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FromtheDepartmentofPharmacy

for Pompe Disease

Marcia J. Wyman, Pharm.D., BCPS Pompe dis- ing as hypertrophic cardiomyopathy, Drug Information Pharmacist ease, also known as acid maltase deLi- generalized muscle weakness, and hy- ciency or glycogen storage disease type potonia in the Lirst few months of life. 1 II, is an inherited autosomal recessive Death, which usually occurs by year 1 if disorder involving an absence or deLi- untreated, is most commonly due to 1 ciency of acid alpha glucosidase (GAA). cardiorespiratory failure. Late-onset Acid alpha glucosidase normally hydro- Pompe disease is characterized by a lyzes lysosomal glycogen to glucose. A slowly progressive myopathy typically deLiciency in GAA results in lysosomal involving skeletal muscle (proximal and accumulation of glycogen, primarily in respiratory) and usually presents in the 1 muscle tissues, which ultimately leads second to sixth decade of life. As skele- to myopathies. tal muscles progressively weaken, pa- tients may become wheelchair-bound and require ventilator support. Cardiac

- -muscle is generally spared and respira- Due to the variability tory failure is the most common cause in clinical manifestation, Pompe disease of death for this subtype. is divided into two general subtypes: 1 infantile-onset and late-onset. These subtypes are based on the age of onset, rate of disease progression, and extent Myozyme ® of organ involvement. Infantile-onset and Lumizyme ®, which are both manu- Pompe disease is characterized by a factured by Genzyme Corporation, are rapidly progressive syndrome present- (Continued on page 2) for Pulmonary Arterial Hypertension Pulmonary arterial hy- in patients with mild to moderate pertension (PAH) is a disease charac- PAH. Macitentan (Opsumit ®, Actelion), terized by restricted blood Llow through an , is the pulmonary arterial circulation approved by the Food and Drug Ad- leading to increased pulmonary ministration (FDA) for patients with  vascular resistance and subsequently PAH to prevent further disease progres- 1 2 FromtheDepartmentofPharmacy right heart failure. The prognosis of sion. Disease progression is deLined as DrugInformationService PAH is poor, with approximately a 15% death, prevention of starting intrave- (216)444-6456,option#1 mortality rate within the Lirst year of nous (IV) or subcutaneous prostanoids,  starting therapy. Both the European or clinical worsening of PAH. It is Comprehensiveinformationabout Society of Cardiology (ESC)/European the third agent in the endothelin medications,biologics,nutrients, Respiratory Society (ERS) and Ameri- receptor blocker pharmacological class, ® anddrugtherapy can College of Cardiology (ACC)/ which includes (Tracleer , ®  American Heart Association (AHA) Actelion) and (Letairis , FormularyInformation guidelines recommend endothelin re- Gilead Sciences). ceptor antagonists as Lirst-line therapy (Continued on page 3) (Continued from page 1) Are there any restrictions/requirements for ob- taining alglucosidase alfa? What are the side effects and monitoring recom- mendations for alglucosidase alfa? References: . Genzyme Corporation. Web. Accessed: 29 Jan. 2014.

2 (Continued from page 1) brisentan is linked to a much lower incidence of docu- How macitentan works: Macitentan blocks the bind- mented drug interactions. 6,7 ing of endothelin-1 (ET-1) to A (ET A) and endothelin receptor B (ET B). This prevents Risk Evaluation and Mitigation Strategies (REMS) ET-1 mediated vasoconstriction, Librosis, proliferation, Program: For all females, macitentan is only available hypertrophy, and inLlammation which can exacerbate through the OPSUMIT ® REMS program due to its risk PAH. Macitentan was developed by altering the struc- of embryo-fetal toxicity. 2 SigniLicant requirements of ture of bosentan to increase safety and efLicacy. 3,4 this program include: Macitentan differs from other endothelin receptor an- • Prescribers must be certiLied with the program by tagonists by having sustained receptor binding and enrolling and completing training enhanced tissue penetration. 5 • All patients (males and females) are required to be enrolled following the instructions on the : Macitentan is primarily metabo- OPSUMIT Patient Enrollment and Consent Form. lized via the cytochrome P450 (CYP) system to Male patients are NOT required to complete sec- its active metabolite, which is accomplished mainly by tion 3 of this enrollment form CYP3A4 and to a lesser extent by CYP2C19. 2 Its active • Females of reproductive potential must comply metabolite achieves three times the plasma concentra- with the pregnancy testing and contraception re- tion of macitentan and is believed to contribute 40% of quirements the drug’s total pharmacologic activity. The half-life of • Pharmacies must be certiLied with the program macitentan and its active metabolite are 16- and and must only dispense to patients who are au- 48-hours, respectively, allowing for once daily dosing. thorized to receive macitentan The half-life of macitentan is nearly three times longer Unlike bosentan, macitentan does not have a REMS than bosentan (16- versus 5-hours, respectively) requirement for monthly liver function tests. 2,6 which requires twice daily dosing. However ambris- entan which has a half-life of 9 hours may be given Conclusion : Macitentan is an oral endothelin receptor once daily. antagonist that blocks both endothelin receptor A and endothelin receptor B. It is FDA-approved for the Dosing and adverse effects : The recommended dose treatment of PAH to prevent disease progression. of macitentan is 10 mg orally taken once daily. 2 The Some advantages over bosentan include once daily drug may be taken with or without food. There are no dosing, fewer drug-drug interactions, and no REMS adjustments for renal or hepatic impairment. Side ef- requirement for monthly liver function test monitor- fects seen include anemia, nasopharyngitis, upper res- ing. Unlike bosentan and ambrisentan, macitentan piratory tract infections, headache, and elevated liver does not have a warning against use in patients with function tests. Unlike bosentan and ambrisentan, moderate to severe hepatic impairment. macitentan does not have a warning against use in pa- References: 2,6,7 tients with moderate to severe hepatic impairment. 1. Harrington RA, Anderson JL, Bates ER, et al. ACC/AHA 2009 Like bosentan and ambrisentan, macitentan is classi- expert consensus document on pulmonary hypertension. J Am Lied as a pregnancy-risk category X which means that it Coll Cardiol 2009;53(17):1573-1619. is contraindicated in pregnancy. 2. Opsumit ® [package insert]. San Francisco, CA: Actelion Phar- maceuticals US, Inc; October 2013. 3. Bolli MH, Boss C, Binkert C, Buchmann S, Bur D, Hess P, at al. Drug Interactions : Since macitentan is extensively The discovery of N-[5-(4-bromophenyl-6-[2-[(5-bromo-2- metabolized through the CYP3A4 system, it can poten- pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide tially interact with medications that either inhibit or (Macitentan), an orally active, potent, dual endothelin receptor antagonist. J Med Chem 2012;55:7849-61. induce this system. Strong CYP3A4 inducers (e.g., ri- 4. Pulido T, Adzerikho I, Channick RN, Delcroix M, Galie N, Ghof- fampin) can decrease the concentration of macitentan rani HA, et al. Macitentan and morbidity and mortality in pul- in the blood; use of macitentan with strong CYP3A4 monary arterial hypertension. N Engl J Med 2013;369:809-18. inducers should be avoided. 2 Strong inhibitors of 5. Iglarz M, Binkert C, Morrison K, Fischli W, GarLield J, Treiber A, et al. Pharmacology of macitentan, an orally active tissue- CYP3A4 (e.g., ketoconazole) can increase the concen- targeting dual endothelin receptor antagonist. J Pharmacol tration of macitentan in the blood therefore, the use of Exp Ther 2008;327:736-45. macitentan with strong CYP3A4 inhibitors should also 6. Tracleer ® [package insert]. San Francisco, CA: Actelion Phar- be avoided. Unlike bosentan which is an inducer of maceuticals US, Inc; October 2012. CYP3A (which includes 3A4 and 3A5) and CYP2C9, 7. Letairis ® [package insert]. Forest City, CA: Gilead Sciences, Inc; August 2013. macitentan exhibits no relevant inhibitory or inducing effects on those CYP . In comparison to the other endothelin receptor antagonists, bosentan has the greatest number of drug interactions, whereas am- 3 Formulary Update

Additions to Adult CCHS Formulary

Pharmacologic Drug Formulary Use Restriction/Comments Class Doses ≤ 100 mg are recommended to be given at bedtime Doses > 100 mg are recommended to Fluvoxamine Treatment of be given twice daily immediate-release SSRI obsessive-compulsive

tablets disorder Fluvoxamine controlled-release capsules were not added to the Formulary Restrictions: For initiation of therapy: Restricted to providers from the Respiratory Treatment of Institute. Prescribers must be regis- Endothelin Macitentan pulmonary arterial tered in the REMS program. Receptor (Opsumit ®) hypertension Antagonist For continuation of therapy: The prescriber must be registered in the REMS program, but does not have to be part of the Respiratory Institute. Restriction: For continuation of therapy only. The patient must be registered with the Adempas ® REMS Riociguat Treatment of sGC Stimulator program under the supervision of a (Adempas ®) CTEPH and PAH certiLied prescriber. The inpatient prescriber does not need to be certi- Lied for continuation of therapy

Treatment of Restriction: Restricted to Obinutuzumab Antineoplastic chronic lymphocytic Hematology/Oncology for (Gazyva ®) Agent leukemia outpatient use only

Used in CRRT as re- Replacement placement solution in Prismasate ® will no longer be used PrismaSol ® BGK 0/2.5 Solution hemoLiltration and for CRRT. hemodiaLiltration

Treatment of short Restriction: For continuation of bowel syndrome home therapy only; provider must Teduglutide GLP-2 analog in patients be a fellow or staff physician from (Gattex ®) dependent on the Intestinal Transplant parenteral nutrition Surgical Service. Treatment of Dietary delirium, sleep wake Melatonin 3 mg tablets Melatonin Supplement reversal, and will be stocked insomnia CRRT=Continuous renal replacement therapy CTEPH= Chronic thromboembolic pulmonary hypertension GLP -- 4 Formulary Update

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5 Formulary Update

- - - - - - GPA=Granulomatosis with polyangiitis MPA=Microscopic polyangiitis

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