta interferon-1a (Rebif), Glatiramer acetate (Copaxone) 2 nd generation injectable to oral agents: Mitoxantrone (Novantrone), Natalizumab (Tysabri), Alemtuzumab (Lemtrada) Oral agents fingolimod, teriflunomide, dimethyl fumarate. Dalfampridine Brand Names have been used in presentation to distinguish products

13 Pre-drug testing All drugs except glatiramer need baseline CBC with diff. & LFTs Fingolimod requires VZV IgG titers, baseline EKG & ophthalmologic exam for macular edema Teriflunomide PPD and negative pregnancy test Natalizumab JCV Ab status Fingolimod, dimethyl fumarate JCV Ab status

14 Follow-up testing Interferons, natalizumab, dimethy fumarate - CBC with diff, LFTs and clinic visits every 3 mo s for 1 year Fingolimod CBC with diff, LFTs & clinic visit 1 mo after starting then every 3 mo s for the first yr. If JCV Ab negative, yearly testing Teriflunomide LFTs monthly for 6 mo s, CBC with diff every 6 mo s. Natalizumab If JCV Ab negative, every 6 mo s. If JCV Ab positive every 3 mo s

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17 Dosing DMTs -injectables Drug Dose Route Frequency β INFN-1a (Avonex) 30 mcg IM Weekly Peg INFN-beta1a 63 mcg x1 SQ (Plegridy) 94 mcg in 14 days then 125 mcg q 14 days β INFN-1b (Betaseron) 0.25 mg SQ Every other day Extavia β INFN-1a (Rebif) 44 mcg SQ Three times per week Glatiramer acetate 20 mg SQ Daily (Copaxone) or 40 mg SQ 3 x week

18 Dosing DMTs -Injectables Drug Dose Route Frequency Mitoxantrone 12 mg/m 2 IV Every 3 months Natalizumab (Tysabri) 300 mg IV Every 4 weeks Alemtuzumab 12 mg/day over 5 days IV Repeat in 1 year Dosing -Oral Agents Drug Dose Route Frequency Fingolimod 0.5 mg PO daily Teriflunomide 7 or 14 mg PO daily Dimethyl fumarate 120 x 7 days then 240 mg PO twice daily Dalfampridine 10 mg PO twice daily

19 Self assessment question Which of the following are oral disease modifying therapies for MS? a. Interferons, copaxone & alemtuzumab b. Copaxone, fingolimod & mitoxantrone c. Fingolimod, teriflunomide & dimethyl fumarate d. Alemtuzumab, natalizumab & copaxone

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21 Injection Site reaction from Glatiramer Acetate

22 DMTs continued Natalizumab (Tysabri) Indicated: Monotherapy for relapsing forms of MS to slow disability & reduce frequency of relapses Should generally be used when other DMTs are ineffective or intolerable or in patients with aggressive disease Dose: 300 mg IV q 4 weeks. TOUCH prescribing program Adverse Effects: Anxiety, fatigue, peripheral edema, infusion related symmptoms, Hypersensitivity rxn, Immunosuppression / Infections & Progressive multifocal leukoencephalopathy (PML)

23 Alemtuzumab (Lemtrada) Alemtuzumab is a CD52-directed cytolytic antibody indicated for B-cell CLL & MS Restricted distribution program Dosing: 12 mg/day IV over 5 days and repeat in year for 3 days Premedicate with diphenhydramine & acetaminophen. Administer Bactrim & acyclovir for PCP & herpes prophylaxis.

24 Dalfampridine ER (Ampyra) US FDA approved 1/2010 Dalfampridine is a K channel blocker indicated to improve walking in pts with MS. Typical Dose: 10mg oral twice daily. Take tablets whole, do not crush or chew. PK: Relative Fo 96%, low ppb, Tmax 3-4hrs, Elimination T1/2 = 5-6 hrs, eliminated renally (>90 %) AEs: seizures, insomnia, dizziness, HA, nausea, contraindicated if Cr Cl < 50 ml/min Efficacy: A phase III study showed improved walking (25 ft) in 43% pts vs 9% placebo

25 Fingolimod (Gilenya) US FDA approved 9/2010 Fingolimod is a sphingosine 1-phosphate receptor modulator indicated to reduce the frequency of clinical exacerbations and to delay accumulation of physical disability with relapsing forms of MS Dose: 0.5 mg orally daily. Available: 0.5 mg caps - Pts need to be observed for 6 hrs after the first dose in an office or clinic for S/S bradycardia / heart block. If med stopped > 2 weeks then restart monitoring as new therapy

26 Fingolimod (Gilenya) Use caution in patients taking beta blockers or antiarrhythmics Live attenuated vaccines should be avoided during the first 2 mo s of therapy Antibody testing for Varicella Zoster virus perform at baseline. If VZV non-immune then vaccinate Ophthalmologic exam at baseline and every 3-4 mo s for macular edema Animal studies suggest teratogenicity: use effective contraception

27 Teriflunomide (Aubagio R ) US FDA approved 9/2012 Teriflunomide has selective reversible inhibition of dihydroorotate dehydrogenase that blocks pyrimidine synthesis in rapidly proliferating cells. For relapsing forms of MS It is the active metabolite of leflunomide Available: 7 and 14 mg tablets Adult dose: 7 or 14 mg orally once daily AE: HA., Incr LFT, alopecia, diarrhea, nausea, paresthesia

28 Dimethyl Fumarate (Tecfidera) US FDA approved 3/2013 Dimethyl fumarate (DMF) has been shown to activate the nuclear factor like 2 (Nrf2) pathway. The Nrf2 pathway is involved in the cellular response to oxidative stress Available: 120 & 240 mg delayed release caps. Swallow whole, do not crush/chew Adult Dose: Start 120 mg twice a day and may incr to 240 mg bid after 7 days

29 Dimethyl Fumarate Protect capsules from light. AE: flushing, abdominal pain, diarrhea & N Pregnancy: unknown effects Monitor CBC at baseline and at least annually. Withholding treatment is warranted with serious infections

30 Absolute contraindications Interferons: LFT s at baseline > 2 x ULN Fingolimod: LFT s at baseline > 2 x ULN, MI, stroke, TIA, unstable angina, decomp. heart failure within 6 mo s, hx of Mobitz type II, 3 rd degree AV block, sick sinus syndrome, baseline QTc > 500 ms, classs Ia or II antiarrhythmics, negative VZV titers, pregnancy Teriflunomide: positive PPD, LFT s > 2x ULN

31 MS Medications Storage Avonex* powder IFN-beta1a Avonex* prefilled Syringe Betaseron IFN-beta1b Refrigerate F or at room temp up to 30 days. After mixing use with in 6 hrs if kept in fridge Refrigerate F or at room temp up to 7 days Room temp. Use immediately after mixing, or within 3 hrs if kept in fridge Extavia IFN-beta1b Room temp up to 77 F. Use immediately after mixing or within 3 hrs if kept in fridge * Do not freeze, protect from heat and light

32 MS Medications Storage Glatiramer* Copaxone Rebif* IFN-beta1a Fingolimod Gilenya DMF Tecfidera Refrigerate F or at room temp up to 30 days Refrigerate F or at room temp up to 30 days Store in original blister pack at room temp Store at room temp. Protect from light, store in original container Alemtuzumab Store at room temp or refrigerate. Use Lemtrada within 8 hrs of dilution * Do not freeze, protect from heat and light

33 MS DMT Annual Drug Cost ** Approximate WAC or Manufacturer published wholesaler price ** Drug Annual Cost ($) Glatiramer (Copaxone) 65,104 Interferon beta-1a - Avonex - Rebif Interferon beta -1a pegylated -Plegridy Interferon beta-1b - Betaseron - Extavia 65,442 70,638 65,442 69,397 57,694

34 MS DMT Annual Drug Cost ** Approximate WAC or Manufacturer published wholesaler price ** Drug Annual Cost ($) Mitoxantrone 3167 Natalizumab Alemtuzumab Oral agents - Fingolimod - Teriflunomide - Dimethy fumarate 64,480 59,250 70,752 66,017 65,520

35 Self Assessment questions Which of the following are common adverse effects among the interferon products utilized for MS? a. Flushing b. Acute kidney injury c. Severe bradycardia d. Flu like symptoms Which of the following products can be stored at room temperature for over 30 days? a. Interferon beta-1a (Avonex) b. Glatiramaer (Copaxone) c. Interferon Beta 1b (Betaseron) d. Interferon-Beta 1a (Rebif)

36 Multiple Sclerosis Take home concepts MS symptoms are from lesions in the CNS Acute relapses: corticosteriods Traditional DMTs are injectable: β interferons, copaxone, mitoxantrone & natalizumab Newer DMTs are oral therapies: Fingolimod, Teriflunomide and dimethyl fumarate Ongoing research: More oral medications

37 Questions Kiranpal S. Sangha, Pharm.D. Clinical Pharmacy Specialist CNS The University of Cincinnati Medical Center Adjunct Asst. Professor Clinical Pharmacy, James L. Winkle UC College of Pharmacy Phone: