Hypertension affects approximately 74.5 million individuals in the United States alone.1 In order for patients to achieve BP goals, a combination of diet, exercise, and medication management is employed. Based on current guidelines, the goal of antihypertensive therapy is a BP less than 140/90 mm Hg, or for patients with diabetes or chronic kidney disease the goal is a BP less than 130/80 mm Hg.2 It has been shown that usually patients need to use a combination of agents to lower their BP, achieve goals, and reduce the incidence of cardiovascular events.3 When using multiple medications, there is a risk of noncompliance, which can lead to treatment failure. The use of fixed-dose combinations of 2 or more antihypertensive agents has been shown to reduce BP to goal, along with improving compliance when compared with giving the medications separately.3 The TRINITY trial showed that using a combination of olmesartan, amlodipine, and hydrochlorothiazide in a fixed-dose administration form was able to achieve BP goals, along with increasing compliance.4

With the results of the TRINITY trial, the FDA granted approval on July 26, 2010, for the fixed-dose medication Tribenzor. This combination product contains olmesartan medoxomil, amlodipine, and hydrochlorothiazide, and is indicated for the treatment of hypertension, but not as initial therapy. This agent should be considered as an option when a patient fails therapy on any two of the following antihypertensive drug classes: angiotensin receptor blockers (ARBs), calcium channel blockers, or diuretics.5 Tribenzor is marketed and distributed by Daiichi Sankyo, Inc.

Mechanism of action

Being a combination product, Tribenzor combines the actions of three different medications, all of which complement each other in effectively relaxing blood vessels and reducing BP. Olmesartan medoxomil is an angiotensin II receptor blocker and exerts its effects by blocking the vasoconstrictor effects of angiotensin II by blocking the binding of angiotensin II to the AT₁ receptor on the vascular smooth muscle.6 Amlodipine is a dihydropyridine calcium channel blocker that prevents the influx of calcium into both the smooth and cardiac muscles.6 This in turn causes a decrease in peripheral vascular resistance, leading to a decrease in BP. Hydrochlorothiazide is a thiazide diuretic that reduces water volume in the blood. This is accomplished through electrolyte reabsorption that helps with excretion of sodium and chloride. This medication also reduces plasma volume, leading to an increase in plasma renin activity.6 The combination of these three agents works together in controlling BP.

Due to the fact that Tribenzor comprises three different medications, it is expected that the peak plasma concentrations of each may be reached at different times after administration. The peak level of amlodipine can be seen within 6 to 8 hours, 1.5 and 3 hours for olmesartan, and 1.5 to 2 hours for hydrochlorithiazide.6 When analyzing the half-life of Tribenzor, one must take into consideration the components. Olmesartan has a half-life of 13 hours, whereas amlodipine has a half-life of 30 to 50 hours.6 Hydrochlorothiazide is eliminated quickly by the kidneys.

Adverse reactions

When analyzing the incidence of adverse reactions of Tribenzor in clinical trial experience, the most commonly seen were dizziness, peripheral edema, headache, fatigue, nausea, and muscle spasms. As noted in the prescribing information, the adverse reactions were the same among all treatment groups and patient populations.6

Dosing and administration

Do not use this medication in patients with severe renal impairment, defined as creatinine clearance (CrCl) less than 30 mL/minute.6 Do not use this medication in the elderly (75 years and older) due to the fact that the usual starting dose of amlodipine is 2.5 mg, which is not available in any of the drug combinations. Tribenzor is not FDA approved as initial hypertension therapy. So, consider using this medication in patients who are currently taking each component separately, or in those who failed therapy with any two of the following agent classes: ARBs, calcium channel blockers, or diuretics.

Contraindications and precautions

Tribenzor is contraindicated in patients who have an allergy to sulfonamide-containing drugs, or in those who are anuric, due to the hydrochlorothiazide component. Tribenzor can alter electrolyte and metabolic levels, as well as cause hypotension in patients who are either volume depleted or hyponatremic. This combination agent should not be used in patients who are pregnant or may become pregnant, due to the fact that this population should not use ARBs, including olmesartan. ARBs can cause fetal abnormalities, even death.6

Special instructions

1. American Heart Association. High Blood Pressure-Statistics.http://www.amercanheart.org/downloadable/heart/1261003279882FS14HBP10.pdf. [Context Link]

2. Chobanion AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. J Am Med Assoc. 2003;289(19):2560-2572. [Context Link]

3. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis. Hypertension. 2010;55(2):399-407. [Context Link]

4. Oparil S, Melino M, Lee J, Fernandez V, Heyrman R. Triple therapy with olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide in adult patients with hypertension: the TRINITY multicenter, randomized, double-blind, 12-week, parallel-group study. Clin Ther. 2010;32(7):1252-1269. [Context Link]

5. Anon. FDA approves Tribenzor. http://www.drugs.com. [Context Link]

6. Tribenzor (olmesartan medoxomil, amlodipine, hydrochlorothiazide) tablets prescribing information. Daiichi Sankyo, Inc., 2010. http://www.tribenzor.com. [Context Link]

Acne

Acne vulgaris is the most common dermatological disorder that affects between 70% and 95% of adolescents and young adults in the United States.1 2 This disorder may persist in many individuals as they progress through their 30s, 40s, and even older.1 Since acne has the greatest prevalence in the adolescent population, these patients experience a greater impact on their emotional and psychological development, and it plays a role in their quality of life.

Some key factors in the development of acne lesions include any of the following: follicular epidermal hyperproliferation followed by follicular plugging; excess secretion of sebum; and increase in activity of Propionibacterium acnes and inflammation. When considering treatment, one must take into account that acne is a skin disease that can be caused by many factors, and medications must be appropriately chosen.1

When treating a patient with acne, one goal of therapy is to minimize the potential of developing drug-resistant bacteria, while at the same time obtaining a positive outcome.3 The most common topical antibiotics used in the treatment of acne are topical clindamycin and topical erythromycin.4 Benzoyl peroxide is recommended only in combination with antimicrobial therapy due to its effects against P. acnes resistance. Topical tretinoin has been shown to reduce follicular keratinization and decrease inflammatory lesions.4

Due to efficacy and compliance issues, combination therapies are more beneficial. Clinical trials have shown that the combination of an antimicrobial and a topical retinoid produces faster results and a greater clearing of lesions. This combination is recommended as first-line treatment in many patients with acne.2

On July 16, 2010, the FDA approved Veltin gel for the treatment of acne vulgaris in patients 12 years of age and older.5 Veltin gel is a combination of clindamycin phosphate 1.2% and tretinoin 0.025% in a water-based gel that contains both an antibiotic and a retinoid. Stiefel, a GlaxoSmithKline company, will be marketing this medication.

Mechanism of action

Veltin, being a combination product, has two specific mechanisms of action associated with it. Tretinoin has the ability to reverse the abnormal desquamation of the affected follicular epithelial turnover and cell maturation, decrease the number of microcomedones (which are precursor lesions), reduce mature comedomes, reduce inflammatory lesions, and can enhance penetration of other medications.4 6 Clindamycin binds to the 50S ribosomal subunit of the bacteria and prevents elongation of peptide chains by interfering with peptidyl transfer, which then suppresses protein synthesis. Clindamycin is bacteriostatic for P. acnes. It also is anti-inflammatory in nature through P. acnes lipase production inhibition. It seems as though topical clindamycin has a greater effect in inhibiting bacteria-induced inflammation.1 6

Adverse reactions

Based on clinical trial experience, Veltin has a few localized medication-related adverse reactions associated with its use. These include application-site reactions, dryness, irritation, exfoliation, erythema, pruritus, and dermatitis. In some patients, sunburn can occur, which warrants the need to use sunscreen daily.6

Dosing and administration

Veltin is available as a gel formulation containing clindamycin phosphate 1.2% and tretinoin 0.025%. The medication is applied once a day before bedtime. A pea-sized amount should be used for the entire area. The gel should be rubbed gently to cover the affected area with a light coat. The eyes, lips, and mucous membranes should be avoided.6

Contraindications and precautions

Veltin is contraindicated in patients who have Crohn disease (also known as regional enteritis), ulcerative colitis, or a history of antibiotic-associated colitis.5 6 It is the clindamycin component that can cause severe colitis and exacerbate the patient's current condition.

There is some systemic absorption associated with the use of clindamycin and some patients may experience diarrhea, bloody diarrhea, or pseudomembraneous colitis while using Veltin. If the patient experiences significant diarrhea, Veltin should be stopped.6

While using Veltin, the patient should avoid sunlight and artificial sunlight, including sunlamps. There is an increased risk of sunburn while using Veltin. The patient should be advised to use sunscreen daily to prevent sunburn.6

There are a few drug interactions that must be evaluated for when starting Veltin. Do not use Veltin in combination with erythromycin due to the potential antagonistic activity with clindamycin. Use Veltin cautiously in conjunction with neuromuscular blocking agents. Clindamycin has been shown to have neuromuscular blocking activity and may enhance the effect of other neuromuscular blocking agents.6

Special instructions

* Inform patients that they may experience an initial acne flare when starting treatment. This flare is a sign of response to therapy and it will improve with time. They need to continue with the medication through this time period.1

1. Abdel-Naser MB, Zouboulis CC. Clindamycin phosphate/tretinoin gel formulation in the treatment of acne vulgaris. Expert Opin Pharmacother. 2008;9(16):2931-2937. [Context Link]

2. Eichenfield LF, Wortzman M. A novel gel formulation of 0.025% tretinoin and 1.2% clindamycin phosphate: efficacy in acne vulgaris patients aged 12 to 18 years. Pediatr Dermatol. 2009;26(3):257-261. [Context Link]

3. Jackson JM, Jan Fu JJ, Almekinder JL. A randomized, investigator-blinded trial to assess the antimicrobial efficacy of a benzoyl peroxide 5%/clindamycin phosphate 1% gel compared with a clindamycin phsophate 1.2%/tretinoin 0.025% gel in the topical treatment of acne vulgaris. J Drugs Dermatol. 2010;9:131-136. [Context Link]

4. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from a global alliance to improve outcomes in acne. J Am Acad Dermatol. 2003;49(suppl 1):S1-S37. [Context Link]

5. Anon. FDA approves Veltin. http://www.drugs.com. [Context Link]

6. Veltin (clindamycin phosphate and tretinoin) gel 1.2%/0.025% prescribing information. Stieffel Laboratories, Inc., 2010. http://www.dailymed.nlm.nih.gov/dailymed/druginfo.cfm?id=21974. [Context Link]

Benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is a condition of increasing age in men. It affects more than half of the men in their 70s, and about 90% of men in their 80s and 90s.1 In affected men there is stromal and glandular epithelial hyperplasia that occurs in the area of the prostate that surrounds the urethra.2 The symptoms that these men experience are described as lower urinary tract symptoms (LUTs) that are divided into voiding symptoms and storage symptoms. The voiding symptoms include reduction in stream, intermittency, hesitancy, straining, and incomplete emptying. These are caused by urethral obstruction due to benign prostatic enlargement (BPE). The storage symptoms associated with LUTs include frequency, nocturia, urgency, and urinary incontinence. These are all due to altered smooth muscle function in the prostate and bladder, and can be due to either BPE or overactive bladder syndrome.3 In addition to all of these symptoms, BPH can cause acute urinary retention, recurrent urinary tract infections, bladder stones, urinary incontinence, hematuria, and renal failure.2

Current treatment options for BPH include the alpha₁-blockers (terazosin, doxazosin, alfuzosin, and tamsulosin), which exert their effects by reducing smooth muscle tone in both the prostate and bladder neck, which enhances flow rate along with symptom relief. The 5 alpha-reductase inhibitors (finasteride and dutasteride) block the conversion of testosterone to dihydrotestosterone. This pathway normally is involved in prostate growth. Blocking this pathway plays a role in symptom management of BPH, as well as improved urine flow.4

Clinical practice guidelines have been established that recommended the combination of an alpha₁-blocker and a 5 alpha-reductase inhibitor in the treatment of BPH.6 7 This recommendation has come from their two different mechanisms of action. With this in mind, GlaxoSmithKline received FDA approval on June 14, 2010, for Jalyn, a fixed-dose combination of dutasteride and tamsulosin, for the treatment of symptomatic BPH.8

Mechanism of action

Jalyn has two mechanisms of action because of the combination of two medications. Dutasteride is a 5 alpha-reductase inhibitor and works by inhibiting the conversion of testosterone to dihydrotestosterone. This inhibition prevents the prostate gland from growing. Tamsulosin is an alpha _1A-adrenoreceptor antagonist, that exerts its action on the receptors, and causes the smooth muscle in the bladder neck and prostate to relax, leading to an increase in urine flow, as well as reducing symptoms associated with BPH.9

Adverse reactions

Based on clinical trial experience, a number of adverse reactions were documented with the use of Jalyn. The most common adverse reactions include decreased libido, erectile dysfunction, ejaculation disorders, breast enlargement, and dizziness.9 In evaluation of the CombAT trial, it was noted that patients using the combination therapy of dutasteride and tamsulosin, experienced a greater incidence of cardiac failure in comparison to each individual component.4 Other adverse reactions documented with the use of Jalyn include hypersensitivity reactions, rash, pruritus, constipation, vomiting, and hypotension.

Dosing and administration

Jalyn is a capsule that contains dutasteride 0.5 mg and tamsulosin 0.4 mg. This medication is taken once daily 30 minutes after the same meal in order to aid its absorption. The maximum recommended dose is one capsule daily. The capsule should not be opened or chewed. No dosing adjustment is needed in patients with moderate to severe renal impairment or those who are elderly. There is no recommendation for dosing adjustments in patients with hepatic impairment.9

Contraindications and precautions

The contraindications to the use of Jalyn include pregnant women, women of childbearing age, pediatric patients, and patients with a hypersensitivity reaction to either dutasteride or tamsulosin.9

Jalyn has a number of drug-drug interactions associated with its use. Be aware of medications that are strong and moderate inhibitors of CYP3A4, inhibitors of CYP2D6, cimetidine, and warfarin. Combining Jalyn with medications in these categories can have the potential to alter the effectiveness of either medication. The use of Jalyn with another alpha-adrenergic antagonist can increase the risk of symptomatic hypotension and development of syncope. BP can drop with the concomitant use of Jalyn with a phosphodiesterase-5 inhibitor.9

Special instructions

* Patients who are taking or have taken Jalyn in the past have the potential of developing intraoperative floppy iris syndrome (IFIS) during cataract surgery. The complications of IFIS during surgery can include poor pupil dilation, iris billowing and prolapse, and progressive miosis.10

1. Siami P, Roehrborn CG, Barkin J, et al. Combination therapy with dutasteride and tamsulosin in men with moderate-to-severe benign prostatic hyperplasia and prostate enlargement: the CombAT (Combination of Avodart and Tamsulosin) Trial Rationale and Study Design. Contemp Clin Trials. 2007;28(6): 770-779. [Context Link]

2. Miller J, Tarter TH. Combination therapy with dutasteride and tamsulosin for the treatment of symptomatic enlarged prostate. Clin Interv Aging. 2009;4:251-258. [Context Link]

3. Becher E, Roehrborn CG, Siami P, Gagnier RP, Wilson TH, Montorsi F. The effects of dutasteride, tamsulosin, and the combination on storage and voiding in men with benign porstatic hyperplasia and prostatic enlargement: 2-year results from the combination of avodart and tamsulosin study. Prostate Cancer Prostatic Dis. 2009;12(4):369-274. [Context Link]

4. Roehrborn CG, Siami P, Barkin J, et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol. 2010;57(1):123-131. [Context Link]

6. Management of benign prostatic hyperplasia. The American Urological Association, 2003, updated 2006. http://www.auanet.org. [Context Link]

7. Roehrborn CG, Siami P, Barkin J, et al. The influence of baseline parameters on changes in international prostate symptom score with dutasteride, tamsulosin, and combination therapy among men with symptomatic benign prostatic hyperplasia and an enlarged prostate: 2-year data from the CombAT study. Eur Urol. 2009;55(2):461-471. [Context Link]

8. Anon. FDA approves Jalyn. http://www.drugs.com. [Context Link]

9. Jalyn (dutasteride and tamsulosin hydrochloride) capsules prescribing information. GlaskoSmithKline, 2010. http://us.gsk.com/products/assets/us_jalyn.pdf. [Context Link]

10. Change DF, Braga-Mele R, Mamalis N, et al. Clinical experience with intraoperative floppy-iris syndrome. J Cataract Refract Surg. 2008;34(7):1201-1209. [Context Link]

Multiple sclerosis

Multiple sclerosis (MS) is the most common nontraumatic inflammatory demyelinating disease of the central nervous system (CNS) in young adults.1 2 MS commonly occurs in the third and fourth decades of life and is consistent with a relapsing course that eventually turns into a chronic condition that leads to increasing disability. It is thought that the demyelination and axonal degeneration is due to the autoreactive T cells in the inflammation process. Medications that are currently approved as immunomodulating therapy include interferon beta, natalizumab, and glatiramer, both of which reduce the rate of relapse in patients with MS.

On September 22, 2010, Gilenya capsules (fingolimod) were approved by the FDA to reduce the rate of MS relapse as well as delay the progression of disability.3 This medication is the first orally administered agent to reduce the symptoms of MS, a welcomed alternative to injectable options. Gilenya is manufactured and distributed by Novartis Pharmaceuticals.

Mechanism of action

Gilenya is a sphingosine-1-phosphate (S1P) receptor modulator. Originally, this medication was studied for the prevention of allograft rejection in kidney transplant patients. S1P is a bioactive lysophospholipid that is formed from the phosphorylation of the intracellular sphingosine. Sphingosine is a breakdown product of sphingomyelin, which is a component of the cell membrane. There are five subtypes of S1P, each with different mechanisms. Sphingosine-1-phosphate type 1 (S1P1), S1P2, and S1P3 are expressed in the immune, cardiovascular, and CNS. S1P4 is found in lymphoid cells. S1P5 is expressed on the oligodendrocytes.1 When S1P is bound to the receptor it plays a role in cell adhesion, migration, proliferation, and survival.

Gilenya is a S1P-receptor modulator. It acts as a functional antagonist of the S1P1. It causes T cells and B cells to become insensitive and prevents lymphocyte egress from lymph nodes.4 5 This then causes a reduced infiltration of these lymphocytes, therefore bringing about neuroprotective and reparative processes in the CNS.4 It is unknown how Gilenya works in the treatment of MS, but it is thought to be due to the decrease of lymphocyte presence in the CNS.6

After oral administration, Gilenya has a bioavailability of 93%. Food does not play a role in its absorption. It takes somewhere between 1 and 2 months until blood levels reach steady state. Gilenya is highly distributed and is largely protein bound. This medication is extensively metabolized by CYP4F2, with some input by CYP2D6, 2E1, 3A4, and 4F12.6 The half-life of Gilenya is 6 to 9 days and it is excreted in the urine.6

Adverse reactions

Based on clinical trial experience, there are a number of adverse reactions that have been documented. The most common adverse reactions associated with Gilenya are headache, diarrhea, back pain, influenza, cough, and an increase in liver transaminase levels.6

Dosing and administration

Gilenya has the potential to cause bradyarrhythmia and atrioventricular block. All patients must be directly monitored for 6 hours after taking the first dose. Most of the patients who developed bradyarrhythmia are those who are concurrently taking a beta-blocker or calcium channel blocker, or have underlying cardiac risk factors.6

Due to the fact that Gilenya reduces lymphocyte counts, patients taking this medication are more prone to infections. Those individuals with active infections, either acute or chronic, should not start treatment with Gilenya.6

Patients taking Gilenya can experience a decrease in their lung function that is dose-dependent. This is seen as the symptom of dyspnea, which can occur as soon as 1 month after starting the medication. It is not recommended to use Gilenya in patients with impaired respiratory function.6

Since Gilenya has been shown to elevate liver enzymes, caution must be taken in using this medication in patients with severe hepatic impairment. No dosing adjustment is needed in this population, but it should not be used when liver enzymes increase while on the therapy.6

Since macular edema has occurred in patients taking Gilenya, it is recommended that an ophthalmologic exam be done at baseline and within 3 to 4 months after starting the drug.6

There are a few drug interactions that must be evaluated for when starting Gilenya. This medication has the potential to cause cardiac rhythm disturbances such as decreased atrioventricular conduction especially when taken with a class Ia or class III antiarrhythmic medication.1 6

1. Horga A, Castillo J, Montalban X. Fingolimod for relapsing multiple sclerosis: an update. Expert Opin Pharmacother. 2010;11(7):1183-1196. [Context Link]

2. Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006;355(11):1124-1140. [Context Link]

3. Anon. FDA approved first oral drug to reduce MS relapses. US Food and Drug Administration. http://www.fda.gov/NewsEvents/Newsoom/PressAnnouncements/ucm226755.htm.[Context Link]

4. Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401. [Context Link]

5. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402-415. [Context Link]

6. Gilenya (fingolimod) capsules prescribing information. Novartis Pharmaceuticals Corporation, 2010. http://www.pharm.us.novartis.com/product/pi/pdf/gilenya.pdf[Context Link]

Pain relief

Even though nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used, there are some adverse reactions that can occur after continuous use. The most common are upper gastrointestinal events, such as ulcers, perforation, obstruction, and bleeding.1 A number of concomitant risk factors can lead to these complications, which include the use of NSAIDs in the elderly population, patients with medical histories of ulcers or upper gastrointestinal symptoms, or taking NSAIDs in combination of corticosteroids, low-dose aspirin, and anticoagulant medications.2

On April 30, 2010, the FDA approved Vimovo, a combination product of naproxen and esomeprazole magnesium. Vimovo is recommended to be used in patients for the relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, and to decrease the development of gastric ulcers in those who are at risk.3 This new combination product is manufactured and distributed by Prozen Inc. and AstraZeneca.

Mechanism of action

Vimovo is a combination product containing both naproxen and esomeprazole magnesium. Naproxen is a NSAID that has an unknown mechanism of action, but is thought to be caused by inhibition of prostaglandin synthetase. The PPI esomeprazole suppresses gastric acid secretion by inhibiting the H+/K+-ATPase in the gastric parietal cell.4

The most commonly experienced adverse reactions seen in the clinical trials of Vimovo included erosive gastritis, dyspepsia, and gastritis.5 There is a slight chance that Vimovo could cause gastric ulceration, but not as great as compared with naproxen use alone (4.1% and 23.1%, respectively). In short, the patients who used Vimovo in the clinical trials had a lower incidence of duodenal ulcers in comparison with those individuals that take naproxen alone.

Dosing and administration

Vimovo is available as a fixed-dosed, delayed-release combination product containing both naproxen and esomeprazole in two different strengths: 375 mg/20 mg and 500 mg/20 mg. It is recommended that this medication be used only twice daily by oral administration. The tablet should be swallowed whole; do not cut, chew, crush, or dissolve the tablet since it is a delayed-release formulation. Vimovo should be taken 30 minutes before meals.4

Vimovo should not be used in any patient who has a documented allergic reaction to naproxen, esomeprazole magnesium, or any of the components of this medication. Patients with asthma, urticaria, or those who have had an allergic reaction to aspirin or NSAIDs should not use Vimovo due to the naproxen component. This combination product is also contraindicated for use during coronary artery bypass graft pain management, and in women in late stages of pregnancy.4

NSAIDs have been associated with causing an increased risk of serious cardiovascular events, myocardial infarction, and stroke. The use of naproxen in Vimovo can cause this risk. It is recommended to use this product at the lowest dose, and shortest duration of therapy as possible. Naproxen also has the potential for causing or exacerbating hypertension, as well as leading to the development of edema and heart failure.4

Special Instructions

1. Miner P, Plachetka J, Orlemans E, Fort JG, Sostek M. Clinical trial: evaluation of gastric acid suppression with three doses of immediate-release esomeprazole in the fixed-dose combination of PN 400 (naproxen/esomeprazole magnesium) compared with naproxen 500 mg and enteric-coated esomeprazole 20 mg: a randomized, open-label, phase I study in healthy volunteers. Aliment Pharmacol Ther. 2010;32(3):414-424. [Context Link]

2. Goldstein JL, Hochberg MC, Fort JG, Zhang Y, Hwang C, Sostek M. Clinical trial: the incidence of NSAID-associated endoscopic gastric ulcers in patients treated with PN 400 (naproxen plus esomeprazole magnesium) vs. enteric-coated naproxen alone. Aliment Pharmacol Ther. 2010;32(3):401-413. [Context Link]

3. Anon. FDA approves Vimovo. http://www.drugs.com. [Context Link]

4. Vimovo (naproxen/esomeprazole magnesium) delayed-release tablets prescribing information. AstraZeneca, 2010. http://www.vimovo.com/prescribing-information.aspx. [Context Link]

5. Goldsetin JL, Hochberg MC, Fort JG, Zhang Y, Sostek M. PN 400 significantly reduces the incidence of gastric ulcers compared with enteric-coated naproxen in patients requiring chronic NSAID therapy regardless of low-dose aspirin use: results from two prospective, randomized controlled trials. Poster presented at the 73rd Annual Scientific Meeting of the American College of Rheumatology; October 16-21, 2009. [Context Link]

Vaccination

Streptococcus pneumoniae, also referred to as pneumococcus, is a large player in bacterial infections causing pneumonia, meningitis, and sepsis. It causes nearly 1 million childhood deaths yearly worldwide.1 These infections, termed invasive pneumococcal disease (IPD), are a leading cause of illness in both children and adults.

In 2000, a 7-valent pneumococcal conjugate vaccine (PCV7, Prevnar) became part of the routine infant immunization schedule. With this implementation, it was seen that children under the age of 5 had a decrease of 76% incidence of IPD.2 PCV7 contains the polysaccharides of the capsular antigens of the seven serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. Even though IPD rates based on these seven serotypes have decreased, IPD from non-PCV7 serotypes have increased.2

On February 24, 2010, a new vaccine was approved by the FDA. Prevnar 13 (Pneumococcal 13-valent conjugate vaccine [Diphtheria CRM197 Protein]) still covers the seven serotypes from PCV7, as well as 6 more serotypes of 1, 3, 5, 6A, 7F, and 19A. These serotypes are each conjugated to a nontoxic diphtheria carrier protein (CRM197).3 4 Prevnar 13 is approved for vaccination of children 6 weeks through 5 years of age (before the sixth birthday) for the prevention of invasive disease caused by S. pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. It is also approved to prevent otitis media caused by serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F.5 This vaccine was developed in response to the increased incidence of PCV7 resistant serotypes. Prevnar 13 is manufactured and marketed by Wyeth Pharmaceuticals, Inc.3

Mechanism of action

Prevnar 13 is able to cause a T-cell-dependent immune response. A T-cell-dependent response, along with T-cell-independent response, is how B cells produce antibodies when an antigenic stimulation occurs. Prevnar 13 contains a carrier protein, which is important in helping T cells produce the signals that cause B-cell maturation, leading to B-cell response and memory. This memory helps with booster responses when a patient is reexposed to pneumococcal polysaccharides and infection.5

Adverse reactions

Throughout clinical trial experience, the safety profiles of both Prevnar 7 (PCV7) and Prevnar 13 (PVC13) were similar. The most commonly seen adverse reactions included bronchiolitis, gastroenteritis, and pneumonia.5 Other potential adverse reactions include injection-site reactions, irritability, disturbances of sleep, changes in appetite, and fever.

Dosing and administration

Prevnar 13 is supplied as a suspension that is a 0.5 mL single-dose prefilled syringe. After shaking the syringe to create a white suspension, the 0.5 mL dose is administered I.M. into the thigh of infants or the deltoid muscle in toddlers and young children according to the vaccination schedules.5

Contraindications and precautions

Prevnar 13 contains polysaccharides of S. pneumoniae conjugated on a nontoxic diphtheria carrier protein. The formulation contains 0.125 mg of aluminum as aluminum phosphate adjuvant and no thimerosal preservative.6 The NP should be aware of any allergies or hypersensitivity reactions to prevent potential reactions. Throughout the immunization process, be sure to evaluate the patient for these reactions or responses.

* Suspected adverse reactions associated with Prevnar 13 should be reported to Wyeth Pharmaceuticals, Inc. at 1-800-934-5556 and VAERS at 1-800-822-7967 or http://vaers.hhs.gov.

1. Pilishvili T, Lexau C, Farley MM, et al. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis. 2010;201(1):32-41. [Context Link]

2. Centers for Disease Control and Prevention (CDC). Invasive penumococcal disease in young children before licensure of 13-valent penumococcal conjugate vaccine-United States, 2007. MMWR Morb Mortal Wkly Rep. 2010;59(9):253-257. [Context Link]

3. Anon. FDA approves Prevnar 13. http://www.drugs.com. [Context Link]

4. Anon. An expanded pneumococcal vaccine (Prevnar 13) for infants and children. Med LettDrugs Ther. 2010;52(1345):67-68. [Context Link]

5. Prevnar 13 (Pneumococcal 13-valent conjugate vaccine [Dipththeria-CRM197 Protein]) suspension for intramuscular injection package insert. Wyeth Pharmaceuticals, Inc., 2010. http://www.prevnar.com. [Context Link]

6. Licensure of a 13-valent pneumococcal conjugate vaccine (PCV 13) and recommendations for use among children-Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep.2010;59:258-261. [Context Link]

New indication

Crestor has been on the market since August 2003. The initial approval included two main indications. Crestor can be used as an adjunct to diet to reduce elevated total cholesterol, low-density lipoprotein (LDL) cholesterol, ApoB, non-high-density lipoprotein (HDL) cholesterol, and triglyceride levels and to increase HDL cholesterol in patients with primary hyperlipidemia and mixed lipidemia. Crestor is also used to slow the progression of atherosclerosis in adult patients as part of the treatment goals of lowering total cholesterol and LDL cholesterol target levels.1 It is also approved as an adjunct to diet in pediatric patients age 10 to 17 years of age with heterozygous familial hypercholesterolemia.

On February 8, 2010, it was announced that Crestor received approval for a new indication of treatment from the FDA, and can be used to reduce the risk of stroke, myocardial infarction, and arterial revascularization procedures in patients who have an increased risk of cardiovascular disease (CVD). These risk factors include age (men age 50 and older, women age 60 and older), high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater, and the presence of at least one additional CVD risk factor (hypertension, low HDL cholesterol, smoking, family history of premature coronary heart disease).2 This new indication for the use of Crestor was based on results of the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial.

JUPITER trial

Published in the New England Journal of Medicine, the JUPITER study looked at the effect of Crestor 20 mg on decreasing the risk of CVD.3 The study used Crestor in patients who were relatively healthy without any underlying hyperlipidemia but tested to have an elevated hsCRP level. The results of the study showed that Crestor is able to reduce the incidence of major cardiovascular events.3

Mechanism of action

Peak levels of Crestor are reached within 3 to 5 hours after administration and absorption. It is metabolized in the CYP450 isoenzyme system by CYP2C9. The half-life of Crestor is 19 hours and is eliminated via the feces.1

Adverse reactions

Based on clinical trial experience, a number of adverse reactions must be kept in mind when prescribing Crestor. Some adverse reactions include rhabdomyolysis with myoglobinuria, liver enzyme test abnormalities, abdominal pain, headache, nausea, and myalgia.1 If a patient experiences an elevation in his or her creatine phosphokinase (CK) levels or develops myopathy, Crestor should be discontinued. It has been noted that this medication may increase the A1c and fasting glucose levels.

Dosing and administration

Crestor dosing begins with a dose of 10 to 20 mg once daily, with a maintenance dose ranging from 5 mg to 40 mg a day. Crestor is administered orally, and should be taken at the same time of the day. Food does not play a role in its absorption.1 Based on the JUPITER study, the recommended dose should be 20 mg daily.3 In patients with severe renal impairment or on dialysis, dosing of Crestor should be 5 mg daily, with a maximum of 10 mg.

Crestor should not be used in patients with a known allergy to the medication or any of its components. Any patient with active liver disease should avoid the use of Crestor due to its effects in the liver and liver function tests.1

Patients taking Crestor may experience skeletal muscle effects of rhabdomyolysis or myopathy. Patients who are at greater risk of developing these effects are those over the age of 65, patients with renal failure, or those with hypothyroidism that is not controlled. Many of the adverse reactions observed with the use of Crestor occurred more frequently with the higher dose.1

There are many drug interactions associated with the use of Crestor due to its metabolism through the CYP450 isoenzyme system. The potential interactions are seen with cyclosporine, gemfibrozil, protease inhibitors (such as ritonavir, lopinavir, atazanavir), warfarin, niacin, and fenofibrate.1 Caution must be taken when administering these medications together.

Special instructions

1. Crestor (Rosuvastatin Calcium) tablets prescribing information. AstraZeneca, 1010. http://www1.astrazeneca-us.com/pi/crestor.pdf. [Context Link]

2. Anon. FDA approves Crestor to reduce stroke, heart attack risk. http://www.drugs.com. [Context Link]

3. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-2207. [Context Link]

Rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune disease that affects close to 1% of the population worldwide and seems to occur in twice as many women as compared with men.1 2 RA has many defining characteristics including fatigue, joint pain, and swelling, leading to progressive joint damage and disability.2-6 This joint damage and bone destruction is caused by cytokine production including tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta).3 Treatment options available for RA include the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). The DMARDs include methotrexate (MTX), leflunomide, sulfasalazine, and hydroxychloroquine.1 4 5 Once patients fail treatment with DMARD therapy, additional options include the biological agents. The TNF antagonists are etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), golimumab (Simponi), and certolizumab pegol (Cimzia). Anakinra (Kineret) is an IL-1 receptor antagonist. The T-cell costimulatory inhibitor available is abatacept (Orencia). Rituximab (Rituxan) is an anti-CD20 monoclonal antibody.

Another target in the treatment of RA would be in the direction of interleukin-6 (IL-6). IL-6 is a pleiotropic proinflammatory cytokine that is found in a number of cell types including lymphocytes, monocytes, and fibroblasts.4 6 7 In patients with RA, it is noted that the IL-6 levels are increased in the serum and synovial fluid, and lead to degradation of cartilage matrix by affecting the function of neutrophils, T cells, B cells, monocytes, and osteoclasts.3 6

Due to this information that shows IL-6 plays a role in the inflammatory process of RA, tocilizumab (Actemra) was approved by the FDA on January 11, 2010. Actemra is indicated for the treatment of adult patients with moderately to severely active RA who have had an inadequate response to one or more TNF antagonist therapies. Actemra is manufactured and distributed by Roche Pharmaceuticals.3-6 Throughout multiple studies, Actemra was shown to be beneficial either in monotherapy or in combination with MTX or DMARD in reducing systemic inflammation and decreasing the clinical symptoms associated with RA.2-4,6,7

Mechanism of action

Actemra is a humanized monoclonal antibody that competitively inhibits the binding of IL-6 to both soluble and membrane-bound IL-6 receptors.1 5 9

The total clearance of Actemra is concentration-dependent. This medication has a biphasic elimination from the circulation due to its distribution into both the central volume and the peripheral volume. The volume of distribution at steady state is 6.4 L. The long half-life of 6.3 days allows for administration of this drug to occur once every 4 weeks. Age, gender, and race do not affect the pharmacokinetics of Actemra.1

Adverse reactions

As seen with other biologicals used for the same indication, the labeling contains a boxed warning related to the risk of serious infections. The infections reported include tuberculosis (TB), and other bacterial, fungal, and viral infections. Before beginning treatment with Actemra, all patients should be screened for TB.5 9

Due to the immunosuppressive activity, Actemra has the potential to increase the risk of malignancies, demyelinating disorders, rare cases of multiple sclerosis, and chronic inflammatory demyelinating polyneuropathy.5 In patients with a history of diverticulitis, there is an increased risk of gastrointestinal perforation. Also, lab values should be assessed for neutropenia, thrombocytopenia, elevation in liver function tests, and lipid abnormalities.9

Other common adverse events documented throughout the clinical trials include upper respiratory tract infections, nasopharyngitis, headache, hypertension, and infusion-related reactions.9

Dosing and administration

Keep in mind that Actemra can be used either as monotherapy or in combination with MTX or other DMARDs. The recommended initial dose is 4 mg/kg once every 4 weeks. This dose is administered via a 60-minute I.V. infusion. If the response is inadequate, the dose can be increased to the maximum of 8 mg/kg every 4 weeks. Doses exceeding 800 mg per infusion is not recommended. Dosing modifications must be made based on liver enzyme abnormalities, low absolute neutrophil count, and low platelet count.9

Contraindications and precautions

There are no contraindications associated with the use of Actemra. The precautions have been touched upon previously and include the risk of serious infection, gastrointestinal perforation, and the need for lab monitoring of neutrophils, platelets, lipids, and liver function. Also, Actemra infusions can cause hypersensitivity reactions, including anaphylaxis, which have been reported.9

Special instructions

1. Oldfield V, Dhillon S, Plosker GL. Tocilizumab: a review of its use in the management of rheumatoid arthritis. Drugs. 2009;69(5):609-632. [Context Link]

2. Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67(11):1516-1523. [Context Link]

3. Garnero P, Thompson E, Woodworth T, Smolen JS. Rapid and sustained improvement in bone and cartilage turnover markers with the anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate. Arthritis Rheum. 2010;62(1):33-43. [Context Link]

4. Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008;58(10):2968-2980. [Context Link]

5. McCluggage LK, Hussar DA. New drugs: Ustekinumab, tocilizumab, and televancin hydrochloride. J Am Pharm Assoc. 2010;50(2):324-327. [Context Link]

6. Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008;371(9617):987-997. [Context Link]

7. Jones G. The AMBITION trial: tocilizumab monotherapy for rheumatoid arthritis. Expert Rev Clin Immunol. 2010;6(2):189-195. [Context Link]

8. Anon. FDA approved actemra. http://www.drugs.com.

9. Actemra (tocilizumab) Injection for Intravenous Infusion Prescribing Information. Genentech, Inc., 2010. http://www.actemra.com. [Context Link]