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Drug updates and approvals: 2017 in review

Mospan, Geoffrey PharmD, BCPS; Mospan, Cortney PharmD, BCACP, BCGP; Vance, Shayna; Bradshaw, Alyssa; Meosky, Kalyn; Bowles, Kirklin

doi: 10.1097/01.NPR.0000526760.22854.f1
Feature: NEW DRUGS: CE Connection

Abstract: In 2017, the FDA approved several new drugs for use in primary care. This article highlights the following new drugs: brodalumab (Siliq), dapagliflozin and saxagliptin (Qtern), dupilumab (Dupixent), oxymetazoline (Rhofade), safinamide (Xadago), and sarilumab (Kevzara).

In 2017, the FDA approved several new drugs for use in primary care. This article highlights the following new drugs: brodalumab (Siliq), dapagliflozin and saxagliptin (Qtern), dupilumab (Dupixent), oxymetazoline (Rhofade), safinamide (Xadago), and sarilumab (Kevzara).

Geoffrey Mospan is an assistant professor of pharmacy at Wingate University School of Pharmacy, Wingate, N.C.

Cortney Mospan is an assistant professor of pharmacy at Wingate University School of Pharmacy, Wingate, N.C.

Shayna Vance is a 4th year PharmD candidate at Wingate University School of Pharmacy, Wingate, N.C.

Alyssa Bradshaw is a 4th year PharmD candidate at Wingate University School of Pharmacy, Wingate, N.C.

Kalyn Meosky is a 4th year PharmD candidate at Wingate University School of Pharmacy, Wingate, N.C.

Kirklin Bowles is a 4th year PharmD candidate at Wingate University School of Pharmacy, Wingate, N.C.

Consult the manufacturer's prescribing label for complete prescribing information including dose recommendations and dose adjustments for each drug.

The authors and planners have disclosed no potential conflicts of interest, financial or otherwise.

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Psoriasis

Brodalumab (Siliq)

Figure

Figure

Siliq is a monoclonal antibody that antagonizes the interleukin-17 receptor A (IL-17RA) and is used to treat moderate-to-severe plaque psoriasis.1 Plaque psoriasis is a chronic, inflammatory multisystem disease characterized by erythematous plaques with silver scales.2 Siliq is a subcutaneous injection manufactured by Valeant Pharmaceuticals and was approved by the FDA in February 2017.1,3

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Indications

Siliq is indicated for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for either systemic therapy or phototherapy and have failed to respond to or have lost response to other systemic therapies.1

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Mechanism of action

Siliq is a human monoclonal immunoglobulin G2k antibody that selectively binds the IL-17RA, blocking the release of proinflammatory cytokines and chemokines.1

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Dosing and administration

Siliq is a subcutaneous injection formulated as a 210 mg/1.5 mL prefilled, preservative-free, single-dose syringe.1 The recommended dose is 210 mg at weeks 0, 1, and 2, then every 2 weeks. If adequate response has not been seen between weeks 12 and 16, discontinuation should be considered, as patients are unlikely to see benefit if not evident by 16 weeks.1

Patients may self-administer injections after training. Siliq is administered into the thigh, abdomen, or outer upper arm (only when someone other than the patient is administering the injection).1 Areas that are bruised, red, scaly, thick, hard, or otherwise appear to be affected by psoriasis should not be used as an injection site. Siliq should be stored in the refrigerator and allowed to reach room temperature 30 minutes before injecting. Once at room temperature, Siliq is stable for up to 14 days and should not be refrigerated again.1

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Contraindications

Siliq is contraindicated in patients with Crohn disease, as it may worsen the disease.1

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Warnings and precautions

Siliq has a black box warning for suicidal ideation and behavior due to suicidal ideation in clinical trials, which included completed suicides. Therefore, Siliq is only available through a risk evaluation and mitigation strategy (REMS) program.1,4 The REMS program includes prescriber certification, a prescriber-patient agreement, and pharmacy certification to dispense the medication. Although a causal association has not been established, prescribers should weigh the potential risks and benefits in patients with a history of depression and suicidal ideation and monitor for them during treatment.1

In clinical trials, Siliq showed increased frequency of fungal and other serious infections; therefore, the risks and benefits should be carefully weighed before initiation in patients with a history of recurrent infections. Live vaccines should not be administered in patients taking Siliq. Patients should be screened for tuberculosis (TB) infection prior to therapy initiation; patients with an active or latent infection should not receive Siliq until TB treatment is completed.1

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Adverse reactions

The most commonly observed adverse reactions in phase III clinical trials were nasopharyngitis, upper respiratory tract infection, headache, and arthralgia.4

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Pharmacokinetics

Following a single dose of Siliq, peak serum concentration is reached in approximately 3 days. Following multiple doses, steady state is achieved by week 4. Bioavailability is approximately 55% with subcutaneous administration, which is influenced by the site of administration and degradation at the site of administration.5 The metabolic pathway has not been characterized; however, it is expected to degrade into small peptides and amino acids.1

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Clinical pearls

  • Siliq has not been studied in renal or hepatic insufficiency; therefore, there are no recommended dosage adjustments.
  • There is no human data on the use of Siliq in pregnancy; however, IgG antibodies cross the placental barrier, which may result in brodalumab exposure to the fetus.
  • The formation of CYP450 enzymes can be decreased by increasing levels of cytokines. This could result in increased exposure to CYP450 metabolized drugs, particularly of importance with narrow therapeutic index drugs.
  • Drug concentration and effects of concomitant drugs should be monitored during the initiation or discontinuation of Siliq.
  • In clinical trials, Siliq was shown to have efficacy superior to that of placebo and ustekinumab (Stelara) with a median time to response of 4 weeks, which is approximately twice as fast as ustekinumab.1,4
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REFERENCES

1. Siliq (brodalumab) [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2017.

2. Menter A, Korman NJ, Elmets CA, et al Guidelines of care for the management of psoriasis and psoriatic arthritis. J Am Acad Dermatol. 2011;65(1):137–174.

3. U.S. Food and Drug Administration. FDA approves new psoriasis drug Siliq. 2017. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm541981.htm.

4. Lebwohl M, Strober B, Menter A, et al Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373(14):1318–1328.

5. U.S. Food and Drug Administration Dermatologic and Ophthalmic Drugs Advisory Committee. FDA briefing document: background package for BLA 761032 Siliq (brodalumab) injection, 210 mg/1.5 mL. 2016. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/dermatologicandophthalmicdrugsadvisorycommittee/ucm511357.pdf.

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Type 2 diabetes mellitus

Dapagliflozin and saxagliptin (Qtern)

In 2016, the prevalence of type 2 diabetes mellitus (T2DM) reached 29 million individuals in the United States in addition to 86 million individuals with prediabetes.1 Diabetes is listed as the seventh leading cause of death in the United States.2 Qtern, a novel product coformulated with two medications, was approved by the FDA on February 28, 2017, for the treatment of T2DM.3 Qtern is manufactured by AstraZeneca.

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Indications

Qtern is indicated to improve glycemic control in addition to diet and exercise in adult patients with T2DM who have inadequate control with dapagliflozin or those already treated with both dapagliflozin and saxagliptin.4 Qtern should only be used in patients who can tolerate 10 mg of dapagliflozin. In addition, the drug is not indicated for patients with type 1 diabetes mellitus or diabetic ketoacidosis.4

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Mechanism of action

Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, acts in the kidneys to prevent reabsorption of glucose back into systemic circulation, which results in an increased amount of glucose excreted in the urine.4 Saxagliptin, a dipeptidyl peptidase-4 inhibitor, prolongs the activity of endogenous incretin hormones, resulting in increased insulin release and decreased glucagon release from the pancreas.4

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Dosing and administration

Qtern is available in only one fixed-dose combination tablet with 10 mg of dapagliflozin and 5 mg of saxagliptin. Patients are instructed to take 1 tablet daily in the morning with or without food.4 Qtern should not be used if the estimated glomerular filtration rate (eGFR) is persistently below 60 mL/min/1.73 m2. Patients with this level of kidney impairment were excluded from clinical trials.4 Furthermore, the efficacy of dapagliflozin is reduced with kidney impairment.5 Patients with liver dysfunction may receive Qtern, although its use in severe hepatic impairment has not been evaluated.4

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Contraindications

Qtern is contraindicated in patients with a serious hypersensitivity reaction to either dapagliflozin or saxagliptin.4 An additional contraindication is for patients with moderate or severe kidney impairment, defined as an eGFR below 45 mL/min/1.73 m2, end-stage renal disease, or dialysis.4

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Warnings and precautions

There are numerous warnings and precautions the clinician must consider prior to initiating Qtern (to determine the risk-benefit ratio) or to monitor during therapy. The warnings stem from well-known adverse reactions of the individual components of Qtern (or both), including the following:

  • Dapagliflozin: hypotension, ketoacidosis, acute kidney injury, urosepsis, pyelonephritis, genital mycotic infections, increased low-density lipoprotein (LDL) cholesterol, bladder cancer
  • Saxagliptin: pancreatitis, heart failure, severe and disabling arthralgia, bullous pemphigoid
  • Combination: hypoglycemia with concomitant use of insulin or insulin secretagogues, hypersensitivity reactions.4
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Adverse reactions

The adverse reactions reported most frequently by patients in clinical trials for Qtern included upper respiratory tract infection, urinary tract infection, dyslipidemia, headache, diarrhea, back pain, genital infection, bone fracture, and arthralgia.4

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Pharmacokinetics

When coformulated in a single tablet, the pharmacokinetics of Qtern are not altered in comparison when each drug is administered separately.4 Saxagliptin is primarily metabolized by cytochrome P450 3A4 enzymes.4 Therefore, it is important to screen for drug interactions that may increase or decrease the serum concentrations of saxagliptin. Saxagliptin and dapagliflozin are both eliminated from the body through the kidneys, and saxagliptin has minor elimination in the feces.4

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Clinical pearls

  • Monitoring parameters for adverse reactions from Qtern include kidney function, signs and symptoms of pancreatitis and heart failure, dehydration, yeast infections, dysuria, hypoglycemia (if used in combination with insulin or insulin secretagogues), LDL, and joint pain.
  • Qtern is not recommended in the second and third trimesters of pregnancy or while breastfeeding.
  • Volume depletion must be corrected prior to starting Qtern.
  • Excretion of glucose in the urine via dapagliflozin can lead to osmotic diuresis, resulting in volume depletion, hypotension, and acute kidney injury (older adult patients and those on diuretic therapy may be at greater risk).
  • Phase III trials demonstrated an average hemoglobin A1C (A1C) reduction of 0.51% to 0.82% at 24 weeks for patients receiving Qtern added to metformin therapy.6,7 In an extension study, the reduction in A1C was maintained at 52 weeks.8
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REFERENCES

1. Announcement: National Diabetes Month—November 2016. MMWR Morb Mortal Wkly Rep. 2016;65(43):1202.

2. Kochanek KD, Murphy SL, Xu J, Tejada-Vera B. Deaths: final data for 2014. Natl Vital Stat Rep. 2016;65(4):1–122.

3. AstraZeneca. FDA approves once-daily Qtern (dapagliflozin and saxagliptin) tablets for adults with type-2 diabetes [News Release]. 2017. http://www.astrazeneca.com/media-centre/press-releases/2017/fda-approves-once-daily-qtern-dapagliflozin-and-saxagliptin-tablets-for-adults-with-type-2-diabetes-240217.html.

4. Qtern [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017.

5. Kasichayanula S, Liu X, Pe Benito M, et al The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus. Br J Clin Pharmacol. 2013;76(3):432–444.

6. Mathieu C, Ranetti AE, Li D, et al Randomized, double-blind, phase 3 trial of triple therapy with dapagliflozin add-on to saxagliptin plus metformin in type 2 diabetes. Diabetes Care. 2015;38(11):2009–2017.

7. Matthaei S, Catrinoiu D, Celi_ski A, et al Randomized, double-blind trial of triple therapy with saxagliptin add-on to dapagliflozin plus metformin in patients with type 2 diabetes. Diabetes Care. 2015;38(11):2018–2024.

8. Mathieu C, Herrera Marmolejo M, González González JG, et al Efficacy and safety of triple therapy with dapagliflozin add-on to saxagliptin plus metformin over 52 weeks in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18(11):1134–1137.

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Atopic dermatitis

Dupilumab (Dupixent)

Atopic dermatitis, the most common type of eczema, is a chronic skin disease that affects approximately 30% of individuals in the United States.1 Dupixent is an interleukin-4 receptor alpha antagonist approved in March 2017 for the treatment of moderate-to-severe atopic dermatitis.2,3 Dupixent is a subcutaneous injection manufactured by Regeneron Pharmaceuticals and marketed by Sanofi-Aventis.2,3

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Indications

Dupixent is indicated for the treatment of adult patients with moderate-to-severe atopic dermatitis with or without topical corticosteroids when the disease is not properly controlled with topical therapies or those therapies are not recommended.1

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Mechanism of action

Dupixent is a human monoclonal IgG4 antibody that blocks interleukin-4 (IL-4) and interleukin-13 signaling by binding the IL-4R alpha subunit. This results in inhibition of the release of proinflammatory cytokines, chemokines, and immunoglobulin E.2

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Dosing and administration

Dupixent is a 300 mg subcutaneous injection formulated as a 300 mg/2 mL single-dose, preservative-free, prefilled syringe. The recommended starting dose is 600 mg given via two 300 mg doses injected at different locations. Following the initial dose, 300 mg is given every other week. If a dose is missed, it should be injected within 7 days, and the normal schedule should be resumed; if a missed dose is not administered within 7 days, the patient should wait until the next dose.

After training, the patient can self-administer the injection. Dupixent is administered by subcutaneous injection into the thigh or abdomen (except for the 2 in [5 cm] around the navel). The upper arm can be used when someone other than the patient administers the injection.2 Injection sites should be rotated, and Dupixent should not be injected into scarred, bruised, tender, or damaged skin. Dupixent should be stored in the refrigerator and before administration, should be removed and allowed to reach room temperature 45 minutes before injecting. Once at room temperature, Dupixent is stable for up to 14 days and should not be refrigerated again.2

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Contraindications

Dupixent is contraindicated in patients with a hypersensitivity to the drug or its excipients.2

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Warnings and precautions

Patients should be advised to report new onset or worsening eye symptoms due to an increased prevalence of conjunctivitis and keratitis with Dupixent observed in trials.2,4 Recovery is expected after treatment for patients who experience conjunctivitis or keratitis.2,4 Patients with comorbid asthma are advised to avoid adjusting or stopping asthma therapy unless otherwise directed by their clinician, as safety and efficacy have not been established in asthma treatment.2,4

In clinical trials, patients were excluded if they had known helminth infections; therefore, it is unknown if Dupixent will influence immune response against helminth infections.2,4 Live vaccines should not be administered in patients taking Dupixent.2

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Adverse reactions

The most common adverse reactions are injection site reactions, keratitis, blepharitis, conjunctivitis, oral herpes, other herpes simplex virus infection, dry eye, and eye pruritus.2,4

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Pharmacokinetics

After the initial 600 mg dose, peak concentrations are achieved within 1 week, and steady state concentrations are achieved by week 16. Dupixent is 64% bioavailable after a subcutaneous injection. The drug should be nondetectable 10 weeks after the last steady-state dose of 300 mg every 2 weeks.2 Currently, there is no information on how the drug is cleared from the body. In chronic inflammation, CYP450 enzyme formation can be altered, and administration of Dupixent with CYP450 substrates should be monitored.2

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Clinical pearls

  • No trials have been conducted in renal or hepatic dysfunction; therefore, there are no recommended dosage adjustments.
  • There is no data available for pregnancy or lactation, but human IgG antibodies are known to cross the placenta and pass into breast milk, so the medication may be transferred from mother to infant.
  • Concurrent administration with CYP450 substrates, particularly medications with narrow therapeutic indices, should be monitored and modified if needed, as Dupixent can modulate formation of CYP450 enzymes.
  • Dupixent showed significant improvement in disease severity, patient-reported symptoms, and quality of life compared with placebo in clinical trials.2,4
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REFERENCES

1. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Handout on health: atopic dermatitis (a type of eczema). 2016. http://www.niams.nih.gov/health_info/atopic_dermatitis/default.asp#a.

2. Dupixent (dupilumab) [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals; 2017.

3. U.S. Food and Drug Administration. FDA news release: FDA approves new eczema drug Dupixent. 2017. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm549078.htm.

4. Simpson EL, Bieber T, Guttman-Yassky E, et al Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335–2348.

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Rosacea

Oxymetazoline (Rhofade)

Rosacea, presenting as persistent facial redness, affects nearly 16 million individuals in the United States.1 Rhofade is an alpha-1A adrenoceptor agonist that provides relief of facial redness for up to 12 hours.2,3 Although Rhofade is not recommended within treatment guidelines, the Rosacea International Expert Group consensus statement has recognized its potential therapeutic role, given emerging concerns of antibiotic resistance due to antibiotic use in rosacea management.4 Rhofade was approved by the FDA in January 2017 and is manufactured by Allergan.3

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Indications

Rhofade 1% cream is indicated for topical use in adults experiencing persistent facial erythema associated with rosacea.2

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Mechanism of action

Rhofade is an alpha-1A adrenoceptor agonist, which provides vasoconstrictive effects in the vascular smooth muscles within the face.2 Through vasoconstriction, Rhofade use results in a decrease of facial redness.2

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Dosing and administration

Rhofade is available as a 30 g or 60 g tube or pump. Each g of Rhofade contains 10 mg (1%) oxymetazoline hydrochloride. Patients should apply a pea-sized amount, in a thin layer to the entire face once a day. The application should cover the entire forehead, nose, cheeks, and chin, even if those areas are not affected by rosacea. Areas that should be avoided include the eyes, lips, open wounds, and irritated skin.

No hepatic or renal adjustments are required due to topical application and limited systemic effects of the medication. Patients should be instructed to wash their hands immediately after applying. When using the pump for the first time, priming is required; the first three pumps should be discarded and not applied topically.2

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Contraindications

No contraindications to Rhofade are currently listed within the manufacturer's prescribing information.2

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Warnings and precautions

Despite being a topical preparation, Rhofade does have warnings and precautions for use due to its mechanism of action.2,3 Rhofade may impact BP control. Patients with uncontrolled cardiovascular disease, orthostatic hypotension, uncontrolled hypertension, or uncontrolled hypotension should be carefully evaluated before initiating Rhofade. The drug also has the potential to cause vascular insufficiency and should be used cautiously in cerebral or coronary insufficiency conditions, including Raynaud phenomenon, Sjögren syndrome, scleroderma, and thromboangiitis obliterans.

In patients with narrow-angle glaucoma, Rhofade may increase the risk of angle closure. If Rhofade is utilized in patients with narrow-angle glaucoma, they should be advised to seek medical attention with any signs or symptoms of acute angle-closure glaucoma.2

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Adverse reactions

Through 4 weeks of treatment with Rhofade in controlled clinical trials, the most common adverse reactions included application site dermatitis; worsening of rosacea lesions; and application site pruritus, erythema, and pain.2

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Pharmacokinetics

Following the standard application of Rhofade, plasma oxymetazoline concentrations were measurable in most patient subjects.2 Rhofade is 56% to 58% bound to human plasma proteins and is minimally metabolized by the liver according to in-vitro studies.2 The excretion of Rhofade following daily application has not yet been characterized in humans. Rhofade has no inhibition or induction effects on any human major cytochrome CYP450 liver enzymes.2

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Clinical pearls

  • No adequate clinical data are available to assess the safety and efficacy of Rhofade in pregnant patients; however, it may have limited systemic effects, as intranasal oxymetazoline has negligible systemic absorption; one article in the literature identified a potential association between second-trimester exposure to oxymetazoline and renal collecting system anomalies.2,5
  • No adequate clinical data are available to assess the safety and efficacy of Rhofade in breastfeeding patients; however, decongestants may decrease milk production. Breastfeeding mothers should be counseled to monitor milk production and consider treatment benefits compared with preferences for duration of breastfeeding.
  • The safety and efficacy of Rhofade have not been evaluated in pediatric patients under the age 18.
  • Due to potential cardiovascular effects, Rhofade should be used cautiously in patients taking beta-blockers, antihypertensive medications, cardiac glycosides, alpha-1 adrenergic receptor antagonists, and monoamine oxidase inhibitors.
  • Rhofade can be considered for relief of periodic flushing symptoms, erythema, and erythematous flares.2,4,5
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REFERENCES

1. National Rosacea Society. Rosacea review. http://www.rosacea.org/rr/2010/winter/article_1.php.

2. Rhofade (oxymetazoline 1% cream) [package insert]. Irvine, CA: Allergan; 2017.

3. Allergan. Allergan announces FDA approval of Rhofade (oxymetazoline hydrochloride) cream, 1% for the topical treatment of persistent facial erythema associated with rosacea in adults. http://www.allergan.com/news/news/thomson-reuters/allergan-announces-fda-approval-of-rhofade-oxymet.

4. Generali JA, Cada DJ. Off-label drug uses oxymetazoline (topical): rosacea. Hosp Pharm. 2013;48(7):558–559.

5. Scolaro K. Colds and allergy. In: Krinsky DL, et al., eds. Handbook of Nonprescription Drugs: An Interactive Approach to Self-Care. 18th ed. Washington, DC: American Pharmacists Association; 2015.

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Parkinson disease

Safinamide (Xadago)

Although carbidopa and levodopa is the drug of choice for treatment of motor symptoms related to Parkinson disease (PD), long-term use is associated with development of motor complications.1 After 4 to 6 years of levodopa treatment, 40% of patients develop motor complications and may require add-on therapy.2 A motor complication that can occur is fluctuations in control of motor symptoms throughout the day, known as “off episodes” (for example, tremor or difficulty walking).1 Xadago is a monoamine oxidase type B inhibitor that is used as adjunctive therapy for PD motor symptoms and was approved by the FDA on March 21, 2017.3,4 Xadago is manufactured by Newron Pharmaceuticals.4

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Indications

Xadago is indicated as add-on therapy for patients with PD who are experiencing “off episodes” while taking carbidopa and levodopa. Xadago does not have evidence to support efficacy as monotherapy for the treatment of PD motor symptoms and should only be used concomitantly with carbidopa and levodopa.3

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Mechanism of action

Xadago selectively and reversibly inhibits monoamine oxidase type B (MAO-B), which is the enzyme responsible for the breakdown of dopamine.3,5 Preventing the breakdown of dopamine results in increased dopaminergic activity in the brain due to increased dopamine levels.3

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Dosing and Administration

Xadago is available as two different strength tablets: 50 mg and 100 mg. Patients should be started on 50 mg administered orally once daily. After 2 weeks of initial therapy, the dose can be increased to 100 mg daily.3 Due to no increase in efficacy and risk of adverse reactions, 100 mg is the maximum recommended daily dose.3 In patients with moderate hepatic impairment (Child-Pugh class B), dosages should not exceed 50 mg per day.3,6

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Contraindications

Xadago is contraindicated in patients with: severe liver impairment (Child-Pugh class C); history of hypersensitivity to Xadago; concurrent use of monoamine oxidase inhibitors or potent inhibitors of monoamine oxidase (linezolid), dextromethorphan, and medications with serotonergic activity (for example, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, tetracyclic or triazolopyridine antidepressants, cyclobenzaprine); methylphenidate, amphetamine and derivatives, opioid drugs (such as tramadol, meperidine, and any related derivatives), and the herbal preparation St. John's wort.3,6

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Warning and precautions

Xadago may raise BP and should be monitored closely, especially in patients who are also receiving sympathomimetic medications (such as nasal decongestants).3 Due to the risk of serotonin syndrome with MAO-B inhibitors and other medications with serotonergic activity, Xadago must not be used with these drugs.3 Sleep attacks or sudden onset of sleep without warning signs occurred in patients enrolled in clinical trials of Xadago. Patients should be advised of this risk and not perform any tasks requiring mental alertness.3

Increasing the levels of dopamine in the brain may lead to hallucinations, psychosis, impulsive, and compulsive behaviors. Patients should be monitored closely for these conditions, and those with a history of psychotic disorders should not receive Xadago.3 Withdrawal symptoms may occur if Xadago is abruptly stopped.3 Additionally, patients should be monitored for dyskinesia and visual changes.3

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Adverse reactions

In clinical trials, the most commonly reported adverse reactions included dyskinesia, hypertension, falls, nausea, insomnia, and increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST).3,5

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Pharmacokinetics

Xadago has a bioavailability of 95% that is independent of a fast or fed state and can therefore be given with or without food.3 Xadago is eliminated by various routes of metabolism. The elimination half-life of Xadago is 20 to 26 hours and primarily excreted in urine as inactive metabolites.3

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Clinical pearls

  • The safety of Xadago in pregnancy and lactation is unknown.
  • In a phase III trial, Xadago 100 mg daily increased “on” time (time when patients experience relief of motor symptoms) without troublesome dyskinesia by approximately 1.5 hours in patients who were experiencing more than 1.5 hours per day of “off episodes” despite pharmacotherapy.
  • Although patients taking recommended doses of Xadago do not need to restrict their intake of dietary tyramine, patients should avoid foods containing large amounts of tyramine (greater than 150 mg) due to the risk of hypertensive crisis.
  • When discontinuing Xadago 100 mg daily, taper down to 50 mg daily for 1 week before stopping to avoid withdrawal symptoms.
  • Several medications interact with Xadago; consult the package insert or a drug information reference before initiating Xadago or other medications.3,5
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REFERENCES

1. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA. 2014;311(16):1670–1683.

2. Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord. 2001;16(3):448–458.

3. Xadago (safinamide) [prescribing information]. Louisville, KY: US WorldMeds; 2017.

4. U.S. Food and Drug Administration. FDA approves drug to treat Parkinson's disease. 2017. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm547852.htm.

5. Schapira AH, Fox SH, Hauser RA, et al Assessment of safety and efficacy of safinamide as a levodopa adjunct in patients with Parkinson disease and motor fluctuations: a randomized clinical trial. JAMA Neurol. 2017;74(2):216–224.

6. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646–649.

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Rheumatoid arthritis

Sarilumab (Kevzara)

Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune disease that primarily affects the joints of the body, although organ involvement may also occur.1 The goal of treatment is to decrease disease activity, improve physical function, and induce remission.2 Medications used to reduce disease activity include disease-modifying antirheumatic drugs (DMARDs) and biologic agents.1 Kevzara is a new IL-6 receptor antagonist biologic agent approved by the FDA on May 22, 2017, for RA.3 Kevzara is manufactured by Regeneron Pharmaceuticals and Sanofi.

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Indication

Kevzara has been approved for treatment of adult patients with moderately to severely active RA who have had an inadequate response or intolerance to one or more DMARDs.4

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Mechanism of action

Kevzara is a human recombinant monoclonal antibody produced by recombinant DNA technology.4 When administered, Kevzara binds to and inhibits interleukin-6 receptors, thereby suppressing proinflammatory mediators produced by the immune system.4

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Dosing and administration

Kevzara is manufactured as a prefilled syringe and injected subcutaneously into the thigh or abdomen at a dose of 200 mg every 2 weeks.4 Patients may self-administer Kevzara after appropriate training.4 A dose reduction or discontinuation of Kevzara is warranted if patients experience decreases in absolute neutrophil count (ANC), platelets, or increases in liver enzymes.4 Kevzara may be used with methotrexate or other nonbiologic DMARDs. There are no dose adjustments required for patients with mild or moderate kidney impairment. Patients with severe kidney impairment (creatinine clearance less than 30 mL/min) or hepatic impairment, including active liver disease, were excluded from clinical trials and should not receive Kevzara.4,5

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Contraindications

The only contraindication is for patients with known hypersensitivity to Kevzara or any of its ingredients.4

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Warnings and precautions

Many of the warnings and precautions for Kevzara are consistent with other monoclonal antibodies and their immunosuppressing properties. As a result, serious infections including TB, viral reactivation or opportunistic infections, and malignancy may occur (see the black box warning in the manufacturer's prescribing information).4 Do not administer Kevzara if the patient has an active infection. Kevzara should be held if patients develop a severe infection, and similar to other immunosuppressing agents, live vaccines should be avoided.4

Lab abnormalities may also occur during Kevzara therapy, which include neutropenia, thrombocytopenia, elevated liver enzymes, and lipid abnormalities.4 Kevzara should not be given to patients with certain abnormal lab values at baseline (ANC less than 2,000 cells/mm3, platelets less than 150,000 cells/mm3, AST or ALT greater than 1.5 times the upper limit of normal).4

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Adverse reactions

Common adverse reactions reported by patients during clinical trials included injection site reaction, neutropenia, increased ALT, upper respiratory tract infection, and urinary tract infection.4

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Pharmacokinetics

Kevzara achieves its maximum concentration 2 to 4 days after administration and reaches steady state in 14 to 16 weeks.4 The half-life of the 200 mg dose is approximately 10 days at steady state. Kevzara is not metabolized or eliminated by the liver or kidneys.4

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Clinical pearls

  • There is insufficient data to determine the safety of Kevzara during pregnancy and lactation.
  • Monitoring parameters during treatment with Kevzara include signs and symptoms of infection, neutrophil count, platelets, liver enzymes, lipid panel, and pregnancy.
  • Test for tuberculosis (TB) prior to starting treatment with Kevzara and treat TB if needed.
  • Due to the ability of Kevzara to suppress the immune system, concomitant treatment with other biologic agents used to treat RA should be avoided.
  • In line with the FDA-approved indication, Kevzara demonstrated efficacy in clinical trials for patients with active, moderate-to-severe RA who previously had an inadequate response to methotrexate or tumor necrosis factor inhibitors.4-6
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REFERENCES

1. Singh JA, Saag KG, Bridges SL Jr, et al 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol. 2016;68(1):1–26.

2. Smolen JS, Landewé R, Bijlsma J, et al EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960–977.

3. Regeneron. Regeneron and Sanofi announce FDA approval of Kevzara (sarilumab) for the treatment of moderately to severely active rheumatoid arthritis in adult patients [News Release]. 2017. http://newsroom.regeneron.com/releasedetail.cfm?ReleaseID=1027419.

4. Kevzara [package insert]. Bridgewater, NJ and Tarrytown, NY: Sanofi Biotechnology and Regeneron Pharmaceuticals, Inc; 2017.

5. Genovese MC, Fleischmann R, Kivitz AJ, et al Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a phase III study. Arthritis Rheumatol. 2015;67(6):1424–1437.

6. Fleischmann R, van Adelsberg J, Lin Y, et al Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors. Arthritis Rheumatol. 2017;69(2):277–290.

Keywords:

2017; atopic dermatitis; eczema; FDA; FDA approved; new drugs; Parkinson disease; plaque psoriasis; rheumatoid arthritis; rosacea; type 2 diabetes mellitus; T2DM

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