12MS6741 BQ Vol 8:Layout 1 - Henry Schein€¦ · 12MS6741_BQ_Vol_8:Layout 1 8/13/12 2:10 PM Page...

Volume 8/Summer 2012B BioTherapeutics

Q u a r t e r l yDiagnostic and Pharmaceutical News for You and Your Medical Practice

Diagnostics I Pharmaceuticals I DxRx Solutions I Continuing Education I News

$4.95

12MS6741_BQ_Vol_8:Layout 1 8/13/12 2:10 PM

Choose the Only FDA-approved HyaluronidaseSynthesized by a Recombinant Process

OTHER clinically utilized hyaluronidase products contain cattle or sheep testes-derived hyaluronidase

See Important Safety Information and Brief Summary of Full Prescribing Information.

cts

Hylenex® recombinant (hyaluronidase human injection) is a Safe, Effective and Low Cost Option*• Hylenex recombinant is:

– the ONLY recombinant human hyaluronidase available and– the lowest priced FDA-approved hyaluronidase available.*

*Cost comparison based on published Wholesale Acquisition Cost per single-use vial comparing FDA-approved available products. Red Book March 2012. Price comparison is not indicative of fi nal customer price and is not intended to be a comparison of safety or effi cacy of drugs.**cGMP= Current Good Manufacturing Practices

Available for Use

FDA-approved

FDA-regulated Manufacturing (cGMP**)

YES

Source of Active Ingredient

Hylenex®

recombinant

YES

YES

RecombinantHuman

YES

Vitrase®

YES

YES

Sheep Testes

Not Since 1999

Wydase®

Not CurrentlyMade

YES

CattleTestes

Not Since 2008

Hydase

YES

Not Since 2010

Amphadase®

YES

YES

Compounded

NO

NO

Cattle Testes

Cattle Testes

Cattle Testes

Not CurrentlyMade

Not CurrentlyMade

Units/mL 150 200 150 150 150 150

2B BioTherapeuticsQ u a r t e r l y

A Henry Schein Publication


Hylenex recombinant (hyaluronidase human injection)

Conforms to WHO Guidelines on Transmissible

Spongiform Encephalopathies1

Henry Schein, Inc. Ordering Information Order Hylenex recombinant (NDC 18657-102-04)Item Code: 248-0470Phone: 1-800-772-4346

n

Packaging

• Preservative free

• Ready to use

• 1 mL single-dose vials

• 150 USP units/mL

• 4 vials per box

Shelf Life

• 18 months

Storage

Unopened in a refrigerator at 2o to 8oC (36o to 46oF). DO NOT FREEZE.

For further information, contact

Halozyme toll free at 855-HYLENEX

(855-495-3639) or visit www.hylenex.com

See Brief Summary of Full Prescribing Information on next page.

bovine = cattleovine = sheepcaprine = goat

• Hylenex recombinant does not contain any animal products.

in which bovine, ovine or caprine materials are used during manufacturethe group

avoid the use of bovine materials in the manufacture of any animal species in which TSEs

naturally occur.

Note: Emphasis added

3 B BioTherapeuticsQ u a r t e r l y



Important Safety Information

• Hypersensitivity to hyaluronidase or any other ingredient in the formulation is a contraindication to the use of this product.

• Discontinue Hylenex recombinant if sensitization occurs.

• Hyaluronidase should not be used to enhance the absorption and dispersion of dopamine and/or alpha agonist drugs.

• Hyaluronidase should not be injected into or around an infected or acutely infl amed area because of the danger of spreading a localized infection.

• Hyaluronidase should not be used to reduce the swelling of bites or stings.

• Hyaluronidase should not be used for intravenous injections because the enzyme is rapidly inactivated.

• Furosemide, the benzodiazepines and phenytoin have been found to be incompatible with hyaluronidase.

• Anaphylactic-like reactions following retrobulbar block or intravenous injections have occurred, rarely.

• Hyaluronidase should not be applied directly to the cornea. It is not for topical use.

The most frequently reported adverse reactions have been local injection site reactions, such as erythema and pain. Hyaluronidase has been reported to enhance the adverse reactions associated with co-administered drug products.

Patients receiving large doses of salicylates, cortisone, ACTH, estrogens or antihistamines may require larger amounts of hyaluronidase for equivalent dispersing effect, since these drugs apparently render tissues partly resistant to the action of hyaluronidase.

Edema has been reported most frequently in association with subcutaneous fl uid administration. The rate and volume of subcutaneous fl uid administration should not exceed those employed for intravenous infusion. As with all parenteral fl uid therapy, observe effect closely, with the same precautions for restoring fl uid and electrolyte balance as in intravenous injections. Special care must be taken in pediatric patients to avoid over hydration by controlling the rate and total volume of infusion. When solutions devoid of inorganic electrolytes are administered subcutaneously, hypovolemia may occur.

Indication

Hylenex recombinant (hyaluronidase human recombinant) is a tissue modifi er indicated as an adjuvant in subcutaneous fl uid administration for achieving hydration, to increase the dispersion and absorption of other injected drugs, and in subcutaneous urography for improving resorption of radiopaque agents.




Reference: 1. World Health Organization. WHO Guidelines on Transmissible Spongiform Encephalopathies in Relation to Biological and Pharmaceutical Products. 2003. Available at:http://www.who.int/bloodproducts/publications/en/WHO_TSE_2003.pdf. Accessed July 18, 2011.

Vitrase®, Wydase® and Amphadase® are all trademarks of their respective companies.

www.halozyme.comHalozyme Therapeutics 11388 Sorrento Valley Road, San Diego, CA 92121. ©Halozyme, Inc. 2012

U.S. Pat. No. 7,767,429Hylenex, the Hylenex logo, Halozyme, Halozyme Therapeutics, and the H logo are trademarks of Halozyme, Inc. 102-0112-00

HYLENEX® recombinant(hyaluronidase human injection)150 USP units/mLRx Only

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATIONThis Brief Summary does not include all the information needed to use HYLENEX recombinant safely and effectively. See full prescribing information for HYLENEX recombinant by visiting www.hylenex.com.

To report SUSPECTED ADVERSE REACTIONS, contact Halozyme Therapeutics, Inc. at 1-877-877-1679 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

INDICATIONS AND USAGESubcutaneous Fluid Administration HYLENEX recombinant is indicated as an adjuvant in subcutaneous fluid administration for achieving hydration.

Dispersion and Absorption of Injected Drugs HYLENEX recombinant is indicated as an adjuvant to increase the dispersion and absorption of other injected drugs.

Subcutaneous Urography HYLENEX recombinant is indicated as an adjunct in subcutaneous urography for improving resorption of radiopaque agents.

CONTRAINDICATIONS HYLENEX recombinant is contraindicated in patients with known hypersensitivity to hyaluronidase or any of the excipients in HYLENEX recombinant. A preliminary skin test for hypersensitivity to HYLENEX recombinant can be performed. The skin test is made by an intradermal injection of approximately 0.02 mL (3 Units) of a 150 Unit/mL solution. A positive reaction consists of a wheal with pseudopods appearing within 5 minutes and persisting for 20 to 30 minutes and accompanied by localized itching. Transient vasodilation at the site of the test, i.e., erythema, is not a positive reaction. Discontinue HYLENEX recombinant if sensitization occurs.

WARNINGS AND PRECAUTIONS Spread of Localized Infection Hyaluronidase should not be injected into or around an infected or acutely inflamed area because of the danger of spreading a localized infection. Hyaluronidase should not be used to reduce the swelling of bites or stings.

Ocular DamageHyaluronidase should not be applied directly to the cornea. It is not for topical use.

Enzyme Inactivation with Intravenous Administration HYLENEX recombinant should not be administered intravenously. Its effects relative to dispersion and absorption of other drugs are not produced when it is administered intravenously because the enzyme is rapidly inactivated.

ADVERSE REACTIONSThe following adverse reactions have been identified during post-approval use of hyaluronidase products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The most frequently reported adverse reactions have been mild local injection site reactions such as erythema and pain. Hyaluronidase has been reported to enhance the adverse reactions associated with co-administered drug products. Edema has been reported most frequently in association with subcutaneous fluid administration. Allergic reactions (urticaria or angioedema) have been reported in less than 0.1% of patients receiving hyaluronidase. Anaphylactic-like reactions following retrobulbar block or intravenous injections have occurred, rarely.

DRUG INTERACTIONSIt is recommended that appropriate references be consulted regarding physical or chemical incompatibilities before adding HYLENEX recombinant to a solution containing another drug.

Incompatibilities Furosemide, the benzodiazepines and phenytoin have been found to be incompatible with hyaluronidase.

Drug-Specific Precautions Hyaluronidase should not be used to enhance the dispersion and absorption of dopamine and/or alpha agonist drugs. When considering the administration of any other drug with hyaluronidase, it is recommended that appropriate references first be consulted to determine the usual precautions for the use of the other drug.

Local Anesthetics When hyaluronidase is added to a local anesthetic agent, it hastens the onset of analgesia and tends to reduce the swelling caused by local infiltration, but the wider spread of the local anesthetic solution increases its absorption; this shortens its duration of action and tends to increase the incidence of systemic reaction.

Salicylates, Cortisone, ACTH, Estrogens and Antihistamines Patients receiving large doses of salicylates, cortisone, ACTH, estrogens or antihistamines may require larger amounts of hyaluronidase for equivalent dispersing effect, since these drugs apparently render tissues partly resistant to the action of hyaluronidase.

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category C. In an embryo-fetal study, mice have been dosed daily by subcutaneous injection with recombinant human hyaluronidase at dose levels up to 2,200,000 U/kg. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at a daily dose of 360,000 U/kg, which represents several orders of magnitude over

the suggested human dose range of 50-300 U of HYLENEX recombinant (0.8-5 U/kg in a 60 kg subject). In a pre- and postnatal development study, mice have been dosed daily by subcutaneous injection with recombinant human hyaluronidase at dose levels up to 1,100,000 U/kg. The study found no adverse effects on sexual maturation, learning and memory of offspring, or their ability to produce another generation of offspring. It is also not known whether HYLENEX recombinant can cause fetal harm when administered to a pregnant woman. HYLENEX recombinant should be given to a pregnant woman only if clearly needed.

Labor and Delivery Administration of hyaluronidase during labor was reported to cause no complications: no increase in blood loss or differences in cervical trauma were observed.

Nursing MothersIt is not known whether hyaluronidase is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when hyaluronidase is administered to a nursing woman.

Pediatric Use Clinical hydration requirements for children can be achieved through administration of subcutaneous fluids facilitated with HYLENEX recombinant. The dosage of subcutaneous fluids administered is dependent upon the age, weight, and clinical condition of the patient as well as laboratory determinations. The potential for chemical or physical incompatibilities should be kept in mind. The rate and volume of subcutaneous fluid administration should not exceed those employed for intravenous infusion. For premature infants or during the neonatal period, the daily dosage should not exceed 25 mL/kg of body weight, and the rate of administration should not be greater than 2 mL per minute. During subcutaneous fluid administration, special care must be taken in pediatric patients to avoid over hydration by controlling the rate and total volume of the infusion.

Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger adult patients.




6


Ta b l e o f C o n t e n t s

The BioTherapeutics Quarterly Journal is published four times a year by Henry Schein, Inc. Henry Schein’s corporate headquarters arelocated at 135 Duryea Road, Melville, NY. For journal sales information or to report corrections, e-mail [email protected] or call Kim Crabtree at 276-688-2090. Note that although we attempt to ensure the currency of the information contained in this publication as of the publication date, new biotherapeutic developments occur continually and, therefore, may not be noted in this publication. Not responsible for typographical errors.

Volume 8/Summer 2012B BioTherapeutics

Q u a r t e r l y

8 Letter to Henry Schein’s Valued Customers

11 Prevalence of Obesity Among Adults with Arthritis

17 New Drug Approvals

18 FDA AlertRegistries Help Moms Measure Medication Risks

21 Diabetes Risk after Gestational Diabetes

27 MMWROutbreak of Meningococcal Disease Associated with an Elementary School

32 First H3N2 Variant Virus InfectionReported for 2012

37 Generically SpeakingBiosimilars

B BioTherapeuticsQ u a r t e r l y



8




A Letter to Henry Schein’s Valued Customers

OUR Mission

To provide health care professionals with a practical

and relevant source of information regarding

diagnostics, pharmaceuticals, and vaccines in a quick

and easy-to-read publication that provides educational

updates and insight to assist you in prevention,

diagnosis, and treatment of disease.

Awareness is key to the prevention of disease. It is in this spirit, that we present our latest edition of the BioTherapeutics Quarterly journal. It is our goal to provide health care practitioners with the latest information regarding the prevention, diagnosis, and treatment of disease.

In this issue, we bring you updates on arthritis, pregnancy registries, gestational diabetes, meningitis, influenza, and generic drugs.

Our first article looks at the prevalence of obesity among adults with arthritis. In a recent study, obesityprevalence on average was 54% higher in adults with arthritis compared with those without arthritis.

In an effort to provide awareness to pregnant women, the FDA has issued an alert to help mothers-to-be, to be aware of registries that collect information on the effects of numerous medications on pregnant women andinfants in an effort to identify and manage risks – and prevent tragedies.

We are also featuring an article this month from the National Diabetes Education Program which addresses therisk of diabetes after experiencing gestational diabetes. Women with a history of gestational diabetes mellitus(GDM) have a 35% to 60% chance of developing diabetes in the next 10 to 20 years. Children born from GDMmothers may also be at increased risk for obesity and type 2 diabetes compared to other children.

A recent MMWR report outlines the outbreak and response of meningococcal disease in an elementary school in 2010. The report discusses what was learned from this outbreak including implementation of a vaccination program.

The CDC reported the first case of H3N2 variant virus infection in the US in 2012.

Don’t forget to check out our New Drug Approvals section on page 17 and our Generically Speaking section on pages 37 and 38.

Sincerely,

Louis FerraroVice President & General ManagerBioTherapeutics, Henry Schein Medical




Cont’d. on page 14






New Drug Approvals

MAY

APRILApril 6, 2012Amyvid (FLORBEAPIR F 18)Manufacturer: Lilly

About this product:Amyvid is a radioactive diagnostic agent forPositron Emission Tomography (PET) imaging ofthe brain to estimate B-amyloid neuritic plaquedensity in adult patients with cognitive impairmentwho are being evaluated for Alzheimer’s Disease(AD) and other causes of cognitive decline. Anegative Amyvid scan indicates sparse to noneuritic plaques, and is inconsistent with aneuropathological diagnosis of AD at the time ofimage acquisition; a negative scan result reducesthe likelihood that a patient’s cognitive impairmentis due to AD. A positive Amyvid scan indicatesmoderate to frequent amyloid neuritic plaques;

neuropathological examination has shown thisamount of amyloid neuritic plaque is present inpatients with AD, but may also be present inpatients with other types of neurologic conditions aswell as older people with normal cognition. Amyvidis an adjunct to other diagnostic evaluations.

April 27, 2012Stendra™ (AVANAFIL)Manufacturer: Vivus

About this product:STENDRA is a phosphodiesterase 5 (PDE5)inhibitor indicated for the treatment of erectile dysfunction

May 1, 2012ELELYSO™ (TALIGLUCERASE ALFA)Manufacturer: Pfizer

About this product:ELELYSO™ (taliglucerase alfa) for injection is ahydrolytic lysosomal glucocerebroside-specificenzyme indicated for long-term enzymereplacement therapy (ERT) for adults with aconfirmed diagnosis of Type 1 Gaucher disease.

May 1, 2012DYMISTA™ (AZELASTINEHYDROCHLORIDE; FLUTICASONEPROPRIONATE)Manufacturer: Meda Pharms

About this product:Dymista Nasal Spray, containing an H1-receptorantagonist and a corticosteroid, is indicated for therelief of symptoms of seasonal allergic rhinitis inpatients 12 years of age and older who requiretreatment with both azelastine hydrochloride andfluticasone propionate for symptomatic relief.


Consumer Health Informationwww.fda.gov/consumer

Registries Help Moms Measure Medication RisksWhether it’s because of the

flu or seasonal allergies, diabetes or epilepsy,

pregnant women must often take prescription medication—usually while worrying about the potential impact on their developing babies.

With studies showing the average woman takes from three to five medi-cations while pregnant, the Food and Drug Administration (FDA) encour-ages drug makers and moms-to-be to participate in pregnancy registry stud-ies that track the risks from drugs taken during pregnancy or breastfeeding.

These studies collect and maintain data on the effects of medications used by pregnant and nursing women on themselves and their babies. Par-ticipants don’t take experimental drugs or medications they would not ordinarily take. Instead, registries collect information on the effects of already approved drugs—for diabe-tes, migraines, epilepsy, and other health issues—prescribed to preg-nant women. The information is then compared to the effects of the drug on women who are not pregnant.

“The FDA’s goal is to have data about the use of medicines during pregnancy for all medicines that are used by women of childbearing potential,” says Karen Feibus, M.D., an FDA expert in maternal health.

Thalidomide Tragedy The effects of the drug thalidomide caused one of the great tragedies of the 1950s. As many as 10,000 babies around the world were born with severe deformities after their moth-ers took the medication for morning




Consumer Health Informationwww.fda.gov/consumer

Find this and other Consumer Updates at www.fda.gov/ForConsumers/ConsumerUpdates

Sign up for free e-mail subscriptions at www.fda.gov/consumer/consumerenews.html

sickness and insomnia.The drug was marketed in Europe,

Japan, Australia, and Canada, but it was taken off the market in the early 1960s when the medical community learned that it caused serious birth defects. According to the March of Dimes, about 40 percent of babies exposed to the drug died before or soon after delivery.

FDA medical officer Frances Kelsey refused to support the drug’s approval in the U.S. because she was uncertain about its safety. Because of this, most babies affected by thalido-mide were born in other countries.

FDA approved the drug in 1998 for treatment of a skin disorder asso-ciated with Hansen’s disease, also called leprosy, and later for bone marrow cancer.

Registries now collect information on the effects of numerous medi-cations on pregnant women and infants in an effort to identify and manage risks—and prevent tragedy.

Registry Use Expands“Pregnancy registries are useful tools for gathering information about the effects of drugs on preg-nant or nursing women and devel-oping infants,” says Dr. Lisa Mathis, director of FDA’s pediatric and maternal health division.

With registries collecting infor-mation on treatments for a range of illnesses—HIV/AIDS, cancer, diabe-tes, and asthma, Feibus says the data help women make informed choices.

“Sometimes leaving a serious med-ical condition untreated during preg-nancy can be riskier to the mother and her developing baby than the medicine itself,” she says.

Congress gave FDA the authority to require drug makers to study the

effects of newly approved medicines on pregnant and nursing women and newborn infants in the FDA Amend-ments Act of 2007.

Under the law, FDA experts also review applications for new drugs and decide if the manufacturer should be required to set up a pregnancy regis-try after approval, says Feibus.

Sometimes health professionals or the drug industry begin a registry without being required to do so—as in the case of the North American Antiepileptic Drug Pregnancy Regis-try, which studies the effects of drugs for the treatment of epilepsy.

Pregnant women with epilepsy are recruited to participate because they must take medicines to control seizures. The Epilepsy Foundation encourages women to enroll in the registry, which is closely monitored by researchers at Massachusetts Gen-eral Hospital, the teaching hospital for Harvard University Medical School.

“By enrolling, you will help women in the future have the best chance of a healthy pregnancy and a healthy baby,” the foundation tells expectant moms in a message on its website.

In May 2008, FDA proposed a new rule that includes putting informa-tion learned from registries—as well as contact information for regis-tries—on labeling for health profes-sionals. The final rule will be pub-lished at the end of a multi-stepped writing and clearance process.

Registries Aid Moms, BabiesFDA says the registries protect the health of mothers and babies because • many pregnant women have

ongoing medical issues that require them to continue taking drugs during pregnancy

• new medical problems may begin or old ones may get worse

• a woman’s body changes during pregnancy and the changes may affect the dosage of a medication she is taking

• a woman often takes medications while she is breastfeeding, potentially exposing her baby to the effects of medicines

• about half of the 6 million pregnancies in the United States each year are unplanned, exposing women and developing babies to drugs before they know they are pregnant

Registries typically collect the wom-an’s demographics and medications being taken. Massachusetts General in Boston lists more than 30 medica-tions being studied, and promises the process will be quick: one 20-minute phone call at the beginning and two five-minute calls after that.

In most instances, a woman can participate in a pregnancy registry by contacting the drug’s maker, her physician, or pharmacist.

Although FDA does not maintain preg-nancy registries, the agency’s Office of Women’s Health has a partial list on the Internet at www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm134848.htm. The list also includes the illness each registry represents.

Registries now collect information on the effects of numerous medications on pregnant women and infants in an effort to identify and manage risks—and prevent tragedy.




Help patients lessen the misery, fast.Patients living with cold sores want relief. Steroid-free, topical Denavir is applied directly to the lesion,1 providing relief from discomfort,

dryness and cracking.2 Denavir targets the virus that causes cold sores,* helping lesions — and cold sore pain — go away faster.** 1

Plus, eligible patients pay no more than $15 with a money-saving coupon (subject to eligibility restrictions and limitations).†

Visit Denavir.com or call 1-888-DENAVIR (1-888-336-2847). *Denavir selectively targets cells infected with HSV-1 and prevents the virus from reproducing.1

**Compared to placebo.

New American Therapeutics, Inc. holds the exclusive right to market and distribute Denavir in the United States. Denavir® is a registered trademark of New American Therapeutics, Inc.

(penciclovir cream, 1%)natxcorp.com

Progress through practical innovation

4 Becker Farm Road, Roseland, NJ 07068 ©2012 New American Therapeutics, Inc. 1/2012 DEN-0072

Denavir® (penciclovir cream, 1%) is indicated for the treatment of recurrent herpes labialis (cold sores) in adults and children 12 years of age and older.

IMPORTANT SAFETY INFORMATIONDenavir should only be used on herpes labialis on the lips or face. Application to mucous membranes is not recommended. Denavir should not be used in patients with known hypersensitivity to the product or any of its ingredients.

There are no adequate and well-controlled Denavir studies in pregnant women; therefore, Denavir should be used during pregnancy only if clearly needed. There is no information on whether Denavir is excreted in human milk after topical administration; a decision whether to discontinue Denavir should take into account the importance of the drug to the mother. The effect of Denavir has not been established in immunocompromised patients. Denavir does not cure cold sores.

In clinical studies, the most common adverse reaction with Denavir was headache, which occurred in 5.3% of patients who received Denavir and 5.8% of patients who received placebo. Other adverse reactions with Denavir occurred in less than 2% of patients and included application site reaction, decreased sensitivity to touch/local anesthesia, taste perversion, and rash.

Other reported adverse reactions have included swelling of the mouth or throat, pain, alterations in sense of smell, abnormal touch sensation, itching, skin discoloration, and hives.

Denavir is available by prescription only. Please see the Full Prescribing Information on the back.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.† If a patient’s co-pay or pharmacy bill exceeds $15, they can present the

certifi cate to the pharmacist for an instant rebate of up to a maximum of $45 for

each Denavir prescription. If their total out of pocket pharmacy bill exceeds $60

for any single Denavir prescription, they will be responsible for the additional

balance. Not valid with any other offer. Subject to eligibility restrictions and limitations. This offer is not valid for prescriptions reimbursed in whole or part

by Medicaid, Medicare, or any other federal or state program (including any

prescription drug programs). This offer is not valid in Massachusetts except for

cash-paying patients, or where otherwise prohibited by law.

References1. Denavir (penciclovir cream 1%) Prescribing Information, Cranford, NJ,

New American Therapeutics, Inc. December 2010. 2. Boon R, Goodman

JJ, Martinez J, et al. for the Penciclovir Cream Herpes Labialis Study Group.

Penciclovir cream for the treatment of sunlight-induced herpes labialis: a

randomized, double-blind, placebo-controlled trial. Clin Ther. 2000; 22:76-90.

Denavir® (penciclovir cream, 1%) is indicated for the treatment of recurrent herpes labialis (cold sores) in adults and children 12 years of age and older.

I WANT YOU TO HELPDEFEND AGAINST COLD SORES.




Prescribing InformationDESCRIPTIONDenavir contains penciclovir, an antiviral agent active against herpes viruses. Denavir is available for topical administration as a 1% white cream. Each gram of Denavir contains 10 mg of penciclovir and the following inactive ingredients: cetomacrogol 1000 BP, cetostearyl alcohol, mineral oil, propylene glycol, purified water and white petrolatum.Chemically, penciclovir is known as 9-[4-hydroxy-3-(hydroxymethyl) butyl]guanine. Its molecular formula is C

10H15N5O3; its molecular weight is 253.26. It is a synthetic acyclic guanine derivative and has the following structure:

Penciclovir is a white to pale yellow solid. At 20°C it has a solubility of 0.2 mg/mL in methanol, 1.3 mg/mL in propylene glycol, and 1.7 mg/mL in water. In aqueous buffer (pH 2) the solubility is 10.0 mg/mL. Penciclovir is not hygroscopic. Its partition coefficient in n-octanol/water at pH 7.5 is 0.024 (logP= -1.62).CLINICAL PHARMACOLOGYMicrobiologyMechanism of Antiviral Activity: The antiviral compound penciclovir has in vitro inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). In cells infected with HSV-1 or HSV-2, viral thymidine kinase phosphorylates penciclovir to a monophosphate form which, in turn, is converted to penciclovir triphosphate by cellular kinases. In vitro studies demonstrate that penciclovir triphosphate inhibits HSV polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes viral DNA synthesis and, therefore, replication are selectively inhibited.Antiviral Activity In Vitro and In Vivo: In cell culture studies, penciclovir has antiviral activity against HSV-1 and HSV-2. Sensitiv-ity test results, expressed as the concentration of the drug required to inhibit growth of the virus by 50% (IC

50) or 99% (IC99) in cell culture, vary depending upon a number of factors, including the assay protocols. See Table 1.

Table 1

Method of Assay Virus Type Cell Type IC50 IC99 (mcg/mL) (mcg/mL)

Plaque Reduction HSV-1 (c.i.) MRC-5 0.2-0.6 HSV-1 (c.i.) WISH 0.04-0.5 HSV-2 (c.i.) MRC-5 0.9-2.1 HSV-2 (c.i.) WISH 0.1-0.8Virus Yield Reduction HSV-1 (c.i.) MRC-5 0.4-0.5 HSV-2 (c.i.) MRC-5 0.6-0.7DNA Synthesis Inhibition HSV-1 (SC16) MRC-5 0.04 HSV-2 (MS) MRC-5 0.05

(c.i.) = clinical isolates. The latent state of any herpes virus is not known to respond to any antiviral therapy.

Drug Resistance: Penciclovir-resistant mutants of HSV can result from qualitative changes in viral thymidine kinase or DNA polymerase. The most commonly encountered acyclovir-resistant mutants that are deficient in viral thymidine kinase are also resistant to penciclovir.PharmacokineticsMeasurable penciclovir concentrations were not detected in plasma or urine of healthy male volunteers (n=12) following single or repeat application of the 1% cream at a dose of 180 mg penciclovir daily (approximately 67 times the estimated usual clinical dose).Pediatric Patients: The systemic absorption of penciclovir following topical administration has not been evaluated in patients <18 years of age.CLINICAL TRIALSDenavir was studied in two double-blind, placebo (vehicle)-controlled trials for the treatment of recurrent herpes labialis in which otherwise healthy adults were randomized to either Denavir or placebo. Therapy was to be initiated by the subjects within 1 hour of noticing signs or symptoms and continued for 4 days, with application of study medication every 2 hours while awake. In both studies, the mean duration of lesions was approximately one-half-day shorter in the subjects treated with Denavir (N=1,516) as compared to subjects treated with placebo (N=1,541) (approximately 4.5 days versus 5 days, respectively). The mean duration of lesion pain was also approximately one-half-day shorter in the Denavir group compared to the placebo group.INDICATIONS AND USAGEDenavir (penciclovir cream) is indicated for the treatment of recurrent herpes labialis (cold sores) in adults and children 12 years of age and older.CONTRAINDICATIONSDenavir is contraindicated in patients with known hypersensitivity to the product or any of its components.PRECAUTIONSGeneralDenavir should only be used on herpes labialis on the lips and face. Because no data are available, application to human mucous membranes is not recommended. Particular care should be taken to avoid application in or near the eyes since it may cause irritation. Lesions that do not improve or that worsen on therapy should be evaluated for secondary bacterial infection. The effect of Denavir has not been established in immunocompromised patients.Information for PatientsDenavir is a prescription topical cream for the treatment of cold sores (recurrent herpes labialis) that occur on the face and lips. It is not a cure for cold sores and not all patients respond to it. Do not use if you are allergic to Denavir (penciclovir) or any of the ingredients in Denavir cream. Before you use Denavir, tell your doctor if you are pregnant, planning to become pregnant, or are breast-feeding.Directions: Wash your hands. Your face should be clean and dry. Apply a layer of Denavir cream to cover only the cold sore area or the area of tingling (or other symptoms) before the cold sore appears. Rub in the cream until it disappears. Apply the cream every 2 hours during waking hours for 4 days. Even though Denavir works at the blister stage, treatment should be started at the earliest sign of a cold sore (i.e. tingling, redness, itching, or bump). Wash your hands with soap and water after using Denavir cream. Store Denavir cream at room temperature (59°- 86°F). Keep out of reach of children.Possible side effects: Denavir cream was well tolerated in clinical studies in patients with cold sores. The most frequently reported side effect was headache. Common skin-related side effects of Denavir cream are application site reactions, local anesthesia, taste perversion, and rash.Carcinogenesis, Mutagenesis, Impairment of FertilityIn clinical trials, systemic drug exposure following the topical administration of penciclovir cream was negligible, as the penciclovir content of all plasma and urine samples was below the limit of assay detection (0.1 mcg/mL and 10 mcg/mL,

respectively). However, for the purpose of inter-species dose comparisons presented in the following sections, an assumption of 100% absorption of penciclovir from the topically applied product has been used. Based on use of the maximal recommend-ed topical dose of penciclovir of 0.05 mg/kg/day and an assumption of 100% absorption, the maximum theoretical plasma AUC

0-24 hrs for penciclovir is approximately 0.129 mcg.hr/mL.Carcinogenesis: Two-year carcinogenicity studies were conducted with famciclovir (the oral prodrug of penciclovir) in rats and mice. An increase in the incidence of mammary adenocarcinoma (a common tumor in female rats of the strain used) was seen in female rats receiving 600 mg/kg/day (approximately 395x the maximum theoretical human exposure to penciclovir following application of the topical product, based on area under the plasma concentration curve comparisons [24 hr. AUC]). No increases in tumor incidence were seen among male rats treated at doses up to 240 mg/kg/day (approximately 190x the maximum theoretical human AUC for penciclovir), or in male and female mice at doses up to 600 mg/kg/day (approximately 100x the maximum theoretical human AUC for penciclovir).Mutagenesis: When tested in vitro, penciclovir did not cause an increase in gene mutation in the Ames assay using multiple strains of S. typhimurium or E. coli (at up to 20,000 mcg/plate), nor did it cause an increase in unscheduled DNA repair in mammalian HeLa S3 cells (at up to 5,000 mcg/mL). However, an increase in clastogenic responses was seen with penciclovir in the L5178Y mouse lymphoma cell assay (at doses ≥1000 mcg/mL) and, in human lymphocytes incubated in vitro at doses ≥250 mcg/mL. When tested in vivo, penciclovir caused an increase in micronuclei in mouse bone marrow following the intravenous administration of doses ≥500 mg/kg (≥810x the maximum human dose, based on body surface area conversion).Impairment of Fertility: Testicular toxicity was observed in multiple animal species (rats and dogs) following repeated intra-venous administration of penciclovir (160 mg/kg/day and 100 mg/kg/day, respectively, approximately 1155 and 3255x the maximum theoretical human AUC). Testicular changes seen in both species included atrophy of the seminiferous tubules and reductions in epididymal sperm counts and/or an increased incidence of sperm with abnormal morphology or reduced motility. Adverse testicular effects were related to an increasing dose or duration of exposure to penciclovir. No adverse testicular or reproductive effects (fertility and reproductive function) were observed in rats after 10 to 13 weeks dosing at 80 mg/kg/day, or testicular effects in dogs after 13 weeks dosing at 30 mg/kg/day (575 and 845x the maximum theoretical human AUC, respectively). Intravenously administered penciclovir had no effect on fertility or reproductive performance in female rats at doses of up to 80 mg/kg/day (260x the maximum human dose [BSA]).There was no evidence of any clinically significant effects on sperm count, motility or morphology in 2 placebo-controlled clinical trials of Famvir® (famciclovir [the oral prodrug of penciclovir], 250 mg b.i.d.; n=66) in immunocompetent men with recurrent genital herpes, when dosing and follow-up were maintained for 18 and 8 weeks, respectively (approximately 2 and 1 spermatogenic cycles in the human).PregnancyTeratogenic Effects-Pregnancy Category B. No adverse effects on the course and outcome of pregnancy or on fetal development were noted in rats and rabbits following the intravenous administration of penciclovir at doses of 80 and 60 mg/kg/day, respectively (estimated human equivalent doses of 13 and 18 mg/kg/day for the rat and rabbit, respectively, based on body surface area conversion; the body surface area doses being 260 and 355x the maximum recommended dose following topical application of the penciclovir cream). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, penciclovir should be used during pregnancy only if clearly needed.Nursing MothersThere is no information on whether penciclovir is excreted in human milk after topical administration. However, following oral administration of famciclovir (the oral prodrug of penciclovir) to lactating rats, penciclovir was excreted in breast milk at concentrations higher than those seen in the plasma. Therefore, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. There are no data on the safety of penciclovir in newborns.Pediatric UseAn open-label, uncontrolled trial with penciclovir cream 1% was conducted in 102 patients, ages 12-17 years, with recurrent herpes labialis. The frequency of adverse events was generally similar to the frequency previously reported for adult patients. Safety and effectiveness in pediatric patients less than 12 years of age have not been established.Geriatric UseIn 74 patients ≥ 65 years of age, the adverse events profile was comparable to that observed in younger patients.ADVERSE REACTIONSIn two double-blind, placebo-controlled trials, 1516 patients were treated with Denavir (penciclovir cream) and 1541 with pla-cebo. The most frequently reported adverse event was headache, which occurred in 5.3% of the patients treated with Denavir and 5.8% of the placebo-treated patients. The rates of reported local adverse reactions are shown in Table 2 below. One or more local adverse reactions were reported by 2.7% of the patients treated with Denavir and 3.9% of placebo-treated patients.

Table 2–Local Adverse Reactions Reported in Phase III Trials

Penciclovir Placebo n= 1516 n=1541 % %

Application site reaction 1.3 1.8Hypesthesia/Local anesthesia 0.9 1.4Taste perversion 0.2 0.3Pruritus 0.0 0.3Pain 0.0 0.1Rash (erythematous) 0.1 0.1Allergic reaction 0.0 0.1

Two studies, enrolling 108 healthy subjects, were conducted to evaluate the dermal tolerance of 5% penciclovir cream (a 5-fold higher concentration than the commercial formulation) compared to vehicle using repeated occluded patch testing methodology. The 5% penciclovir cream induced mild erythema in approximately one-half of the subjects exposed, an ir-ritancy profile similar to the vehicle control in terms of severity and proportion of subjects with a response. No evidence of sensitization was observed.Post-Marketing ExperienceThe following events have been identified from worldwide post-marketing use of Denavir in treatment of recurrent herpes labialis (cold sores) in adults. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Denavir cream.General: Headache, oral/pharyngeal edema, parosmia.Skin: Application site reactions, aggravated condition, decreased therapeutic response, erythematous rash, local edema, pain, paresthesia, pruritus, skin discoloration and urticaria.OVERDOSAGESince penciclovir is poorly absorbed following oral administration, adverse reactions related to penciclovir ingestion are un-likely. There is no information on overdose.DOSAGE AND ADMINISTRATIONDenavir should be applied every 2 hours during waking hours for a period of 4 days. Treatment should be started as early as possible (i.e., during the prodrome or when lesions appear).HOW SUPPLIEDDenavir is supplied in a 1.5 gram and 5 gram tube containing 10 mg of penciclovir per gram.1.5 gram NDC 50816-624-015 gram NDC 50816-624-05Store at controlled room temperature, 20°-25° C (68°-77°F) [see USP]QUESTIONS? call 1-866-736-8798.

262F400

December 2010

DEN-0042

Manufactured for New American Therapeutics, Inc.Cranford, NJ 07016by Novartis Pharma GmbH, Wehr, Germany

©2010 New American Therapeutics, Inc. Printed in U.S.A.




U.S. Department of Health and Human ServicesCenters for Disease Control and Prevention

Morbidity and Mortality Weekly Report

Weekly / Vol. 61 / No. 13 April 6, 2012

During March 10–31, 2010, the Oklahoma State Department of Health (OSDH) investigated an outbreak of meningococcal (Neisseria meningitidis) disease involving a consolidated school district of 1,850 students in rural northeastern Oklahoma. An OSDH field investigation team and the Rogers County Health Department (RCHD) established operations at the affected elementary school as soon as the outbreak was recognized. Five cases of meningococcal disease (including one probable case) were identified among four elementary school students and one high school student. Two students died; two recovered fully, and one survivor required amputation of all four limbs and facial reconstruction. All N. meningitidis isolates were serogroup C with the same multilocus sequence type and an indistinguishable pulsed-field gel electrophoresis pattern. To interrupt the outbreak, mass vaccination and chemoprophy-laxis clinics were conducted in the population at risk; 1,459 vaccinations and 1,063 courses of antibiotics were adminis-tered. Children eligible for the Vaccines for Children (VFC) program received 1,092 of the vaccine doses, demonstrating that VFC is a feasible funding source for vaccine during an outbreak response.

Outbreak and Response On the morning of March 10, 2010, OSDH was notified

that a boy aged 7 years (student A) had been hospitalized with suspected meningococcal meningitis on the basis of a preliminary cerebrospinal fluid (CSF) culture result (Figure). After N. meningitidis confirmation, RCHD conducted a rou-tine contact investigation. Four household members received chemoprophylaxis, and one close contact of the patient was advised to seek chemoprophylaxis.

The next morning, during a 2-hour period, three additional cases of suspected meningococcal disease (in students B, C, and D), including one fatality (student B), were reported to OSDH (Figure). All four patients attended a prekindergarten

through 2nd grade lower elementary school in a consolidated school district with a total enrollment of approximately 1,850 students. Four noncontiguous buildings (lower elementary, upper elementary, middle school, and high school) on a single campus provided classrooms and other facilities for children in prekindergarten through 12th grade.

The occurrence of four cases within 48 hours prompted OSDH and RCHD to begin outbreak control measures consist-ing of providing chemoprophylaxis to children in selected grades and to other patient contacts to provide short-term protection of the population at risk. RCHD mobilized personnel to operate an interim mass chemoprophylaxis clinic onsite at the school. The clinic began operation at noon on March 11 (Figure), after the OSDH field epidemiology team arrived with antibiotics.

Chemoprophylaxis was targeted initially to the 443 stu-dents and 50 faculty members in the lower elementary school and to close contacts of the patients. American Academy of Pediatrics guidelines recommend oral rifampin in 4 doses over 2 consecutive days or a single-dose intramuscular ceftriaxone injection for use as chemoprophylaxis against meningococcal disease among children (1). Intramuscular ceftriaxone was selected as the agent for children in the lower elementary school to ensure rapid initiation of chemoprophylaxis and to alleviate concerns regarding noncompliance with a 4-dose regimen of an unpalatable medication.

Outbreak of Meningococcal Disease Associated with an Elementary School — Oklahoma, March 2010

INSIDE222 HIV, Other STD, and Pregnancy Prevention

Education in Public Secondary Schools — 45 States,

2008–2010

229 Influenza Outbreaks at Two Correctional Facilities

— Maine, March 2011

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MMWR / April 6, 2012 / Vol. 61 / No. 13

The MMWR series of publications is published by the Office of Surveillance, Epidemiology, and Laboratory Services, Centers for Disease Control and Prevention (CDC), U.S. Department of Health and Human Services, Atlanta, GA 30333.

Suggested citation: Centers for Disease Control and Prevention. [Article title]. MMWR 2012;61:[inclusive page numbers].

Centers for Disease Control and PreventionThomas R. Frieden, MD, MPH, Director

Harold W. Jaffe, MD, MA, Associate Director for ScienceJames W. Stephens, PhD, Director, Office of Science Quality

Stephen B. Thacker, MD, MSc, Deputy Director for Surveillance, Epidemiology, and Laboratory ServicesStephanie Zaza, MD, MPH, Director, Epidemiology and Analysis Program Office

MMWR Editorial and Production StaffRonald L. Moolenaar, MD, MPH, Editor, MMWR Series

John S. Moran, MD, MPH, Deputy Editor, MMWR SeriesTeresa F. Rutledge, Managing Editor, MMWR Series

Douglas W. Weatherwax, Lead Technical Writer-EditorDonald G. Meadows, MA, Jude C. Rutledge, Writer-Editors

Martha F. Boyd, Lead Visual Information Specialist

Maureen A. Leahy, Julia C. Martinroe, Stephen R. Spriggs, Terraye M. Starr

Visual Information SpecialistsQuang M. Doan, MBA, Phyllis H. King

Information Technology Specialists

MMWR Editorial BoardWilliam L. Roper, MD, MPH, Chapel Hill, NC, Chairman

Matthew L. Boulton, MD, MPH, Ann Arbor, MIVirginia A. Caine, MD, Indianapolis, IN

Jonathan E. Fielding, MD, MPH, MBA, Los Angeles, CADavid W. Fleming, MD, Seattle, WA

William E. Halperin, MD, DrPH, MPH, Newark, NJKing K. Holmes, MD, PhD, Seattle, WADeborah Holtzman, PhD, Atlanta, GATimothy F. Jones, MD, Nashville, TN

Dennis G. Maki, MD, Madison, WIPatricia Quinlisk, MD, MPH, Des Moines, IA

Patrick L. Remington, MD, MPH, Madison, WIJohn V. Rullan, MD, MPH, San Juan, PR

William Schaffner, MD, Nashville, TNDixie E. Snider, MD, MPH, Atlanta, GA

John W. Ward, MD, Atlanta, GA

At approximately 4:00 p.m., OSDH was notified that stu-dent D had died and that two additional lower elementary stu-dents had been hospitalized with fever and rash (students E and F). Although these two illnesses were eventually found not to

be cases of N. meningitidis infection on the basis of laboratory and clinical findings, that evidence did not become available until the following week. With the reports of an additional death and additional patients, the OSDH field team expanded

FIGURE. Timeline of major events involving invasive meningococcal disease outbreak based in an elementary school and public health response — Oklahoma, March 2010

Abbreviations: RCHD = Rogers County Health Department, OSDH = Oklahoma State Department of Health.

Student A

reported ill

Students B, C,

and D reported

fatality reported

RCHD and OSDH

chemoprophylaxis

clinic

Second fatality

reported, and

student E and F

reported ill

High school

student G reported

ill, and second

chemoprophylaxis

clinic operated

Third

chemoprophylaxis

clinic operated

Vaccination

outreach at a

Active

surveillance

ends

10 11 12 22–26 31191613 21

School district spring break 6:20–

8:20 a.m.

12:00

p.m.

4:00

p.m.

March 2010

Mass vaccination

clinic operated






MMWR / April 6, 2012 / Vol. 61 / No. 13

chemoprophylaxis eligibility to select older students who had participated in reading instruction that placed them in direct contact with younger children in classrooms where cases were identified and to select persons who rode on buses with the patients, a total of approximately 400 additional contacts. During March 11–12, the first two chemoprophylaxis clinics operated for approximately 16 hours and administered 846 chemoprophylaxis doses.

On March 12, suspected meningococcal disease in a high school student in the district (student G) was reported to OSDH on the basis of clinical suspicion (Figure). As an additional precaution and to facilitate the chemoprophylaxis clinics, school district officials, in consultation with OSDH, dismissed all classes and canceled all extracurricular activities 1 day earlier than the scheduled, week-long spring break. Also on March 12, OSDH recommended mass meningococcal vaccination for all students, faculty, and staff members in the affected school district as a definitive outbreak control measure. Culture confirmation of N. meningitidis infection in student G was obtained on March 15.

On March 19, RCHD operated a mass meningococcal vaccination clinic at the school gymnasium, followed by vac-cination outreach at the community physician’s office during March 22–26 (Figure). A total of 1,459 doses of meningococ-cal vaccine (i.e., 1,426 doses of quadrivalent meningococcal conjugate vaccine, plus 33 doses of quadrivalent meningococcal polysaccharide vaccine [MPSV4] for those aged >55 years) were administered, resulting in vaccination of approximately 68% of students aged 4–18 years. During March 11–31, OSDH conducted active surveillance in six surrounding counties but identified no additional outbreak-linked cases.

Case Characteristics A confirmed case of invasive meningococcal disease was

defined as isolation of N. meningitidis from a normally sterile body site. A probable case was defined as N. meningitidis DNA detected by polymerase chain reaction without organism isolation in a suspected patient. A suspected case was defined as physician-reported fever and any rash in a person linked epidemiologically to a patient with a confirmed case. Two suspected cases (in students E and F) ultimately were excluded. Four cases (in students A, C, D, and G) were confirmed, and one case (in student B) was classified as probable (Table). The five patients ranged in age from five to 18 years.

All five patients required hospitalization. Meningococcemia was present in four patients, two of whom also had isola-tion of N. meningitidis from cerebrospinal fluid (Table). Formalin-fixed, paraffin-embedded central nervous system tissues were obtained at autopsy from the two decedents, and

immunohistochemical and molecular evidence of infection with N. meningitidis was observed in the tissues. The four patients with confirmed cases had isolation of N. meningitidis serogroup C, further characterized as multilocus sequence type ST-11 with an indistinguishable pulsed-field gel electrophoresis pattern (H46N06.0037).

The five patients were in three different grades. Three of the patients, including the index patient (student A) were in the same 2nd grade classroom. One patient with confirmed meningococcal disease (student C) was in a kindergarten class-room with a younger sibling of the index patient, and the fifth patient (student G) sang in close proximity to an older sibling of the index patient in two school choirs. None of the five patients had received a meningococcal vaccination previously.

Reported by

Kristy Bradley, DVM, Lauri Smithee, PhD, Oklahoma State Dept of Health. Thomas Clark, MD, Henry Wu, MD, Raydel Mair, MS, Brian Harcourt, PhD, Leonard Mayer, PhD, Susanna Schmink, Div of Bacterial Diseases, National Center for Immunization and Respiratory Diseases; Christopher Paddock, MD, Sherif Zaki, MD, Div of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases; Steven Grube, MD, EIS Officer, CDC. Corresponding contributor: Steven Grube, [email protected], 404-791-4663.

What is already known on this topic?

Meningitis caused by Neisseria meningitidis is an uncommon,

often fatal, infectious disease. Outbreak response can include

vaccination, and if vaccination is implemented, postexposure

chemoprophylaxis may be administered to protect persons

until vaccine-induced immunity develops.

What is added by this report?

In 2010, an outbreak of five cases of meningococcal disease,

two fatal, occurred in an Oklahoma prekindergarten through

12th grade school complex. Four patients attended the same

lower elementary school, and one was a high school student. All

cases were caused by indistinguishable isolates of serogroup C

N. meningitidis. To stem the outbreak, public health authorities

provided chemoprophylaxis to 1,063 persons and vaccination

to 1,459. Of 1,250 children aged 4–18 years who received

quadrivalent meningococcal conjugate vaccine, 87% were

eligible for the federal Vaccines for Children (VFC) program.

What are the implications for public health practice?

During a rapidly progressive meningococcal disease outbreak in a

school, a prompt and coordinated public health response

following established outbreak guidelines is needed to protect

those at risk. VFC is a potential funding source for purchasing

vaccine for eligible children aged 9 months–18 years in an

outbreak setting.







MMWR / April 6, 2012 / Vol. 61 / No. 13

Editorial Note

School-related meningococcal disease outbreaks generate considerable community anxiety and require rapid, intensive public health response. In the United States, annual inci-dence of invasive meningococcal infection is approximately 0.5 cases per 100,000 population (2) with <1,200 cases of invasive disease reported to CDC in 2008 (3). In Oklahoma, during 2005–2009, incidence was 0.5 cases per 100,000 population, the lowest rate since 1978. In both Oklahoma and nationwide, children aged <1 year experience the highest incidence of disease (3). Approximately 5% of all cases occur during outbreaks, and elementary schools account for only 25% of school-based outbreaks (4). Case-fatality ratios are higher for outbreak-associated cases than for sporadic cases (5).

In 2009, estimated meningococcal vaccination coverage among Oklahoma teens was 29.5%, ranking 46th among states; coverage for the United States overall was 53.6% (6). During the menin-gococcal disease outbreak described in this report, the majority of those affected were aged 5–7 years, typically considered an age group at low risk and not recommended for routine immuniza-tion against meningococcal disease (7). In this outbreak, the rapid succession of reported cases suggested that additional cases were likely, necessitating immediate public health intervention.

Meningococcal vaccination was implemented as the defini-tive outbreak control measure based on a primary attack rate of 162 per 100,000 population (three primary cases in a school complex population of 1,850) (8). Vaccination is the preferred method for establishing long-term protection, and in contrast to polysaccharide vaccine, use of conjugate vaccine can achieve greater impact at lower coverage levels because of herd immunity (9,10). However, the immune response to vac-cination takes 7–10 days to develop, whereas the majority of cases occur soon after the index case in school-based outbreaks (4). One third of cases occur within 2 days and three fourths within 14 days. Close household contacts of patients are at 500- to 1,000-fold increased risk and are recommended to receive chemoprophylaxis. In contrast, the estimated incidence of secondary meningococcal disease among school children is 2.5 per 100,000, or a relative risk of 2.3 (4).

If a public health decision is made to implement vaccina-tion as an outbreak control measure after two or more cases are reported in a school, administration of chemoprophylaxis to the population at risk also should be considered, both to offer short-term protection to at-risk persons and potentially to limit transmission. Mass chemoprophylaxis is most likely to be effective when administered quickly and completely to a well-defined or closed cohort. The rapid occurrence of cases in school clusters suggests that transmission occurs rapidly among susceptible children. Each school-based outbreak has unique characteristics, including various case numbers and frequency, serogroup, and physical setting; public health and school officials should tailor their responses accordingly.

When a case in a high school student was identified dur-ing this outbreak, the population considered “at risk” was expanded, and the vaccination campaign was extended to all unvaccinated students, faculty members, and administrative personnel at the four district schools. VFC-eligible children aged 11–18 years were able to receive meningococcal vaccine at no charge. Because an outbreak was declared, thereby clas-sifying the children involved in the outbreak as at increased risk for disease, children aged 4–10 years who met federal VFC program eligibility criteria also were able to receive free meningococcal vaccine.

State funds were available to purchase only 25% of the total 1,459 doses of vaccine administered among all age groups, including all vaccine administered to adult school employees. Of the 1,426 quadrivalent meningococcal conjugate vaccine doses administered, 1,250 doses were administered to chil-dren aged 4–18 years, of whom 1,092 (87%) were deemed VFC-eligible, illustrating that use of VFC funds can bolster vaccination coverage among eligible children in an outbreak setting. In addition, federal Section 317 funding* was used to purchase vaccine for children ineligible for VFC vaccine. Subsequently, a joint resolution by the Advisory Committee on Immunization Practices and VFC clarified that children aged 9 months–10 years who are associated with an outbreak

* Additional information available at http://www.hhs.gov/recovery/programs/cdc/immunizationgrant.html.

TABLE. Patient, clinical, and laboratory characteristics involving confirmed and probable cases of meningococcal disease (N = 5) based at an elementary school — Oklahoma, March 2010

Case Classification Grade Disease onset Purpuric rash ICU Died

Specimens with positive test results for Neisseria meningitidis

Culture specimen PCR specimen

A Confirmed 2nd grade March 8 Yes Yes No Blood/CSF Blood/CSF

B Probable 2nd grade March 10 Yes Yes Yes None Blood/Cerebral tissue

C Confirmed Kindergarten March 10 Yes Yes No Blood Blood

D Confirmed 2nd grade March 10 Yes Yes Yes Blood/CSF Blood/CSF

G Confirmed 12th grade March 10 No No No Blood None

Abbreviations: ICU = intensive-care unit, CSF = cerebrospinal fluid, PCR = polymerase chain reaction.






MMWR / April 6, 2012 / Vol. 61 / No. 13

of disease caused by a vaccine-preventable meningococcal serogroup are among those eligible for VFC (7).

Early in the outbreak investigation, school officials expedi-tiously agreed to host the chemoprophylaxis and vaccination clinics. Local emergency medical services were present and assisted in monitoring for adverse events associated with the chemoprophylaxis and vaccination clinics held at the school. The school used its automated parent-calling system to provide details regarding who was being advised to receive preven-tive chemoprophylaxis and vaccine. In addition to county and state public health agencies, local medical, fire, and law enforcement personnel mobilized quickly to help support the chemoprophylaxis clinics. The rapid, coordinated response was associated with high compliance with vaccination, which likely contributed to outbreak cessation.

References 1. American Academy of Pediatrics. Meningococcal infections. In: Pickering

LK, Baker CJ, Kimberlin DW, Long SS, eds. Red book: 2009 report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009.

2. Cohn AC, MacNeil JR, Harrison LH, et al. Changes in Neisseria meningitidis disease epidemiology in the United States, 1998–2007: implications for prevention of meningococcal disease. Clin Infect Dis 2010;50:184–91.

3. CDC. Summary of notifiable diseases—United States, 2008. MMWR 2010;57(54).

4. Zangwill KM, Schuchat A, Riedo FX, et al. School-based clusters of meningococcal disease in the United States: descriptive epidemiology and a case-control analysis. JAMA 1997;277:389–95.

5. Brooks R, Woods CW, Benjamin, DK Jr, Rosenstein NE. Increased case-fatality rate associated with outbreaks of Neisseria meningitidis infection, compared with sporadic meningococcal disease, in the United States, 1994–2002. Clin Infect Dis 2006;43:49–54.

6. CDC. National, state, and local area vaccination coverage among adolescents aged 13–17 years—United States, 2009. MMWR 2010; 59:1018–23.

7. CDC. Advisory Committee on Immunization Practices, Vaccines for Children Program. Vaccines to prevent meningococcal disease. Resolution no. 6/11-1. Atlanta, GA: Advisory Committee on Immunization Practices; 2011. Available at http://www.cdc.gov/vaccines/programs/vfc/downloads/resolutions/06-11mening-mcv.pdf. Accessed April 3, 2012.

8. CDC. Control and prevention of serogroup C meningococcal disease; evaluation and management of suspected outbreaks: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1997;46(No. RR-05):13–21.

9. Krause G, Blackmore C, Wiersma S, Lesneski C, Gauch L, Hopkins RS. Mass vaccination campaign following community outbreak of meningococcal disease. Emerg Infect Dis 2002;8:1398–403.

10. Weiss D, Stern EJ, Zimmerman C, et al. Epidemiologic investigation and targeted vaccination initiative in response to an outbreak of meningococcal disease among illicit drug users in Brooklyn, New York. Clin Infect Dis 2009;48:894–901.





32

First H3N2 Variant Virus InfectionReported for 2012




April 12, 2012 – The first human infection with an influenza A H3N2 variant (H3N2v) virus in 2012 has been reported in a child bythe state of Utah . CDC has confirmed this virus is very similar to the 12 H3N2v viruses that infected 12 people in the United Statesin the latter half of 2011. The virus contains genes from human, swine and avian influenza viruses, and the M gene from the 2009H1N1 virus. Swine exposure has been reported for this case. Animal and public health investigations are currently underway todetermine the source of this infection and if there are additional human cases. The report will be officially reported in the April 13,2012 FluView influenza surveillance report.

After seeking medical care for a fever in late March, the patient in Utah tested positive for influenza A and was treated withoseltamivir, which is one of two antiviral drugs known as “neuraminidase inhibitors” currently recommended by CDC for thetreatment of influenza virus infections, including infections with variant influenza viruses. The child recovered at home.

The case in Utah was detected through routine surveillance, when the influenza-positive sample from the medical visit was forwardedto the state public health laboratory for further characterization. Testing at the state public health laboratory identified the sample as apossible variant influenza virus. Follow-up testing at CDC confirmed that this is an influenza A H3N2v virus.

When a virus that is known to circulate in swine but not in people is identified in a person, it is called a “variant influenza virus.” The case in Utah brings the number of human infections with H3N2v viruses detected in the United States to 21 since July 2009.Thirteen of those 21 H3N2v viruses have had the 2009 H1N1 M gene and have occurred since July 2011. Twelve of these 13 caseshave occurred in children younger than 18 years old. All patients have recovered from their illness. The previously identified 12human infections with viruses like this one occurred in Indiana (2), Pennsylvania (3), Maine (2), Iowa (3) and West Virginia (2)between July and November 2011. None of the 13 viruses studied have any genetic markers known to confer resistance to theneuraminidase inhibitors oseltamivir (Tamiflu®) or zanamivir (Relenza®).

About half of the 12 infections in 2011 with H3N2v viruses like this one involved the patients being exposed to swine beforebecoming ill. The prevalence of this virus in swine is unknown, but it has been detected in U.S. swine through the United StatesDepartment of Agriculture’s (USDA) swine influenza surveillance program . Limited human-to-human transmission with this virus issuspected to have occurred in Iowa and West Virginia in November 2011.

An article in the April 13, 2011 Morbidity and Mortality Report Weekly Report entitled “Antibodies Cross-Reactive to Influenza A(H3N2) Variant Virus and Impact of 2010–11 Seasonal Influenza Vaccination on Cross-Reactive Antibodies” looked at whether aseasonal flu shot might create antibodies that would be protective of infection with these H3N2v viruses. The study found that theseasonal flu shot would not be expected to protect against H3N2v in young children, and would only provide limited protectionagainst H3N2v viruses in adults. The study results imply that if these H3N2v viruses were to begin to spread easily and widely inpeople, an H3N2v-specific influenza vaccine would be needed to provide the best protection against H3N2v viruses.

CDC produced an H3N2v vaccine candidate virus. A precautionary vaccine against H3N2v is in development and will likely be readyfor clinical trials in the coming months.

The total number of variant influenza virus infections in humans reported in the United States since December 2005 now stands at 36.The remaining 15 infections were with other variant influenza viruses, including H1N2v and H1N1v.

Human infections with influenza viruses that commonly circulate in swine are still rare events, but the frequency with which theyhave been detected has increased recently. These cases should be carefully investigated jointly by public and animal health officials todetermine the source of the infection and ensure that no additional human infections occur or that there is no ongoing human-to-human transmission.

Source: http://www.cdc.gov/flu/spotlights/h3n2v-variant-utah.htm





Biosimilars

According to the FDA’s website,1 Biological products include a wide range of products such as vaccines, blood and blood components,allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. Biologics can be composed of sugars, proteins, or nucleicacids or complex combinations of these substances, or may be living entities such as cells and tissues.

Biologics are isolated from a variety of natural sources - human, animal, or microorganism - and may be produced by biotechnology methodsand other cutting-edge technologies. Gene-based and cellular biologics, for example, often are at the forefront of biomedical research, and maybe used to treat a variety of medical conditions for which no other treatments are available.

While the law2 signed by President Obama on March 23, 2010, amends the Public Health Service Act (PHS Act) to createan abbreviated licensure pathway for biological products that are demonstrated to be “biosimilar” to or “interchangeable”with an FDA-licensed biological product, it was nearly 2 years later that the FDA finally published draft guidance as to theregulations defining the pathways to submit applications. On February 9th 2012 the FDA published the following 3documents:

• Scientific Considerations in Demonstrating Biosimilarity to a Reference Product:• Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product:• Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price

Competition and Innovation Act of 2009:

What do these new guidelines mean?Critics have claimed that while these regulatory guidances suggested some wins for biosimilar manufacturers (FDA clarifiedthat some innovator data can be used to support a biosimilar application) there were other aspects of the guidance that werenot as favorable. Interchangeability still remains the big question mark and this ongoing issue with interchangeability mayprove to be a barrier for biosimilar manufacturers from the utilization and payer management perspectives. The basis of costsavings is that the FDA approval pathway for biosimilars, similar to the model for small molecules, would be significantlyless onerous than that of a branded biologic. The FDA has yet to fully detail how and if it will establish interchangeability,and because of this unknown factor (which potentially can considerably drive up development costs), economists are hesitantto predict any significant cost savings. If the FDA’s final rule regarding biosimilar requirements for submissions, expected tobe published later this year, mandates that drug companies perform additional human and animal testing to proveinterchangeability then cost savings may drop to as little as 10%-20% from the originators product. This would be much less than what the present administration had been hoping for (according to the Congressional Budget Office more than $13 billion over the next 10 years) when they included this in their 2010 landmark healthcare reform act. This pales incomparison to the savings, in many instances of 90% or more, for traditional or small molecules generic medicines.

Many healthcare experts express concerns over how this market will work and the many unknowns, including the potentialfor drawn out patent litigations, may mean that the consumer may not see financial benefits from this part of the legislationuntil the end of this decade.

Who will benefit?According to IMS Health, the global market for biosimilars in 2010 was $311 million, the vast majority of those salesgenerated in Europe. It is expected to increase to $2 billion-$2.5 billion in 2015. The European Medicines Agency (EMA),the FDA's European counterpart, had previously issued a means to approve biosimilars in 2005, which has since been utilizedto launch biogenerics of Epogen® (epoeitin alfa) and Neupogen® (filgrastim) throughout Europe.3


38

Biosimilars cont’d.




In the US, the situation has remained stagnant for decades now; biotech manufacturers have enjoyed a benefit unparalleled inthe pharmaceuticals arena: open-ended exclusivity to their products. These companies controlled this status by convincingthe Food and Drug Administration that their products, derived from proteins and other compounds from living cells, weretoo complex and esoteric to be successfully reproduced by generic manufacturers. Now that the door has been opened tocompetition, the question still remains as to which companies will be best suited to compete. As the obstacles to entry willmost probably include significant amounts of capital to overcome, it is a good bet that only the largest and most experiencedcompanies will participate including those that have already launched biosimilars in Europe: Teva, the world’s largest genericdrug manufacturer; Sandoz, the generic division of Novartis, and Hospira, the largest supplier of injectable pharmaceuticalsin the US, are the names most frequently mentioned. Recently, some U.S. brand name drug competitors have announcedtheir interest in biosimilars as well. Amgen established a partnership with Watson to develop generic versions of cancerdrugs, Baxter paid Momenta Pharmaceuticals to develop six biogeneric drugs, and Biogen and Samsung set up a newbiosimilar joint venture.4

Several other big pharma companies have recently filed legal actions to prevent or delay biosimilars from entering the USmarket. This past April Abbott Laboratories filed a citizen’s petition with the FDA asking the agency not to approve anybiosimilars for its rheumatoid arthritis blockbuster drug, Humira. Abbott’s argument is that for a generic biosimilar to getapproved would mean that the FDA would have no choice but to utilize trade secrets that Abbott supplied in their originalHumira BLA application.

Separately, Amgen recently announced it has a new patent protecting the blockbuster anti-inflammatory drug Enbrel, whichcould protect it from generic rivals for another 17 years. Enbrel had been expected to fall off patent in October of next year.

Just how much and how soon the American consumer will benefit from the introduction of biosimilars into the US remainsan open question that may takes years to answer.

Footnotes:(1) http://www.fda.gov/BiologicsBloodVaccines/ResourcesforYou/default.htm(2) Patient Protection and Affordable Care Act (Affordable Care Act). This pathway is provided in the part of the law knownas the Biologics Price Competition and Innovation Act (BPCI Act). Under the BPCI Act, a biological product may bedemonstrated to be “biosimilar” if data show that, among other things, the product is “highly similar” to an already-approvedbiological product.(3) Biosimilars: Big Pharma's Next Big Thing? Amanda Alix - The Motley Fool(4) Fitch: FDA Proposed Guidelines Open the Door to BiosimilarsSource: Business Wire Publication date: 2012-02-10


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