SUBHAN ALLAH US/CANADIAN PHARMACY EXAMS EDNAN UNDERSTANDING MULTIPLE SCLEROSIS (MS) COPY RIGHT PROTECTED Page 1

Transcription

1 UNDERSTANDING MULTIPLE SCLEROSIS (MS) Pathogenesis: Multiple sclerosis (MS) is the most common immune-mediated disease of the central nervous system (CNS) that specifically affects the nerves in the brain, spinal cord, and optic nerve. Characterized by progressive neurologic dysfunction, MS is centrally associated with gradual destruction of the myelin sheath (the fatty covering that protects nerve cells), which essentially makes it difficult for nerves to send and receive messages. Demyelination, inflammation, and axon degeneration are the major pathologic mechanisms that cause the clinical characteristics of MS; however, the main cause of the disease remains unknown. The incidence and prevalence of MS vary geographically. Nearly 400,000 individuals in the United States and more than 2.5 million individuals worldwide are affected by MS, making it one of the most common neurologic disabilities. MS is more prevalent at latitudes located farther from the equator and less common in areas closer to the equator. Researchers speculate that the increased exposure to sunlight and vitamin D may provide protective effects to those living closer to the equator. MS-related health care costs are estimated to be more than $10 billion annually. The effects of MS can be devastating, and it remains the most common disabling neurologic condition in young adults. Epidemiology and Risk Factors: MS is more common in women than men and is often diagnosed between ages 20 and 50 years. Although MS may possibly have a genetic component, researchers believe other factors may be involved, including infection, geographic location, and environmental causes. MS is more common in Caucasians, but recent studies suggest more and more cases are being diagnosed among Hispanics, Asians, and native Africans. Sign and Symptoms: Symptoms of MS vary among individuals, and may appear suddenly and disappear unpredictably. Because MS can affect any area of the spinal cord, brain, and optic nerve, MS can cause almost any neurologic symptom. The most common early symptoms include tingling and numbness in the arms, legs, trunk, and face, or stiffness and weakness in an extremity. Early visual disturbances include pain or partial blindness in 1 eye, nystagmus, double vision, diplopia, eye pain, and poor vision. Other symptoms may include difficulty in concentration, cognitive impairment, dizziness, and sad thoughts. Later problems include bowel or bladder control, spastic muscles, and sexual dysfunction. The initial attacks are generally mild and self-limiting, and the condition is usually identified in retrospect once the diagnosis of MS is made. Diagnosis: The diagnosis of MS is ultimately a clinical decision that is based on weighing the factors that support the diagnosis against those that fail to support it. Guidelines from the International Panel on MS Diagnosis, also called the Revised McDonald Criteria, provide diagnostic criteria for MS. The diagnostic classification scheme and magnetic resonance imaging (MRI) criteria remain complicated and tedious, and this complexity limits their use in everyday practice. Furthermore, the specificity of these criteria is relatively low, emphasizing the importance of clinical judgment in excluding other diagnoses. Patients are monitored over time with neurologic exams, MRIs, and the use of Kurtzke Expanded Disability Status Scale (EDSS). The EDSS is used to quantify disability in 8 functional systems (ie, pyramidal, cerebellar, brain stem, sensory, bowel and bladder, visual, cerebral, other) and allows neurologists to assign a functional system score in each of these. Neurologic exams are used to evaluate changes in coordination, motor and sensory function, and reflexes. The most sensitive recommended test to detect lesions and changes in the CNS is the MRI. Neurologists use serial MRIs to confirm diagnosis and to monitor response in therapy and worsening symptoms over time. COPY RIGHT PROTECTED Page 1

2 Types of MS: Four clinical subtypes of MS were defined in 1996, depending upon individual characteristics: Relapsing-re-mitting MS (RRMS), primary progressive MS (PPMS), secondary progressive MS (SPMS), and progressive-relapsing MS (PRMS). RRMS is the most common type, affecting nearly 85% of diagnosed patients. It is characterized by clearly defined relapses with full recovery or with sequelae and residual deficit upon recovery. There is no disease progression during the periods between disease relapses. After tissue damage accumulates over many years, patients typically enter SPMS progressive phase, which is characterized by an initial relapsingremitting disease course, followed by progression with or without occasional relapses, minor remissions, and plateaus. Approximately 10% of patients have gradually worsening manifestations from onset with occasional plateaus and temporary minor improvements allowed, which defines PPMS. Patients with PPMS tend to be older, and generally respond less effectively to standard therapies. PRMS is the rarest type, affecting approximately 5% of patients. It is characterized by progressive disease from onset, with clear acute relapses, with or without full recovery. Progression continues during the periods between disease relapses. Cognitive Impairment: Approximately 50% of patients with MS show signs of cognitive impairment. Research indicates that neurodegeneration in MS occurs in the early stages of the disease and appears to be progressive, causing axonal damage and a decline in brain volume over time. In some cases, neurodegeneration may develop prior to clinical evidence of MS and may continue after the inflammatory process is suppressed. As such, cognitive deficits may occur independently of physical disability, which complicates their recognition. Although as a general tendency the frequency and severity of cognitive dysfunction may increase with worsening physical disability, correlation is poor. Patients with progressive MS may have advanced disability but normal cognitive function, whereas those with minimal physical disability may have significant cognitive impairment. The various aspects of cognitive functioning affected by MS include attention, information processing efficiency, executive functioning, processing speed, and memory. The most commonly affected areas of cognition appear to involve processing speed and visual learning/memory, whereas typically unaffected functions include simple attention (eg, repeating digits) and essential verbal skills (eg, word naming and comprehension). Most studies indicate that general intelligence remains intact in patients with MS; however, some investigations have detected slight but significant deficiencies. Overt dementia is rare and the more common clinical presentation is one of specific and subtle cognitive deficits that may vary substantially among patients. As expected, the impact of cognitive dysfunction on functional status in MS is significant, with affected patients having greater difficulty in performing routine household tasks and being less likely to remain employed. Pharmacists should be aware that the presence of cognitive impairment may also interfere with health care decisions, including poor compliance with treatments, unrealistic expectations of treatments, and excessive reliance on "alternative" or unproven remedies. Impaired memory function may reduce the likelihood of timely medication administration and may impair correct injection technique. Pharmacotherapy: Currently there is no cure. Acute symptomatic exacerbations of MS are generally treated with a short course of high doses of corticosteroids, usually methylprednisolone, dexamethasone, prednisone, or prednisolone, to reduce the inflammation process. Response is usually seen within 5 days of therapy initiation. Short-term side effects of steroids include insomnia, headache, increased appetite, and psychosis. For patients exhibiting other symptoms including fatigue, amantadine or selective serotonin reuptake inhibitors (SSRIs) (sertaline, fluoxetine) are recommended. Because the majority of patients experience pain in the form of spasticity, baclofen, diazepam, clonazepam, tizanidine, and clonidine are also recommended. For management of depression, antidepressants can be recommended, including SSRIs and selective norepinephrine reuptake inhibitors (venlafaxine, duloxetine, desvenlafaxine). For bowel problems, anticholinergics (eg, dicyclomine), stool softeners (eg, docusate), and laxatives (eg, sennoside) are recommended. COPY RIGHT PROTECTED Page 2

3 Goals of therapy include controlling symptoms, improving functioning, preventing disease progression, and reducing long-term disability. First line Treatments Injectables: Injectable treatments include disease-modifying drugs (DMDs) (i.e., immunomodulatory agents) such as interferon beta-1a (Avonex weekly intramuscular [IM] injection or Rebif, 3 times weekly subcutaneous [SC] injection), interferon beta 1-b (Betaseron, Extavia; alternateday subcutaneous injection), and glatiramer acetate (Copaxone daily subcutaneous injection). Interferons differ in their dosing schedules and routes of administration, but share a common adverse effect profile, which often includes flu-like symptoms, injection site reactions, laboratory abnormalities, menstrual abnormalities, depression, palpitations, and dyspnea. Flu-like symptoms often begin within a few hours of administration and usually last no more than 24 hours, which may be quite significant for injections that are given every other day or 3 times weekly. Injection site reactions may include unusual effects such as lipoatrophy (atrophy of fatty tissue under the skin) or common events such as erythema, sensitivity, or swelling at the site of injection. Glatiramer acetate is very commonly associated with injection site reactions, which are known to occur in up to 90% of patients and are accompanied by considerable erythema in surrounding areas. Compared with injection site reactions associated with interferon, those related to glatiramer are much more sensitive, painful, and longer lasting, but they have similar preventive techniques. Glatiramer is less commonly associated with postinjection systemic reactions, which may present as chest tightness and panic type symptoms. Reducing subsequent injections to 25% of the usual dose and then increasing by 25% of dose/week may minimize occurrence of these reactions. Mitoxantrone (Novantrone) and natalizumab (Tysabri) are efficacious but, due to the possibility of increased side effects, they should be reserved for patients with progression of symptoms despite prior treatment with interferons or glatiramer. Mitoxantrone carries a boxed warning regarding potentially fatal heart failure and acute myelogenous leukemia. Natalizumab has a risk of developing multifocal leukoencephalopathy, an irreversible virus-mediated demyelination syndrome that is potentially fatal. It must be dispensed under a Risk Evaluation and Mitigation Strategy (REMS) program with a reporting mechanism to the FDA. CHARACTERISTICS OF MS DISEASE MODIFYING DRUGS Drug Dosage/Indication/storage Adverse effects Monitoring Interfeon beta 1 a (Rebif) 8.8mcg/0.2mL, 22mcg/0.5mL, 44mcg/0.5mL; soln for SC inj; Relapsing forms of multiple sclerosis (MS), to decrease the frequency of clinical exacerbations and delay accumulation of physical disability. Adults: SC inj at least 48hrs apart, preferably in the PM. Rotate inj site. Initially 4.4mcg 3 times per week for 2 weeks then titrate. Inj site reaction/necrosis, flulike symptoms, abdominal pain, psychiatric disorders, elevated liver enzymes, hematologic abnormalities, rash, Discontinue if jaundice or other signs of liver dysfunction occur. Alcohol abuse. Thyroid abnormalities. Monitor CBCs, thyroid, and liver function. Elderly. Pregnancy C Store at 2 to 8C or 6 to 46F contains albumin (human); preservative-free Rotate injection site Interferon beta b (Avonex) 30mcg per prefilled syringe Interferon beta-1b (Betaseron) 0.3mg; per vial Treatment of relapsing forms of multiple sclerosis to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations in patients with first clinical episode and MRI consistent with MS. 18yrs: 30mcg IM once weekly. May titrate dose to reduce severity of flu-like symptoms; dosed once weekly To reduce the frequency of clinical exacerbations in patients with relapsing forms of multiple sclerosis (MS), and in those who have experienced a first clinical episode and have MRI features consistent Flu-like symptoms, asthenia, anemia, headache, GI upset, depression, blood dyscrasias, seizures necrosis, lymphopenia, flu-like symptoms, myalgia, leukopenia, neutropenia, increased Monitor hemoglobin, CBC, differential, platelets, blood chemistries, liver and thyroid function, and for autoimmune disorders. Pregnancy C Rotate injection site Refrigerate and protect from light. Vial may be stored at room temperature up to 30 days and syringes up to 7 days. Myelosuppression. Monitor for worsening CHF, depression, elevated transaminases, jaundice: may need to discontinue therapy. Obtain hemoglobin, CBC, differential, platelets, blood COPY RIGHT PROTECTED Page 3

4 Glatiramer (Copaxone) 20mg/mL; soln for SC inj Fingolimod (Gilenya) 0.5 mg cap Natalizumab (Tysabri) 300mg/15mL; soln; for IV infusion after dilution; Mitoxantrone (Novantrone) 2 mg/ml Dalfampridine (Ampyra) 10 mg ER tab Oral MS Therapies: with MS. Adults: 18yrs: initially mg (0.25mL) SC every other day; increase over 6 weeks to 0.25mg (1mL) SC every other day. immunomodulator To reduce the frequency of relapses in patients with relapsing-remitting multiple sclerosis, including those who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis. Adults: 20mg SC daily. Sphingosine 1-phosphate receptor modulator. For relapsing forms of multiple sclerosis (MS): to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. Adults: 0.5mg once daily. Immunomodulator Relapsing forms of MS Adults: Give by IV infusion over 1 hour; monitor during and for 1 hour post-infusion. 300mg every 4 weeks. Discontinue after 12 weeks of induction therapy if no therapeutic response Anthracenedione Secondary progressive MS and progressive relapsing MS 12mg/m 2 intravenously every 3 months. Potassium channel blocker To improve walking in patients with multiple sclerosis Adults: 10mg every 12 hours. liver enzymes, headache, pain, rash, insomnia, abdominal pain Inj site and post-inj reactions, vasodilatation, rash, dyspnea, chest pain, asthenia, infection, pain, nausea, arthralgia, anxiety Headache, influenza, diarrhea, back pain, increased liver transaminases, cough, hypertension; transient decreased heart rate and AV conduction Headache, fatigue, arthralgia, infections, allergic reactions (discontinue if occurs; do not restart), hepatotoxicity (monitor and discontinue if occurs), nausea, cholelithiasis, urticaria GI upset, infection, fever, alopecia, dyspnea, hypersensitivity reactions, bluish-green urine, sclera discoloration UTI, insomnia, dizziness, headache, GI upset, asthenia, back pain, balance disorder, MS relapse, paresthesia chemistries; liver function (at 1, 3, and 6 months then periodically). Pregnancy C Store at room temperature but once reconstituted then store in fridge and use within 3 hours. Refrigerate. Pregnancy category B Risk of bradyarrhythmia; observe all patients for bradycardia for at least 6 hours after first dose with hourly pulse and BP measurement. Obtain ECG prior to dosing and at the end of observation period. Preservative-free. Liver enzymes, bilirubin Myelosuppression; do not administer if baseline neutrophil count <1500 cell/mm 3. Monitor CBCs, platelets, liver function tests prior to each course. Monitor for signs of infection. Pregnancy category C Baseline renal function Store at room temperature COPY RIGHT PROTECTED Page 4

5 In summer 2011, the FDA approved fingolimod (Gilenya), the first oral DMD indicated for reduction in frequency of exacerbations and to delay accumulation of physical disability in relapsing forms of MS. Fingolimod works by decreasing the migration of lymphocytes into the CNS, which may play a role in modifying the disease. Because it works by reducing peripheral lymphocytes to 20% to 30% of baseline, the drug is associated with increased risk of life-threatening infection, especially viral illness. Varicella zoster vaccine should be administered 1 month prior to initiation of therapy with fingolimod. The manufacturer recommends avoiding using life-attenuated vaccines during and for 2 months following treatment with fingolimod. The FDA recommends monitoring for signs of bradycardia for at least 6 hours after the first dose, and additionally recommends hourly pulse and blood pressure measurements for all patients initiating therapy. Electrocardiogram testing should be performed prior to dosing and at the end of the observation period, and cardiovascular monitoring should continue until any symptoms resolve. Based on the new warning, fingolimod is now contraindicated in patients with certain preexisting or recent (within the past 6 months) heart conditions or stroke, or in those who are taking certain antiarrhythmic medications. Dalfampridine (Ampyra) is an orally administered potassium channel blocker used to improve walking speed in people who have MS. Dalfampridine may be used alone or with other medications that control the symptoms of MS. The FDA is also updating the Ampyra labeling to clarify recommendations that renal function be assessed in patients before starting the drug and monitored at least annually during treatment. In patients who miss a dose, double or extra doses should not be administered, as that may increase seizure risk. Dalfampridine is contraindicated in patients with a history of seizure disorder and moderate or severe renal impairment (creatinine clearance <50 ml/min). Potential Treatment of Cognitive Impairment: Both glatiramer acetate and natalizumab have accumulated some neuroprotection evidence indicating an ability to reduce formation of black holes (MS lesions associated with neurodegeneration) and brain atrophy, but whether these measures actually translate into clinical benefits on cognition remain unclear. Interferon beta-1a has been shown to have a positive effect on processing speed, learning, and memory, but these results are inconsistent as well, largely because most wellcontrolled studies of MS therapies do not include cognition as a primary outcome. The more recently approved lipophilic immunomodulatory agent fingolimod has been shown to reduce the number of inflammatory T cells in the circulation and within the CNS (due to penetration of the blood brain barrier), ultimately reducing the potential for nerve cell damage. Thus far, animal studies with fingolimod indicate an overall neuroprotective effect, but human data are not yet available. COPY RIGHT PROTECTED Page 5