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October 2010 FAQs

Questions

Are antivirals safe to use during the first trimester of pregnancy?

What are the differences among modes of renal replacement therapy?

What are current recommendations to minimize risk of nephrogenic systemic fibrosis with gadolinium-based contrast agents?

What are the new recommendations for the 2010-2011 Flu Season?


Answers

Are antivirals safe to use during the first trimester of pregnancy?

Introduction

Medication use during pregnancy is of particular concern because of the potential harmful effects on fetal development.1 However, medication use is often necessary for treatment and/or prevention of a number of conditions including herpes simplex and zoster infections. The antiviral agents, acyclovir, valacyclovir, and famciclovir, typically used to treat these infections, are classified as Pregnancy Category B based on results from animal studies that demonstrated no adverse effects. Manufacturers of these agents maintain a pregnancy registry to track outcomes of infants born to mothers who take these medications during pregnancy. Although these registries track the incidence of birth defects in infants exposed to the drug, the data are limited by voluntary reporting and the lack of a control group. Other studies on acyclovir use during pregnancy have not demonstrated an association with birth defects; however, due to small sample sizes, conclusions regarding the drug's safety during pregnancy have not been definitive.1-4 The findings of a recent study published by Pasternak and colleagues in the Journal of the American Medical Association ( JAMA) that evaluated antiviral use in early pregnancy in a larger population of women are summarized below.

Antiviral use in early pregnancy

A recent retrospective cohort study utilizing data from multiple Denmark patient registries sought to determine whether an association exists between the development of major birth defects and exposure to acyclovir, valacyclovir, or famciclovir during the first 3 months of pregnancy.5 The study population, which was obtained from the Medical Birth Register, included infants born between January 1, 1996 and September 30, 2008. The Medical Birth Register contains details about all births in Denmark. Mothers who used any of the specified oral antivirals or topical acyclovir or penciclovir from 4 weeks before conception to delivery were identified through the Prescription Drug Register. The National Patient Register was then used to determine the number of major birth defects diagnosed within the first year after birth within the study population. Infants with major birth defects were identified using the International Classification of Diseases (ICD-10) codes for major congenital anomalies. Birth defects as a result of known causes including but not limited to chromosomal changes, genetic syndromes, or congenital viral infections were excluded.

Over 830,000 infants were included in the study cohort.5 Major birth defects occurred in over 19,000 infants or 2.4% of the entire study population. Of the 1804 pregnancies with antiviral exposure in the first trimester, 40 (2.2%) major birth defects were detected (Table 1). This was not found to be significantly different to the percentage of major birth defects (2.4%) observed in the unexposed pregnancies (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.68 to 1.27). Adjustment for confounding variables such as mother's smoking status, presence of other infectious disease, and use of other medications such as chemotherapy or antibiotics revealed no significant change in the initial findings. Use of a specific antiviral was not associated with a greater incidence of major birth defects. The incidence of major birth defects in infants exposed to acyclovir was 2.0% (OR 0.82, 95% CI 0.57 to 1.17), 3% for those exposed to valacyclovir (OR 1.21 95% CI 0.56 to 2.62), and 3.8% for patients that took famciclovir (OR 1.63, 95% CI 0.20 to 13.05). It is important to note that acyclovir was the most common antiviral prescribed (n = 1561) and the number of exposures to valacyclovir (n = 229) and famciclovir (n = 26) were relatively small. Exposure to topical acyclovir or penciclovir did not demonstrate an increased incidence of major birth defects compared to no exposure to these agents. Additionally, antiviral exposure during the second and third trimesters compared to no exposure was not associated with development of major birth defects (OR 0.84, 95% CI 0.64 to 1.11).

Table 1. Number of birth defects present or absent with or without antiviral exposure in the first

trimester of pregnancy.

Birth defect present

Birth defect absent

Total

Exposed to antiviral

40

1764

1804

Not exposed to antiviral

19,920

816,071

835,991

Total

19,960

817,835

837,795

Subgroup analysis of the type of birth defect revealed only one significant association to antiviral exposure.5 The number of cardiac birth defects was higher when any antiviral was used 1 to 4 weeks prior to conception compared to no antiviral use (1.3% vs. 0.8%, respectively) during this period (OR 1.71, 95% CI 1.05 to 2.79). The authors attributed this finding to chance since the period in which cardiac defects most commonly occur is between 6.5 and 8 weeks after conception.

Limitations to the data, as noted by the authors, include the unknown incidence of planned abortion or miscarriage due to detected birth defects, the data in the National Patient Register was limited to patients in the hospital setting, not including birth defects that occurred after the first year of life, and the lack of ability to assess adherence to antiviral medications.5 Based on the findings of the study, the authors concluded that the use of acyclovir in the first 3 months of pregnancy can be considered safe but the effects of valacyclovir and famciclovir requires further investigation due to the limited number of exposures to these agents in their study.

An editorial published in the same issue of JAMA discusses the importance of these findings and the need for more answers.6 The study confirms that acyclovir is not associated with the development of major birth defects. However, it does not have enough data to determine whether it is associated with a risk for a specific type of defect. According to the editorialists, teratogens generally cause specific malformations. Although a large number of pregnancies were evaluated in this study, the number of individual defects was too small to identify a pattern or trend of certain types of defects. Other limitations discussed are similar to the authors' discussion including unknown adherence to antiviral therapy, undetected birth defects that occurred after the first year, and inability to draw conclusions regarding the safety of valacyclovir or famciclovir.

Summary

The recent study by Pasternak and colleagues confirms the safety of acyclovir use in early pregnancy. However, conclusions regarding the safety of valacyclovir or famciclovir use during pregnancy cannot be made from the current analysis. Although, current guidelines from the American College of Obstetricians and Gynecologists (ACOG) recommend either acyclovir or valacyclovir for the management of herpes in pregnancy, acyclovir currently has the most safety data to support its use in this patient population. Prescribers should continue to evaluate the risks and benefits of antiviral therapies for patients and educate their patients on these issues.

References

  1. Briggs GG, Freeman RK, Gaffe SJ. Drugs in pregnancy and lactation. 8th ed. Philadelphia, PA: Lippincott Williams& Wilkins; 2008.
  2. Stone KM, Reef-Eldridge R, White AD, et al. Pregnancy outcomes following systemic prenatal acyclovir exposure: conclusions from the international acyclovir

Pregnancy registry, 1984-1999. Birth Defects Res A Clin Mol Teratol. 2004;70(4):201-207.

3. Ratanajamit C, Vinther Skriver M, et al. Adverse pregnancy outcome in women exposed to acyclovir during pregnancy: a population-based observational study. Scand J Infect Dis. 2003;35(4):255-259.

4. Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in

England. Br J Obstet Gynaecol. 1998;105(8):882-889.

  1. Pasternak B, Hviid A. Use of acyclovir, valacyclovir, and famciclovir in the first

trimester of pregnancy and the risk of birth defects. JAMA. 2010;304(8):859-866.

  1. Mills JI, Carter TC. Acyclovir exposure and birth defects: an important advance, but more are needed. JAMA. 2010;304(8):905-906.
  2. ACOG Committee on Practice Bulletins. Clinical management guidelines for obstetrician-gynecologists. No. 82 June 2007. Management of herpes in pregnancy. Obstet Gynecol. 2007;109(6):1489-1498.

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What are the differences among modes of renal replacement therapy?

Patients with acute or chronic kidney disease often require renal replacement therapy (also known as dialysis) upon deterioration of kidney function in order to remove undesirable waste products from the body. In the United States, there are approximately of 450,000 patients with end stage renal disease (ESRD), the majority of whom require dialysis.1 Acute renal failure (ARF) is a common complication in critically ill patients occurring in up to 30% of patients; 70% of these patients require some form of dialysis.2,3 There are a variety of factors that determine when it is appropriate to initiate dialysis in a patient; however, the primary factor for chronic kidney disease patients is a glomerular filtration rate (GFR) of less than 15 millimeter per minute per 1.73 m2.4 Other factors taken into consideration for initiation of dialysis in both acute and chronic kidney disease patients include symptoms of uremia, hyperkalemia, volume overload, or acidosis.1,2

Mechanisms of dialysis

The principles of dialysis are based on allowing water and solute transportation through a semipermeable membrane from the body into the dialysis fluid with the mechanisms as follows3:

  1. Diffusion: solutes are moved across a semipermeable membrane by concentration gradient from higher solute concentration to lower solute concentration.
  2. Ultrafiltration: water is moved across a semipermeable membrane by osmotic pressure; the pressure gradient is known as the transmembrane pressure gradient.
  3. Convection: water is moved across a semipermeable membrane by transmembrane pressure gradient (similar to ultrafiltration) but solutes are "dragged" with the water; both small-molecular-weight substances such as blood urea nitrogen, creatinine, and potassium as well as large-molecular-weight substances such as inulin, β2-microglobulin, tumor necrosis factor, and vitamin B12 can be moved. When the ultrafiltration rate is increased to provide convection clearance of solutes, this is known as hemofiltration.

Renal replacement therapies - chronic kidney disease

In the setting of chronic kidney disease there are 2 primary modes of dialysis: hemodialysis or peritoneal dialysis.

Hemodialysis

  • Hemodialysis (HD) is commonly used in patients with ESRD. It is typically required 2 to 3 times per week with each session lasting approximately 2 to 4 hours.1,3 There are 3 pertinent components for HD: the blood delivery system, the composition of the dialysate, and the dialyzer. Access to the patient's blood is obtained by a fistula, graft, or catheter. The blood is then pumped from the access to the dialyzer. Dialysate is pumped in the opposite direction through the dialyzer. The waste material solutes are removed primarily by diffusion while ultrafiltration removes excess volume. The degree of solute clearance known as the "dialysis dose" depends on blood flow rate. The primary advantage of HD is the ability to rapidly remove substances and excess volume; however, HD can cause systemic hypotension in approximately of 20% to 30% of patients because of rapid fluid and electrolyte removal.

Peritoneal dialysis

  • In peritoneal dialysis (PD), the peritoneal membrane in the abdomen is used as an endogenous semipermeable membrane.1 The dialysis fluid is pumped into the peritoneal cavity and the waste products are removed by diffusion from the blood into the dialysis fluid. The dialysate is drained and reinstilled periodically. PD may be completed by continuous ambulatory peritoneal dialysis (CAPD), continuous cyclic peritoneal dialysis (CCPD), or a combination of both. In CAPD the dialysis solution is manually infused and exchanged 3 to 5 times daily throughout the day then instilled at bedtime and exchanged in the morning. In CCPD the exchange is automated and is typically performed while the patient sleeps.

Renal replacement therapies - acute renal failure

In patients with acute renal failure, HD is more typically employed than PD. In this setting there are a variety of HD options beyond the intermittent HD described above for chronic kidney disease. Each is described below.

Sustained low-efficiency dialysis or extended daily dialysis

  •  Sustained low-efficiency dialysis (SLED) or extended daily dialysis (EDD) is a minor modification to intermittent HD where the blood is pumped at a rate of 200 mL/min with a dialysate rate of 300 mL for 6 to 12 hours (compared with a blood flow rate of 200 to 300 mL/minute and a dialysate rate of 500 to 800 mL/minute in intermittent HD). SLED/ EDD is performed with the use of a traditional dialysis machine. The major advantage of this method compared with intermittent HD is improved hemodynamic stability.

Continuous renal replacement therapy

  • Continuous renal replacement therapy (CRRT) is a general term for several processes that can first be divided by the type of access. 2,3 Continuous arteriovenous renal replacement requires both arterial and venous access and is no longer commonly used because of poor solute removal and complications of arterial cannulation. Continuous venovenous renal replacement is now more commonly used. There are several types of continuous venovenous renal replacement therapies described below.
    •  Slow-continuous ultrafiltration (SCUF): SCUF is process of removing fluid but does not allow for significant solute clearance. 3 It is typically used for volume overloaded patients with or without renal failure, such as congestive heart failure patients refractory to diuretics.
    •  Continuous venovenous hemofiltration (CVVH): In CVVH the solutes are removed by convection; no dialysate is used.2,3 Typically ultrafiltration rates of 1 to 2 L/hour are used. Because of the large amount of fluid removed, CVVH may cause volume contraction, hypotension, and loss of electrolytes. Intravenous crystalloid fluid replacement is necessary to be administered either prefilter or postfilter to replenish fluids and desired solutes.
    • Continuous venovenous hemodialysis (CVVHD): In CVVHD solutes are removed by diffusion. Similar to intermittent HD the dialysate runs countercurrent to the blood flow but at a slower rate of 1 to 1.2 L/hour.2,3
    • Continuous venovenous hemodiafiltration (CVVHDF): CVVHDF is a combination of diffusion solute removal (CVVHD) and convection solute removal (CVVH). Due to the high rate of ultrafiltration, intravenous fluid replacement is required.

Renal replacement therapy - affects on medications

Pharmacists are frequently asked to dose-adjust medications in patients with kidney disease including those receiving dialysis. Removal of drugs can occur when blood containing a drug passes through the semipermeable membrane and into the dialysate.5 It is important to understand which type of dialysis the patient is receiving, as it impacts drug dosing. For example, PD removes drugs less efficiently than HD. However, there are a number of other drug-related factors that play a role in determining how much drug is removed during dialysis. Table 1 describes factors affecting drug removal.

Table 1. Factors affecting drug removal in dialysis modalities.5

Factors Effects
Molecular weight (MW) The molecular size of the molecule compared with the size of the pores in the membrane determines dialyzability
Low-flux filters:
  • Small drugs molecules (MW <500 Daltons [Da]) are readily removed; the overall dialyzability of the drug is then influenced by other factors including blood flow, dialysate rate, and membrane surface area
  • Moderate drugs molecules (MW 500 to 1,000 Da) have a decreased ability to pass through the semipermeable membrane
  • Large drug molecules (MW >1,000 Da) are not removed
High-flux filters:
  • Large drug molecules that were not readily removed via a low-flux filter may be removed
Hemofiltration:
  • The filter used for hemofiltration (eg, CVVH) has a larger pore size than that used in HD allowing drug molecules up to 20,000 Da to pass through the semipermeable membrane
Water/lipid solubility ility Drugs with a high degree of water solubility will tend to partition in water-based dialysis fluid while lipid-soluble drugs tend to remain in the blood
Plasma protein binding Unbound drugs are able to pass through the semipermeable membrane for removal; however, drugs bound to proteins are too large to pass
Volume of distribution (Vd) Large Vd drugs are not easily removed from the body because they are principally located at tissue binding sites and only a small amount of total drug is removed from the blood; when dialysis is complete, re-equilibration between blood and tissue may occur resulting in increased serum concentrations of the drug

Summary

Renal replacement therapies are complex processes with even more complex nomenclature. Pharmacists are often requested to provide recommendations for the dosing of medications in patients receiving a variety of different renal replacement therapies. It is important for the pharmacist to understand the type of renal replacement therapy and recognize factors that could influence drug dosing.

References

1. Liu KD, Chertow GM, "Chapter 275. Dialysis in the Treatment of Renal Failure" (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J: Harrison's Principles of Internal Medicine, 17e: http://www.accessmedicine.com/content.aspx?aID=2881053.

2. Liu KD, Chertow GM, "Chapter 273. Acute Renal Failure" (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J: Harrison's Principles of Internal Medicine, 17e: http://www.accessmedicine.com/content.aspx?aID=2872603.

3. O'Reilly P,Tolwani A. Renal replacement therapy III: IHD, CRRT, SLED. Crit Care Clin. 2005;21(2):367-378.

4. National Kidney Foundation. Disease Outcomes Quality Initiative (KDOQI) guidelines and practice recommendations for hemodialysis, peritoneal dialysis adequacy, and vascular access 2006. Available at: http://www.kidney.org/professional/kdoqi. Accessed August 29, 2010.

5. Bauer LA, "Chapter 3. Drug Dosing in Special Populations: Renal and Hepatic Disease, Dialysis, Heart Failure, Obesity, and Drug Interactions" (Chapter). Larry A. Bauer: Applied Clinical Pharmacokinetics, 2e: http://www.accesspharmacy.com/content.aspx?aID=3518709.

Prepared by: Usasiri Srisakul, PharmD

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What are current recommendations to minimize risk of nephrogenic systemic fibrosis with gadolinium-based contrast agents?

Gadolinium-based contrast agents (GBCAs) are used to enhance images obtained during magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Use of contrast media increases the visualization of anatomical structures, thereby facilitating accurate diagnosis. The GBCAs available in the United States are listed in Table 1.1,2 Gadolinium is a metal element formulated for therapeutic use by complexing with various chelators. Stability of these gadolinium-chelator complexes vary, with linear non-ionic complexes associated with decreased stability compared to other formulations.3 All GBCAs are renally eliminated.

Table 1. Gadolinium-based contrast agents.1.2

Chemical name Brand name Approval date Formulation
Gadopentetate dimeglumine Magnevist 1988 Linear ionic complex
Gadoteridol Prohance 1992 Macrocyclic
Gadodiamide Omniscan 1993 Linear non-ionic complex
Gadoversetamide Optimark 1999 Linear non-ionic complex
Gadobenate dimeglumine Multihance 2004 Linear ionic complex
Gadofosveset trisodium Ablavar 2008 Linear ionic complex
Gadoxetate disodium Eovist 2008 Linear ionic complex

Nephrogenic systemic fibrosis

Although effective, GBCAs are not without risk. Hypersensitivity reactions and acute renal failure have been reported, but nephrogenic systemic fibrosis (NSF) is the most significant safety concern.4 This systemic syndrome is characterized by pain, pruritis, and edema.3 Other signs of NSF include skin lesions, erythema, and cutaneous discoloration. Edema, usually localized to the hands and lower extremities, progresses to fibrotic, hard, tight skin with indurations sometimes likened to an "orange peel" appearance, joint stiffness/contractures, immobility, and sometimes permanent disability. Fibrotic lesions can also develop in pulmonary and pericardial tissues, skeletal muscle, and kidneys; systemic involvement has led to fatalities. Nephrogenic systemic fibrosis was first reported in patients with renal failure in 1997, and in 2006 it was first associated with exposure to GBCAs in a case series of 9 dialysis patients.3,5 Lack of a temporal relationship may have delayed recognition of the link between GBCAs and NSF, since symptoms of disease may not manifest until months after GBCA exposure.3

The International Center for Nephrogenic Fibrosing Dermatopathy Research registry contained 325 biopsy-confirmed reports of NSF at the end of 2009. 6 Most cases have occurred in patients with glomerular filtration rate less than 30 mL/min/1.73m2, acute kidney injury, and those undergoing dialysis. To date, NSF has not been reported in patients with normal renal function. Higher than recommended GBCA doses, such as the double and triple doses commonly used for MRA procedures, and repeat doses appear to increase the risk for NSF.

The reason for increased prevalence of NSF in patients with renal insufficiency is not fully known; however, it is believed to result from dissociation of the gadolinium ion from the chelator, a process called transmetalation.7 Agents with lower stability are more likely to undergo this transformation in the setting of renal impairment, thus liberating more gadolinium. Free gadolinium is a toxic element and has been associated with development of fibrosis through direct tissue effects and via inflammatory mediators. This combination of factors may explain why NSF has only been reported in patients with renal insufficiency and is more common with less stable GBCAs.

Treatment of NSF is currently limited to supportive care interventions such as physical therapy to maintain joint mobility.3 Various medical therapies have been tried with limited success, and although dialysis effectively removes GBCAs, the delay between exposure and symptom onset usually eliminates this as a therapeutic option.

Recommendations to minimize risk of NSF - recent FDA actions

In response to the debilitating and potentially fatal nature of this disease and the lack of effective treatments, the Food and Drug Administration (FDA) issued a notice about GBCAs in 2006.8 The public health advisory announcement warned of the potential relationship between NSF/nephrogenic fibrosing dermatopathy (NFD) and GBCAs in patients undergoing MRI and MRA procedures, based on 25 cases in Danish and Australian patients receiving gadodiamide (Omniscan). Pending review of the FDA's investigation, healthcare providers were urged to use GBCAs cautiously (if at all) in patients with creatinine clearance less than 15 mL/min or in those undergoing dialysis. In addition, the warning recommended initiation of dialysis in patients with severe renal dysfunction after GBCA exposure, despite lack of evidence to support this approach.

Boxed warnings discussing the risk of NSF and NFD in patients with severe renal insufficiency (glomerular filtration rate < 30 mL/min/1.73m 2) were added to the labeling of all GBCAs in 2007.9 The warning mentions that patients with chronic liver disease and those just before and after liver transplant are also at risk due to the potential for hepatorenal syndrome and recommends avoidance of GBCAs in all at-risk patients.

Most recently, in September 2010, the FDA requested a change to the labeling of GBCAs to further minimize the risk for NSF.1 The label change request was made in response to recommendations from the December 2009 joint meeting of the Cardiovascular and Renal Drugs Safety and Risk Management Advisory Committees.3 After review of 519 published cases, the joint committee confirmed an increased risk of NSF in patients with advanced chronic kidney disease or acute renal failure, and a positive relationship between increased GBCA doses and NSF. The new labeling is summarized below:1

  • Since this condition has been reported exclusively in patients with renal impairment, all patients should undergo screening prior to GBCA administration in order to prevent exposure in high-risk patients.
  • Screening should focus on identification of patients with acute kidney injury or chronic, severe kidney disease. Acute kidney injury may be detected clinically, but chronic kidney disease requires laboratory monitoring for definitive diagnosis.
  • Gadopentetate dimeglumine (Magnevist), gadodiamide (Omniscan), and gadoversetamide (Optimark) have a new contraindication in patients with acute kidney injury or chronic, severe kidney disease.
  • Avoid use of GBCAs in patients with impaired drug elimination unless the diagnostic information is not available from any other imaging modality.
  • Patients should be monitored for the development of symptoms consistent with NSF after GBCA exposure.
  • Do not administer repeat doses of GBCAs during a single procedure.

These recommendations are consistent with a consensus statement from the American College of Radiology subcommittee on safe use of contrast media. 10

All cases of NSF have been identified through voluntary reports during postmarketing surveillance, so the true comparative risk between agents is unknown. The 3 agents with the new contraindication have been associated with the greatest number of NSF reports, which may be due to their higher utilization compared to the other agents and longer time on the market compared to recently-approved agents.3

If GBCA use in a patient with renal impairment is absolutely necessary, it may be prudent to choose an agent associated with fewer reports of NSF such as gadobenate dimeglumine (Multihance), gadoteridol (Prohance), gadofosveset trisodium (Ablavar), or gadoxetate disodium (Eovist). According to the European Society of Urogenital Radiology Contrast Media Safety Committee, Multihance, Ablavar, and Eovist are associated with medium risk for NSF and Prohance is low-risk.11 Several studies have demonstrated low incidence of NSF when these agents were used in patients with renal impairment.12-15

Summary

Nephrogenic systemic fibrosis is a debilitating disease, strongly associated with exposure to GBCAs, and which occurs predominately in patients with renal dysfunction. Although the total number of reported cases is small, the potentially fatal nature of NSF and lack of available treatments has prompted the FDA to provide warnings and screening recommendations with a goal of minimizing GBCA exposure in patients with renal impairment. Currently, clinicians are urged to screen all patients for renal dysfunction prior to administration and avoid Magnevist, Omniscan, and Optimark in patients with any degree of renal impairment.

References

  1. Food and Drug Administration. FDA Drug Safety Communication: New warnings for using gadolinium-based contrast agents in patients with kidney dysfunction. http://www.fda.gov/Drugs/DrugSafety/ucm223966.htm. September 9, 2010. Accessed September 17, 2010.
  2. Food and Drug Administration. Slides for the December 8, 2009 Joint Meeting of the Cardiovascular and Renal Drugs and Drug Safety and Risk Management Advisory Committees. http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/
    CardiovascularandRenalDrugsAdvisoryCommittee/ucm196216.htm . January 5, 2010. Accessed September 17, 2010.
  3. Chen AY, Zirwas MJ, Heffernan MP. Nephrogenic systemic fibrosis: a review. J Drugs Dermatol. 2010;9(7):829-834.
  4. Omniscan [prescribing information]. Princeton, NJ: GE Healthcare, Inc; 2010.
  5. Grobner T. Gadolinium: a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006;21(4):1104-1108.
  6. Weinreb JC, Abu-Alfa AK. Gadolinium-based contrast agents and nephrogenic systemic fibrosis: why did it happen and what have we learned? J Magn Reson Imaging. 2009;30(6):1236-1239.
  7. Bardin T, Richette P. Nephrogenic systemic fibrosis. Curr Opin Rheumatol. 2010;22(1):54-58.
  8. Food and Drug Administration. Public Health Advisory - Gadolinium-containing Contrast Agents for Magnetic Resonance Imaging (MRI). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/
    DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm053112.htm
    . June 8, 2006. Updated June 22, 2010. Accessed September 17, 2010.
  9. Food and Drug Administration. FDA Requests Boxed Warning for Contrast Agents Used to Improve MRI Images. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108919.htm . May 23, 2007. Updated June 18, 2009. Accessed September 17, 2010.
  10. American College of Radiology. Manual on Contrast Media. Nephrogenic systemic fibrosis. http://www.acr.org/SecondaryMainMenuCategories/quality_safety/
    contrast_manual/NephrogenicSystemicFibrosis.aspx
    . Updated 2010. Accessed September 18, 2010.
  11. European Society of Urogenital Radiology. ESUR guidelines on contrast media. http://www.esur.org/Contrast-media.51.0.html. Updated August 2008. Accessed September 22, 2010.
  12. Abujudeh HH, Rolls H, Kaewlai R, et al. Retrospective assessment of prevalence of nephrogenic systemic fibrosis (NSF) after implementation of a new guideline for the use of gadobenate dimeglumine as a sole contrast agent for magnetic resonance examination in renally impaired patients. J Magn Reson Imaging. 2009;30(6):1335-1340.
  13. Martin DR, Krishnamoorthy SK, Kalb B, et al. Decreased incidence of NSF in patients on dialysis after changing gadolinium contrast-enhanced MRI protocols. J Magn Reson Imaging. 2010;31(2):440-446.
  14. Chrysochou C, Power A, Shurrab AE, et al. Low risk for nephrogenic systemic fibrosis in nondialysis patients who have chronic kidney disease and are investigated with gadolinium-enhanced magnetic resonance imaging. Clin J Am Soc Nephrol. 2010;5(3):484-489.
  15. Altun E, Martin DR, Wertman R, Lugo-Somolinos A, Fuller ER 3rd, Semelka RC. Nephrogenic systemic fibrosis: change in incidence following a switch in gadolinium agents and adoption of a gadolinium policy--report from two U.S. universities. Radiology. 2009;253(3):689-696.

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What are the new recommendations for the 2010-2011 Flu Season?

Background

Seasonal influenza is an acute respiratory illness caused by influenza A or B viruses.1,2 Yearly outbreaks occur worldwide and usually begin in the late fall and continue until spring. Complications that may result in serious illness leading to hospitalization or death occur most frequently in persons aged ≥65 years, children aged <2 years, and persons of any age who have medical conditions that place them at higher risk. 1

In the U.S. alone, 25 to 50 million cases of the flu are reported yearly during seasonal epidemics.2 Although the majority of cases are not severe, complications result in about 200,000 hospitalizations and 30,000 deaths per year. On a global scale, the influenza virus causes about 500,000 deaths yearly, making it the highest death rate associated with a vaccine-preventable disease. Additionally, the U.S. incurs an annual societal cost of >$37 billion from influenza, resulting from days lost from work or school and increased use of the healthcare system from visits to the emergency department and physician offices.

There are 2 types of influenza viruses that cause epidemics in humans. Influenza A viruses are related to seasonal flu epidemics while influenza B causes periodic outbreaks, primarily in long-term care facilities.1,2 Influenza A viruses have 2 surface antigens, hemagglutinin and neuraminidase, for which the virus is categorized based on each antigen's subtype. For example, H1N1 corresponds with the hemagglutinin subtype 1 and neuraminidase subtype 1. The most prevalent disease causing subtypes of influenza A include the H3N2 and H1N1.

The human body builds immunity against the influenza virus by developing antibodies against the surface antigens, especially hemagglutinin. 1,2 However, immunity to 1 subtype does not translate into immunity to other subtypes or other types of influenza. In addition, small changes in the hemagglutinin and/or neuraminidase molecules caused by point mutations create an antigenic drift, resulting in the need for annual vaccinations to protect against the particular antigenic variant causing seasonal flu epidemics each year. In comparison, antigenic shifts are caused by genetic reassortment as opposed to a point mutation. This was most likely the case in development of the novel 2009 pandemic H1N1 influenza virus.

Guidelines

Vaccination remains the cornerstone for preventing influenza. The Advisory Committee on Immunization Practices (ACIP) provides yearly guidelines on the prevention and treatment of influenza (Table 1).1 Pediatric guidelines from the American Academy of Pediatrics (AAP) are consistent with the ACIP recommendations for the 2010-2011 flu season.3

Table 1. The Advisory Committee on Immunization Practices (ACIP) recommendations and changes for the 2010-2011 flu season.1,4

  1. Routine immunization (annual vaccination) is now recommended for anyone ≥6 months as soon as vaccine is available.
  2. Children aged 6 months to 8 years whose vaccination status is unknown or who have never received seasonal influenza vaccine before (or who received seasonal vaccine for the first time in 2009-2010 but received only 1 dose in their first year of vaccination) as well as children who did not receive at least 1 dose of influenza A (H1N1) 2009 monovalent vaccine regardless of previous influenza vaccine history should receive 2 doses of 2010-2011 seasonal influenza vaccine (minimum interval 4 weeks) during the 2010-2011 season.
  3. The 2010-2011 trivalent vaccines will contain the 2009 H1N1 pandemic virus and will be comprised of the following strains: A/California/7/2009 (H1N1)-like (derived from the 2009 H1N1 pandemic influenza A), A/Perth/16/2009 (H3N2)-like, and B/Brisbane/60/2008-like antigens.
  4. A newly approved inactivated trivalent vaccine containing 60 mcg of hemagglutinin antigen per influenza vaccine virus strain (Fluzone HD (High Dose [Sanofi Pasteur]) is an alternative inactivated vaccine for persons aged ≥65 years.
  5. Previously approved inactivated influenza vaccines that were approved for expanded age indications in 2009 include Fluarix (GlaxoSmithKline) for persons aged ≥3 years and Afluria (CSL Biotherapies) for persons aged ≥9 years. A new inactivated influenza vaccine, Agriflu (Novartis), has been approved for persons aged ≥18 years. Afluria was initially FDA approved for ages ≥6 months; however, due to post-marketing reports of fever and febrile seizures in children, especially in those aged <5 years, the ACIP recommends that Afluria should not be used in children aged 6 months to 8 years.4
  6. In the event of a supply shortage, vaccination efforts will be focused on the following individuals:
    • Aged 6 months to 4 years (59 months)
    • Aged ≥50 years
    • Chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, neurologic, hematologic, or metabolic disorders (including diabetes mellitus)
    • Immunosuppressed (includes immunosuppressive medications or human immunodeficiency virus)
    • Pregnant during flu season
    • Aged 6 to 18 years and receiving long-term aspirin due to risk of Reyes syndrome after influenza virus infection
    • Residents of nursing homes and other chronic-care facilities
    • American Indians/Alaska Natives
    • Morbidly obese (Body Mass Index ≥40)
    • Healthcare personnel
    • Household contacts and caregivers of children aged <5 years and adults ≥50 years, with emphasis on vaccinating contacts of children aged <6 months
    • Household contacts and caregivers of persons with medical conditions that put them at a higher risk for severe complications from the flu

H1N1 Update

In 2009, the world witnessed a pandemic caused by an antigenic shift in the H1N1 influenza virus.5,6 The first reported case was found in California in April of 2009. What followed was a series of outbreaks globally throughout the summer months and continuing into the winter, when a heightened level of disease was reported. Not only did the novel H1N1 show complete dominance over the regular seasonal flu, it was also unique because most of the complications were seen in those <65 years of age, particularly those between the ages of 50 to 64 years with underlying medical conditions.1,5

According to the World Health Organization, a post-pandemic phase has been declared for the this H1N1 virus.5,7 At the present time, the virus has spread to all countries. People of all ages have some immunity and summer outbreaks have not been reported. In addition, the seasonal influenza A and influenza B are once again being reported in many countries. It is predicted that the 2009 H1N1 pandemic virus will circulate for the next several years, similar to seasonal influenza viruses.

Despite being in the post pandemic stage, some countries are still reporting H1N1 outbreaks, such as India and New Zealand.5,7 The H1N1 virus can be present for many years with severity varying during individual influenza seasons. Continued outbreaks are expected, with more severe cases in younger age groups and pregnant women. Measures that may reduce risk include vaccines and hand and respiratory hygiene.

Vaccine Availability

Table 2 shows the availability of influenza vaccine for the 2010-2011 flu season and includes the ACIP recommendations for the different age groups, manufacturer information, how the vaccine is supplied, and mercury content.8 All influenza vaccines are trivalent inactivated vaccines (TIV) and administered intramuscularly except for FluMist, which is a live attenuated vaccine (LAIV) that is given intranasally. Also note that Fluzone High Dose ( HD) is a new high dose TIV recommended for adults ≥65 years of age.

Table 2. Vaccines available for the 2010-2011 influenza season. 8

Manufacturer Trade Name How Supplied Mercury content (mcg/ 0.5 mL dose) Recommended age group Number of doses
Sanofi Pasteur Fluzone
0.25 mL prefilled syringe
0.5 mL prefilled syringe
0.5 mL vial
5 mL multidose vial
0
0
0
25
6-35 mos
≥36 mos
≥36 mos
≥6 mos
1 or 2*
1 or 2*
1 or 2*
1 or 2*
Fluzone HD (High-Dose) 0.5 mL prefilled syringe 0 ≥65 years 1
Novartis Vaccines and Diagnostics Fluvirin
5.0 mL multidose vial
0.5 mL prefilled syringe
25
<1
≥4 years 1 or 2*
Agriflu 0.5 mL prefilled syringe 0 ≥18 years 1
GlaxoSmithKline Biologicals Fluarix 0.5 mL prefilled syringe 0 ≥3 years 1 or 2*
ID Biomedical Corp. (subsidiary of GlaxoSmithKline) FluLaval 5.0 mL multidose vial 25 ≥18 years 1
CSL Biotherapies Afluria 0.5 mL prefilled syringe 0 ≥9 years 1
MedImmune FluMist 0.2 mL sprayer, divided dose, equally between each nostril 0 2 to 49 years 1 or 2*

*Children aged 6 months to 8 years should receive 2 doses of the 2010-2011 vaccine, spaced ³4 weeks apart if any of the following apply: 1) they did not receive at least 1 dose of an influenza A (H1N1) 2009 monovalent vaccine, 2) they have never received a seasonal influenza vaccine, or 3) they were vaccinated for the first time with the seasonal 2009-2010 seasonal vaccine but received only 1 dose.

The intranasal LAIV is not recommended in children aged <2 years or adults ³50 years of age.9 It should also be avoided in people with the following health conditions:

  • Pregnant
  • Arthritis
  • Asthma
  • HIV/AIDS
  • ≤5 years with a history of recurrent wheezing
  • Children or adolescents receiving aspirin therapy
  • History of Guillain-Barré within 6 weeks of receiving flu vaccine
  • Severe egg allergy or allergy to any component of intranasal vaccine

Fluzone HD

Fluzone HD is an inactivated influenza virus vaccine indicated for those ≥65 years of age for immunity against influenza A virus subtypes and influenza B.10 The rationale behind the higher dose for persons aged ≥65 years are a greater risk for hospitalization and death from seasonal influenza and a lower antibody titer response to influenza hemagglutinin (an established correlate of protection against influenza) upon vaccination, compared with younger adults.11

The higher dose vaccine has been shown in clinical trials to produce a higher immune response than the standard dose vaccine.12-14 However, it is important to note that there has been no published controlled clinical studies demonstrating a decrease in influenza disease after vaccination with Fluzone HD.10,11

Fluzone HD is supplied in prefilled syringes containing 4 times the amount of influenza virus hemagglutinin than the regular influenza vaccines. 10 While the standard dose of inactivated trivalent influenza vaccines contain a total of 45 mcg (15 mcg of each of the 3 recommended strains) of influenza virus hemagglutinin antigen per 0.5 mL dose, Fluzone HD contains a total of 180 mcg (60 mcg of each strain) of influenza virus hemagglutinin antigen in each 0.5 mL dose.

Antiviral Drug Therapy Updates

There are 2 antiviral drugs recommended by the CDC this season: Tamiflu (oseltamavir) and Relenza (zanamivir).15 Both are neuraminidase inhibitors with Tamiflu available in pill or liquid form and Relenza is available as an inhaled powder.15,16

Most healthy people with the flu do not need to be treated with antiviral drugs.15,16 Antiviral drug therapy is recommended for treatment in those who are very sick with the flu (i.e., hospitalized) and people sick with the flu and have a greater chance of serious flu complications including:

  • Children <2 years old (children aged 2 to 4 years also have a higher rate of complications compared to older children, although the risk for these children is lower than the risk for children aged <2 years)
  • Adults ≥65 years
  • Pregnant women and women up to 2 weeks from end of pregnancy
  • People with certain medical conditions (such as asthma, heart failure, chronic lung disease) or a weak immune system (due to illnesses such as diabetes and HIV)
  • People <19 years of age who are receiving long-term aspirin therapy

In conclusion, influenza viruses continue to cause serious morbidity and mortality, particularly in high-risk populations. Immunization with the 2010-2011 influenza trivalent seasonal influenza vaccine should take place and recommendations from the ACIP and AAP should be followed. For frequent updates this flu season visit: www.cdc.gov/flu/whatsnew.htm.

References

1. Centers for Disease Control and Prevention. Prevention and control of influenza with vaccines. MMWR Morb Mortal Wkly Rep. 2010;59(8):1-68.

2. Hermsen HD, Rupp ME. Influenza. In: Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Physiological Approach. 7th ed. New York, NY: McGraw Hill Inc; 2008:1791-1799.

3. American Academy of Pediatrics, Committee on Infectious Diseases. Policy statement--recommendations for prevention and control of influenza in children, 2010-2011. Pediatrics. 2010. www.pediatrics/org/cgi/doi/10.1542/peds.2010-2216. Accessed September 20, 2010.

4. Centers for Disease Control and Prevention. Update: recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding use of CSL seasonal influenza vaccine (Afluria) in the United States during 2010-11. MMWR Morb Mortal Wkly Rep. 2010;59(31):989-993.

5. World Health Organization. What is post-pandemic? www.who.int/csr/disease/swineflu/frequently_asked_questions/post_pandemic/en/index.html Accessed August 19, 2010.

6. Centers for Disease Control and Prevention. The 2009 H1N1 pandemic: summary highlights, April 2009-April 2010. www.cdc.gov/h1n1flu/cdcresponse.htm. Accessed August 19, 2010.

7. World Health Organization. Director-General's opening statement at virtual press conference (August 10, 2010): H1N1 in post-pandemic period. www.who.int/mediacentre/news/statements/2010/h1n1_vpc_20100810/en/index.html. Accessed August 19, 2010.

8. Centers for Disease Control and Prevention. Influenza vaccines recommendation by the Advisory Committee on Immunization Practices (ACIP) for different age groups-United States, 2010-11 season. www.cdc.gov/flu/protect/vaccine/vaccines.htm. Accessed September 9, 2010.

9. Flu.gov. The seasonal flu vaccine. www.flu.gov/individualfamily/vaccination/index.html. Accessed August 25, 2010.

10. Fluzone [package insert]. Swiftwater, PA: Sanofi Pasteur; 2010.

11. Centers for Disease Control and Prevention. Licensure of a high-dose inactivated influenza vaccine for persons aged ³65 years (Fluzone High-Dose) and guidance for use-United States, 2010. MMWR Morb Mortal Wkly Rep. 2010;59(16):485-486.

12. Falsey A, Treanor J, Tornieporth N, Capellan J, Gorse G. Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older. J Infect Dis. 2009;200(2):172-180.

13. Couch RB, Winokur P, Brady R, et al. Safety and immunogenicity of a high dose trivalent influenza vaccine among elderly subjects. Vaccine. 2007;25(44):7656-7663.

14. Keitel WA, Atmar RL, Cate TR, et al. Safety of high doses of influenza vaccine and effect on antibody responses in elderly persons. Arch Intern Med. 2006;166(10):1121-1127.

15. Centers for Disease Control and Prevention. What you should know about flu antiviral drugs. www.cdc.gov/flu/antivirals/whatyoushould.htm#box. Accessed August 25, 2010.

16. Zachary K, Hirsch M, Thorner A. UpToDate: treatment of seasonal influenza in adults. www.uptodate.com/online/content/topic.do?topicKey=pulm_inf/14708&selectedTitle=1%7E150&source=search_result#references. Accessed August 19, 2010.

Prepared by: Quynh Nguyen, PharmD

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