This program provides information on new drugs and biological agents approved during the period 7/1/05 through 6/30/06, including advice to convey to patients to maximize treatment outcomes. Emphasis is on new molecular entity drugs.

Upon completion of this program, the participant should be able to:

1. Match the new drugs/biologicals by generic name, proprietary name, and chemical name when relevant;
2. Identify the indication(s), pharmacologic action(s), and significant pharmacokinetic principles of the drugs/biologicals;
3. Recognize important therapeutic uses of the products;
4. Demonstrate an understanding of adverse effects and toxicity, and significant drug-drug and drug-food interactions for the new drugs/biologicals;
5. Identify the dose range and dosage form(s) available for the new drugs/biologicals; and,
6. Select specific information to convey to patients or their caregivers when counseling on the new drugs/biologicals and/or conditions for which they are indicated.

BACKGROUND

The Center for Drug Evaluation and Research (CDER) arm of the United States Food and Drug Administration (FDA) decides whether to approve a drug to be marketed for a specific indication. The FDA’s Center for Biologics Evaluation and Research (CBER) determines the same for biological agents. This program addresses new molecular entity (NME) drugs and selected new biologicals approved during July 1, 2005 through June 30, 2006. These products are listed in Table 1. Additional continuing pharmacy education programs that discuss other new drugs and interesting biologicals approved in recent years can be found at www.thecesolution.com/ce/index.asp.  

Table 1. New Molecular Entity (NME) Drugs and Biologicals Approved Between 7/1/05 and 6/30/06^223,224

Generic Name // Proprietary Name                 Dosage                                    Date of   (Applicant/Sponsor)                                       Form                                        Approval

Abatacept // Orencia                                          Lyophilized powder (for               12/05
  (Bristol-Myers Squibb)                                      solution) for IV infusion

Alglucosidase alfa // Myozyme                            Solution for IV infusion                4/06
  (Genzyme)

Anidulafungin // Eraxis                                        Solution for IV infusion                2/06
  (Vicuron)

Darunavir // Prezista                                           Tablets                                      6/06
  (Tibotec)

Dasatinib // Sprycel                                            Tablets                                      6/06
  (Bristol-Myers Squibb)

Decitabine // Dacogen                                        Lyophilized powder (for               5/06
  (MGI Pharma)                                                  solution) for IV infusion 

Deferasirox // Exjade                                          Tablets for oral                           11/05
  (Novartis)                                                         suspension 

Hyaluronidase // Hydase                                     Injection                                    10/05
  (PrimaPharm) 

Insulin, human (rDNA) // Exubera                        Dry powder for                              1/06
  (Pfizer)                                                            Inhalation 

Lenalidomide // Revlimid                                     Capsules                                   12/05
  (Celgene) 

Lubiprostone // Amitiza                                       Capsules                                   1/06
  (Sucampo) 

Mecasermin (rDNA origin) // Increlex                    Solution for SC                          8/05
  (Tercica)                                                          injection 

Nelarabine // Arranon                                          Solution for IV                            10/05
  (GlaxoSmithKline)                                            infusion

Nepafenac // Nevanac                                         Ophthalmic suspension              8/05
  (Alcon) 

Quadrivalent Human Papillomavirus                     Vaccine for IM                           6/06
(Types 6, 11, 16, 18) Recombinant                      injection
Vaccine // Gardasil  (Merck & Co) 

Ramelteon // Rozerem^*                                       Tablets                                      7/05
  (Takeda Global) 

Ranibizumab // Lucentis                                     Solution for intravitreal                6/06
  (Genentech)                                                    injection 

Ranolazine // Ranexa                                         Tablets                                      1/06
  (CV Therapeutics) 

Rasagiline // Azilect                                           Tablets                                      5/06
  (Teva) 

Sorafenib // Nexavar                                           Tablets                                      12/05
  (Bayer Pharmaceuticals) 

Sunitinib // Sutent                                              Capsules                                   1/06
  (Pfizer) 

Varenicline // Chantix                                         Tablets                                      5/06
  (Pfizer)_______________

Approval does not necessarily correlate with drug product availability. While approval is a function of the FDA, product availability (marketing) is a function of the agent’s manufacturer/distributor. Thus, the products listed in Table 1 may or may not have been released into therapy at the time this monograph was prepared.

This monograph presents information that must be restrictive in scope, as it is intended only to provide a brief introduction to a limited number of newly approved products. The reader is urged to consult each product’s prescribing information leaflet (package insert) and other references for further details. Such labeling may include outcomes of comparative clinical trials.

CONTENTS

Infection Control: Anidulafungin, Darunavir, Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine

Cancer Therapy: Dasatinib, Decitabine, Lenalidomide, Nelarabine, Sorafenib, Sunitinib

            Endocrine Modifiers: Insulin, human (rDNA) for inhalation, Mecasermin

            Central Nervous System Drugs: Rasagiline, Varenicline

Ophthalmic Products: Nepafenac, Ranibizumab

Other Treeatments: Abatacept, Alglucosidase, Deferasirox, Hyaluronidase, Lubiprostone, Ranolazine

INFECTION CONTROL

ANIDULAFUNGIN (Eraxis)

Fungal Infections

Pathogenic fungi in humans are saprophytes.—they live on dead or decaying organic matter. They cause infection when airborne spores invade the tissue of the lungs or paranasal sinus, or when hyphae (fungal filaments) or spores are inadvertently inoculated into the skin or cornea. Acquiring an infection from another person is extremely rare, except for ringworm. Therefore, hospitalized patients with fungal infections do not usually require special isolation. Candida albicans normally inhabits the mouth and intestine; it rarely reaches deeper tissues, but infection can occur when mucosal or cutaneous barriers are damaged by disease, surgery, trauma, or catheterization. Fungal infection may impart partial protection against reinfection. People living in areas where fungal organisms are endemic are less subject to infection than newcomers into the area.

Epidemiology.—C albicans is the most common cause of mucosal candidiasis, being responsible for about half of all cases of Candida infections.¹ Other Candida species of importance are C glabrata, C parapsilosis, and C tropicalis, all of which are generally less susceptible to conventional antifungal agents. Candidiasis is a general term that describes a number of clinical syndromes caused by Candida. Considered together, the Candida species constitute the leading causes of nosocomial (hospital or institutionally acquired) blood infections in the United States. Candidiasis is often preceded by increased Candida colonization (superinfection) due to broad-spectrum antibiotic therapy. Oropharyngeal thrush is especially prone to occur in neonates and individuals with diabetes mellitus or HIV infection, and is common in persons with poorly fitting dentures. Vulvovaginal candidiasis is common during the third trimester of pregnancy. Candida can enter the urinary tract through an indwelling bladder catheter. Cutaneous candidiasis usually involves macerated skin, such as that in the diapered area of infants. The organism can pass from the colonized surface into blood (candidemia) or deep tissue when the integrity of the mucosa or skin is violated, as, for example, by perforation of the gastrointestinal tract through trauma, surgery, peptic ulceration, or by mucosal damage due to cytotoxic drug therapy used for treating cancer. Although Candida is not a normal constituent of the skin, secretions from the mouth, rectum, or vagina, as well as drainage from surgical wounds or tracheostomy sites, can contaminate the hub or entrance site of a catheter in an umbilical or central vein. Intravenous drug abuse or third-degree burns are additional conditions that can lead to deep candidiasis.²

Esophageal candidiasis is one of the most common deep-seated candidal infections and is often asymptomatic. It can cause substernal pain or a sense of obstruction on swallowing, and may be mistaken for pain of cardiac origin. It is often associated with significant morbidity but is seldom fatal. Most lesions occur in the distal third of the esophagus, appearing on endoscopy as areas of redness and edema, focal white patches, or ulcers. Esophageal candidiasis can cause bleeding and impaired gastrointestinal function.

Invasive fungal infections constitute one of the most important causes of morbidity and mortality in immunocompromised patients and hematopoietic stem cell transplantation recipients. Over the past quarter century, the incidence of invasive fungal infections increased markedly, as much as 25% in hematopoietic stem cell transplantation recipients, and up to 50% in HIV-infected persons. C albicans along with Aspergillus species account for the majority of cases.

Eraxis

Historically, the mainstay for management of invasive fungal infections has been amphotericin B (Fungizone, others). A broad-spectrum antifungal with potent fungicidal activity, amphotericin B has a serious toxicity profile. A search has been under way over the years for effective but less toxic antifungals.² The azole derivatives, itraconazole and fluconazole, were introduced in the 1980s; however, their use, despite widespread acceptance, has been limited by their narrow spectra of activity and increasing concern regarding the emergence of azole-resistant Candida species. More recently, drug development has focused on a new class of antifungals, the echinocandins (“candins”), which includes caspofungin (Cancidas) and micafungin (Mycamine),³ and now, anidulafungin, a semisynthetic cyclic lipopeptide¹ that offers an alternative therapy for several types of infections.⁴ The echinocandin antifungals have shown superb clinical efficacy and a more favorable adverse-event profile compared to older antifungal agents.⁵

Mechanism of action/microbiology.—Anidulafungin is a noncompetitive inhibitor of 1,3-β-D-glucan synthase, a fungus-specific enzyme complex that is required for synthesis of 1,3-β-D-glucan, an essential component of fungal, but not mammalian, cell walls.^6,7 The fungal cell wall provides shape and stability and serves as a protective barrier against injury and osmotic instability, conditions that can lead to cell lysis and fungal cell death.⁸ It also possesses adhesive molecules that permit the fungus to attach to and invade the host. Glucan is a fibrillar polysaccharide consisting of three helically entwined linear polymers of glucose. Its presence is critical to fungal cell walls and comprises 30%–60% of Candida cell walls. When 1,3-β-D-glucan synthase is inhibited, the fungal cell wall is deficient in 1,3-β-D-glucan. As a result, its integrity is compromised and cells can become irregularly shaped and swollen. Mature cells may fail to separate from the parent cells and form aberrant buds instead. Anidulafungin exhibits in vitro activity against C albicans, C glabrata, C parapsilosis, and C tropicalis, including strains resistant to fluconazole; Aspergillus; and Pneumocystis.^2,5 Emergence of resistance to anidulafungin has not been studied and it remains active against C albicans that has become resistant to fluconazole. Cross-resistance with other echinocandins has not been substantiated to date. The range of activity of echinocandin antifungals is summarized in Table 2.

Table 2. Range of activity of the echinocandin antifungals²²⁵ 

Highly active

• Candida albicans
• Candida glabrata
• Candida tropicalis
• Candida krusei
• Candida kefyr
• Pneumocystis carinii*

Very active

• Candida parapsilosis
• Candida guilliermondi
• Aspergillus fumigatus
• Aspergillus flavus
• Aspergillus terreus
• Candida lusitaniae

Some activity

• Coccidioides immitis
• Blastomyces dermatididis
• Scedosporium spp
• Paecilomyces variotii
• Histoplasma capsulatum

Inactive

• Zygomycetes
• Cryptococcus neoformans
• Fusarium spp
• Trichosporum spp

_________________________
^*Only active against cyst form, and probably only useful for prophylaxis.

Adverse effects.—Histamine-mediated symptoms have been reported, including rash, urticaria, flushing, pruritus, dyspnea, and hypotension. These events are rare when the rate of infusion is less than 1.1 mg/min.

Drug safety was assessed in 929 individuals in premarketing clinical trials. A total of 633 patients received anidulafungin at daily doses of 50 or 100 mg. Four hundred eighty-one patients received the drug for ≥14 days. Adverse events included diarrhea; increased ALT, AST, alkaline phosphatases and hepatic enzyme levels; hypokalemia; and deep vein thrombosis.

Drug interactions.—Anidulafungin is eliminated (90%) by slow chemical degradation with less than 10% eliminated as intact drug in the feces.⁷ Thus, it is neither significantly metabolized by human cytochrome P450 or by isolated human hepatocytes, nor significantly inhibits the activities of clinically important human CYP isoenzymes (1A2, 2C9, 2D6, 3A4). It is only moderately bound to plasma proteins. No clinically relevant interactions have been reported with drugs likely to be coadministered with anidulafungin.^7,9

Indications and uses.—Eraxis is indicated for use in the treatment of esophageal candidiasis, candidemia, and other forms of Candida infections (intra-abdominal abscess, peritonitis). The drug has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida, and has not been studied in sufficient numbers of neutropenic patients to assess efficacy in this group. Specimens for fungal culture and other laboratory studies should be obtained prior to therapy. Therapy may be initiated before the results of culturing and other laboratory studies are known. Once these results become available, antifungal therapy should be adjusted accordingly.

Dosage, administration, and availability.—Like other echinocandins, anidulafungin is administered by intravenous infusion. The recommended dose for candidemia and other Candida infections (intra-abdominal abscess, peritonitis) is 200 mg on Day 1, followed by 100 mg daily thereafter. Duration of treatment should be based on the patient’s clinical response; usually, antifungal therapy should continue for at least 14 days after the last positive culture. The recommended dose for esophageal candidiasis is a single 100 mg loading dose on Day 1, followed by 50 mg daily thereafter. The rate of infusion should not exceed 1.1 mg/min. Eraxis should be continued for a minimum of 14 days and for at least 7 days following resolution of symptoms. Because of the risk of relapse of esophageal candidiasis in patients with HIV infections, suppressive antifungal therapy may be considered after a course of active treatment. No dosing adjustments are required for patients with renal or hepatic insufficiency or persons with HIV infection, patients using concomitant medications, or those in other special populations.

Eraxis is supplied in single-use vials containing 50 mg of anidulafungin.

DARUNAVIR (Prezista)

Human Immunodeficiency Virus 

The human immunodeficiency virus (HIV) has been the focus of in-depth scientific inquiry since its identification more than two decades ago as the causative agent for the acquired immune deficiency syndrome (AIDS). HIV is the most widely studied virus in history.¹⁰ The incidence of AIDS in the United States increased rapidly from its onset, peaked in the early 1990s, and then declined somewhat beginning in the mid-1990s.¹¹ Since 1998, however, declines in both incidence and deaths leveled off. Today, the number of persons in the United States living with HIV is increasing, partly due to longer lifespan resulting from effective drug therapy and improved lifestyles. Nonetheless, AIDS results in more than 15,000 premature deaths each year in the United States with more than 2.8 million deaths each year worldwide. The Centers for Disease Control and Prevention (CDC) estimates that approximately 40,000 persons become infected with HIV each year in the United States¹² This includes more than 300 infants per year who contract HIV because their mothers are infected.

Epidemiology.—HIV is transmitted primarily by behaviors that encourage exchange of blood or body fluids containing the virus and/or HIV infected cells. The virus has been identified in blood and blood products, semen, vaginal secretions, breast milk, tears, urine, cerebrospinal fluid, and saliva; however, only HIV in blood, semen, breast milk, and vaginal fluids is a serious source of infection.¹³

The risk of acquiring the infection from a single sexual event is relatively low (Table 3). Transmission via sexual contact depends on the type and frequency of encounters and presence of risk factors such as unprotected sex. The incidence of HIV transmission in persons who do not use condoms or who use them incorrectly is increased significantly, compared with the incidence in persons who do practice protected sex. The greatest per-act risk for HIV transmission is associated with blood transfusion, needle sharing during illicit drug use, receptive anal intercourse, and percutaneous needlestick injuries.¹⁴

^*Estimates of risk for transmission from sexual exposures assume no condom use
^±Refers to oral intercourse performed on a man

Immune defects.—The hallmark of AIDS is a deficiency within the immune system that leads to increased susceptibility to fatal opportunistic infections such as Pneumocystis carinii.¹⁵ This occurs because the virus invades and destroys CD4⁺ lymphocytes (T-helper cells), its primary target. CD4⁺ T-lymphocytes normally assist B cells in producing antibodies, stimulate T-cytotoxic cells (CD8⁺) to lyse virus-infected cells and tumor cells, and activate the body’s macrophages to eliminate intracellular pathogens. Their inactivation and/or destruction compromise cell-mediated and humoral-immunity mechanisms, which in turn increase susceptibility to opportunistic pathogens and lead to death.

A number of factors modify the risk for HIV infection and disease progression (Table 4). Multiple sexual contacts and venereal disease that results in genital ulcers are primary risk factors. Host genetic differences apparently play a role since some individuals do not become infected despite multiple HIV exposures. Age at infection is an important consideration in that a person’s immune response diminishes naturally with increasing age. The presence of other infectious microbials such as cytomegalovirus is an important factor. The strain of HIV may also play a role.

Table 4. Factors that affect HIV infection and disease progression

• Multiple sexual contacts
• Occurrence of other infectious diseases
• Host genetic differences
• Age at infection
• Strain of HIV
• Characteristics of long-term nonprogressors
   - low virus load; small number of infected cells
   - neutralizing antibodies
   - strong activity of CD8⁺ CTL lymphocytes
   - predominance of TH1 lymphocytes

Three distinct stages are recognized in the infection process. The first is the acute phase (also referred to as the diagnostic window or serological latency) that follows immediately after HIV infection. Viral nucleic acid and the HIV p24 antigen can be detected in the host serum but no host antibodies to HIV can be found. The host is therefore seronegative (antibodies to HIV are not present). During this phase, HIV RNA levels in the blood peak at about 6 weeks following infection, then decline. The CD4+ T cell count declines rapidly during the 6 weeks postinfection then begins a slight increase.^16,17

An estimated 40%–90% of patients acutely infected with HIV will experience symptoms of acute retroviral syndrome (Table 5).^18,19 However, acute HIV infection is often not recognized by primary care clinicians because of the similarity of its symptoms to those of influenza, infectious mononucleosis, or other illnesses. Additionally, acute infection can occur asymptomatically.²⁰

Antibodies to HIV can usually be detected about 6–8 weeks postinfection but may not be observed until 3 months postinfection.¹⁶ Appearance of host antibodies is referred to as seroconversion. This marks the beginning of the second (chronic) stage of infection. The host antibody response to the virus matures during this stage to result in increasing titres of antibody over the next several years. HIV RNA concentrations in the blood remain stable and the host CD4+ T cell count begins to fall steadily.¹⁷

The third stage of HIV infection is marked by onset of clinical AIDS. This stage is distinguished by clinical symptoms associated with immunodeficiency that include the onset of opportunistic infections such as Pneumocystis carinii, as mentioned earlier, and/or other bacterial, viral, or fungal infections.

Prezista

Darunavir was approved to be taken concurrently with ritonavir (Norvir) by patients with HIV strains that are resistant to more than one protease inhibitor.^21-24 Ritonavir inhibits hepatic cytochrome P450 CYP3A enzymes, the intestinal P-glycoprotein efflux pump, and possibly intestinal CYP3A, such that there is a significant increase in blood levels of darunavir when coadministered with ritonavir, compared with darunavir administered alone.

Mechanism of action/microbiology.—The enzyme protease is required for HIV infectivity. Protease cleaves the viral (Gag-Pol) polyproteins into active viral enzymes (reverse transcriptase, protease, and integrase) and structural proteins. All protease inhibitors, including darunavir, bind reversibly to the active site of protease to prevent it from cleaving the viral precursor polyproteins, and thereby block subsequent viral maturation.^25,26 Infected cells that are subjected to a protease inhibitor produce viral particles that are immature and noninfectious; therefore, HIV is checked.^27,28

Adverse effects.—The most common adverse events reported in premarketing clinical trials were diarrhea, nausea, headache, and nasopharyngitis. Due to the need for coadministration of Prezista with 100 mg of ritonavir, adverse effects associated with ritonavir must be considered. Because it contains a sulfur moiety, Prezista should not be taken by patients allergic to sulfonamide derivative drugs.

Drug interactions.—Prezista and ritonavir both inhibit CYP3A. Coadministration of Prezista and ritonavir with drugs that are primarily metabolized by CYP3A may therefore result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events. The package insert should be consulted for in-depth information on the extensive list of interactive drugs.

Coadministration of Prezista is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (eg, those with a narrow therapeutic index). These drugs include dihydroergotamine, ergonovine, ergotamine, methylergonovine, pimozide, midazolam, and triazolam. The manufacturer also warns against taking St. John’s wort. Included on the product’s bottle label is the statement to patients and health care professionals: “Find out about medicines that should not be taken with Prezista.”

Indications and uses.—Prezista, coadministered with 100 mg ritonavir, and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus infection in antiretroviral treatment–experienced adult patients, such as those with HIV-1 strains resistant to more than one protease inhibitor.

Dosage, administration, and availability.—The recommended dose of Prezista is 600 mg (two 300-mg tablets) twice daily along with ritonavir 100 mg twice daily and with food. The tablets should be swallowed whole with liquid such as water or milk and not be crushed or chewed, just before eating food.

There are no data regarding the use of Prezista in patients with varying degrees of hepatic impairment; therefore, specific dosage recommendations cannot be made. No dose adjustment is required in patients with moderate renal impairment. There are no pharmacokinetic data available in HIV-1 infected patients with severe renal impairment or end-stage renal disease. When administered with food, the C_max and AUC of darunavir, coadministered with ritonavir, are approximately 30% higher relative to the fasting state. Therefore, Prezista tablets should always be taken with food.

Prezista is available as oval-shaped, film coated tablets containing darunavir ethanolate equivalent to 300 mg of darunavir per tablet. Prior to opening the bottle, Prezista should be stored in a refrigerator. After opening, the tablets may be stored at room temperature but must be used within 60 days.

QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (Gardasil)

Human Papillomavirus Infection

The human papillomavirus (HPV) group represents approximately 100 small DNA viruses that infect stratified squamous epithelium in different areas of the body. One group, the cutaneous HPV, leads to hand and plantar warts. Another group of approximately 40 types of HPV can infect the mucosal and cutaneous surfaces of the anogenital tract and the oropharynx and upper airways.²⁹ Most infections are asymptomatic,³⁰ although HPV can cause medical problems that range from benign anogenital warts to invasive cancer, especially uterine cervical cancer.

It is now accepted that HPV infection is necessary for development of virtually all cervical squamous cell carcinomas and adenocarcinomas.^31,32 Most genital HPV infections occur through sexual intercourse, shortly after onset of sexual activity. There is a 50% risk within 5–7 years of the first sexual contact, with a 70% lifetime risk.³³ Most HPV infections are transient, however, and only 3%–10% of women who have a persistent infection with HPV contract cervical cancer.³²

Cervical cancer holds the distinction of being the second most common cancer in women worldwide, and the most frequent in developing countries.³¹ It is the eleventh most common cancer among women in the United States, with an estimated 10,370 new cases and 3710 deaths in 2005. (The most prevalent cancer in the world is breast cancer.) Eighty-three percent of new cases occur in developing countries.³⁴ Cervical cytology (ie, the Papanicolaou [“Pap”] test) has been the basis for preventing cervical cancer,^33,35 because invasive cervical cancer typically is preceded by incremental grades of dysplasia or incipient cancers called cervical interepithelial neoplasias (CIN). Low-risk HPV types, including HPV types 6 and 11, the primary cause of anogenital warts, are mainly associated with low-grade CIN and other squamous cell abnormalities. In contrast, high-risk HPV, including types 16, 18, 31, 33, 35, 45, 51, 52, 56, 58, 59, and 66, are preferentially associated with high grade CIN (CIN 2/3). HPV types 16 and 18 are responsible for 71% of cervical cancers; the seven next most common types cause an additional 19%.

Used correctly, cervical cytology screening is effective for detecting CIN before it progresses to cancer.³² However, it is associated with emotional distress and estimated financial costs of $6 billion a year in the United States alone.³⁶ A vaccine to protect against genital HPV would therefore add greatly to cervical cancer prevention and be a cost-effective use of health care resources.

Gardasil 

Gardasil is a noninfectious recombinant, quadrivalent vaccine prepared from the highly purified virus-like particles (VLPs) of the major capsid protein of HPV Types 6, 11, 16, and 18. These proteins are produced by separate fermentations in recombinant Saccharomyces cerevisiae.^37,38 Gardasil is reported to be 95%–100% effective against HPV Types 6, 11, 16, and 18.

Mechanism of action.—HPV is specific for humans, but animal studies with papillomaviruses suggest that the efficacy of the VLP vaccines is attained through development of humoral immune responses. Gardasil prevents HPV 6-, 11-, 16-, and/or 18-related cervical cancer, cervical dysplasias, vulvar or vaginal dysplasias, or genital warts.³⁸

Adverse effects.—In premarketing clinical trials, vaccine-related adverse experiences included pain, swelling, erythema, pruritus, and fever.

Indications and uses.—Gardasil is a vaccine indicated in girls and women 9–26 years of age for the prevention of the following diseases caused by Human HPV types 6, 11, 16, and 18:

·                    Cervical cancer

·                    Genital warts (condyloma acuminata) and the following precancerous or dysplastic lesions:

·                    Cervical adenocarcinoma in situ

·                    Cervical intraepithelial neoplasias grade 2 and grade 3

·                    Vulvar intraepithelial neoplasias grade 2 and grade 3

·                    Vaginal intraepithelial neoplasias grade 2 and grade 3

·                    Cervical intraepithelial neoplasias grade 1

The vaccine does not protect against diseases that are not caused by HPV. Individuals with impaired immune responsiveness—whether due to use of immunosuppressive therapy, a genetic defect, HIV infection, or other causes—may have reduced antibody response to active immunization.

As is true of other intramuscular injections, Gardasil should not be given to individuals with bleeding disorders, including hemophilia or thrombocytopenia, or to others using anticoagulant therapy unless the potential benefits from the vaccine clearly outweigh the risk of administration. If the decision is made to administer Gardasil to such individuals, it should be given cautiously with measures to avoid the risk of hematomas.

Dosage, administration, and availability.—Gardasil is given intramuscularly as 3 separate doses: first dose at elected date, second dose 2 months after the first dose, and third dose 6 months after the first dose. Injections should be administered in the deltoid region of the upper arm or in the higher anterolateral area of the thigh. Gardasil should not be injected intravascularly. Gardasil is available in 0.5-mL single-use vials.

CANCER THERAPY

Progress in Cancer Control

Prevention and treatment of cancer are among the nation’s most urgent health concerns. Cancer is the second leading cause of death behind heart disease in the United States, and the disease that many people fear most. More than 1.3 million new cancer cases will be diagnosed in the United States this year and more than a half million people will die from the direct or indirect effects of cancer or its complications.³⁹

At the same time, there is good news. Nearly 10 million people in the United States today are living with a cancer history. Of this group, 1.5 million were diagnosed more than 20 years ago. This means that people with cancer are living longer today than in the past.⁴⁰ Their quality of life is also improved greatly. More than two-thirds of people with cancer can now expect to live 5 or more years; for children with cancer, their 5-year survival now exceeds 75%.^39,41 Cancer treatment techniques—including chemotherapy, surgery, radiation therapy, and auxiliary treatments—are definitely improving mortality, morbidity, and overall quality of life.

Nonetheless, patients perceive a diagnosis of cancer as one of the most traumatic events that can happen.⁴⁰ Separate from prognosis, a diagnosis brings with it an altered self-image and perception of his or her role in the home and workplace. A person who has just been diagnosed with pancreatic cancer has the same prognosis as that of a person with aortic stenosis who experiences the initial symptoms of congestive heart failure (median survival about 8 months). The patient with heart disease may remain functional and maintain a self-image as a fully intact person who has only a malfunctioning or diseased organ. The patient with pancreatic cancer, by contrast, has a completely altered self-image. He or she is often viewed differently by family and anyone who knows the diagnosis. He or she is being invaded by a pathology that could be anywhere in the body, so every ache or pain is significant.

Risk.—The greatest risk factor for cancer overall is age. Two-thirds of all cases are in persons over age 65. For the interval between birth and age 39 years, 1 in 72 men and 1 in 51 women will develop cancer; for the interval between ages 40 and 59, 1 in 12 men and 1 in 11 women will develop cancer; and for the interval between ages 60 and 79, 1 in 3 men and 1 in 5 women will develop cancer.⁴⁰

DECITABINE (Dacogen) AND LENALIDOMIDE (Revlimid)

Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) is a term that collectively describes a heterogeneous group of bone marrow disorders characterized by production of immature and abnormally functioning blood cells.⁴² An estimated 7,000–12,000 new cases of MDS are diagnosed in the United States each year,⁴³ indicating they are at least as common as chronic lymphocytic leukemia, the most common form of leukemia in the Western world. The highest prevalence of MDS is in older patients;⁴⁴ the median age at onset in the United States is the mid- to late-60s. The true incidence and prevalence of MDS are uncertain since cancer registries often fail to include them.⁴² Survival rates range from 6 months to many years for the different MDS subtypes.

Most patients with MDS are asymptomatic early in their disease and their condition is discovered on a routine blood count. Others are symptomatic with anemia. Anemia is frequently macrocytic but refractory to treatment with folate and vitamin B₁₂. Neutropenia and/or thrombocytopenia, alone or in combination, may be present initially or appear later. Examination of the blood shows morphologic abnormalities such as hypogranulated neutrophils with hyposegmented nuclei and large platelets. Bone marrow is usually cellular with various morphologic abnormalities. Twenty percent of patients, however, have bone marrow that is hypoplastic—similar to that in aplastic anemia.

It is hypothesized that the MDS group are clonal disorders of hematopoietic stem cells that evolve into acute myeloid leukemia. According to this view, clonal transformation occurs at the level of a committed myeloid stem cell that can transform into erythrocytes, platelets, and granulocytes and monocytes. Families have been reported, although rare, with an inherited genetic predisposition and multistep progression to MDS.⁴⁵ Whether idiopathic MDS is a true proliferation of multipotent stem cells, however, is unknown. The biologic hallmark of these stem cells in MDS is a defective capacity for differentiation and self-renewal. The outcome of this abnormality is probably amplified in elderly persons because the aging process itself may not only deplete stem cells but also modify the marrow microenvironment. This is especially relevant in persons with occupational or environmental exposure to chemical and physical hazards. MDS results in death from bleeding and infection in the majority of patients.⁴²

Dacogen

Dacogen is a NME drug granted orphan status. Drugs with this categorization are developed to treat rare diseases or conditions (in the United States) in cases numbering 200,000 or less.⁴³

Mechanism of action.—Following phosphorylation, decitabine is incorporated into DNA where it inhibits DNA methyltransferase.⁴⁶ This results in hypomethylation of DNA and cellular differentiation or apoptosis (programmed cell death). Decitabine-induced hypomethylation in neoplastic cells is believed to restore normal function to genes that are critical for controlling cellular differentiation and proliferation. Nonproliferating cells are relatively insensitive to decitabine.⁴⁶

Adverse effects.—In premarketing clinical trials, the most common adverse reactions included neutropenia and thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia. Complete blood and platelet counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle.

Drug interactions.—Formal drug interaction studies with decitabine have not been conducted. In vitro studies utilizing liver microsomes suggest that the drug is unlikely to inhibit or induce cytochrome P450 enzymes. The study results show that decitabine is not a substrate for cytochrome P450 enzymes. Moreover, plasma protein binding is negligible (<1%); thus, interactions due to displacement of more highly protein bound drugs from their binding sites on plasma proteins are not expected.

Indications and uses.—Dacogen is indicated for treatment of patients with MDS including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and Intermediate-1, Intermediate-2, and High-risk International Prognostic Scoring System groups.

Dosage, administration, and availability.—The recommended dose is 15 mg/m² by continuous intravenous infusion over 3 hours, repeated every 8 hours for 3 days. Patients may be premedicated with standard anti-emetic therapy. The 3-day cycle should be repeated every 6 weeks. Patients should be treated for a minimum of 4 cycles; however, a complete or partial response may take longer than 4 cycles. Treatment may be continued as long as the patient continues to benefit. Following administration of the recommended dosage for the first cycle, dosage for subsequent cycles should be adjusted as needed. Dacogen is supplied as a sterilized powder for injection in single-dose vials containing 50 mg of decitabine.

Revlimid

Thalidomide has been used in treating MDS because of its effect to inhibit angiogenesis, but a response takes several weeks, and its neurotoxicity limits its use.⁴⁴ Lenalidomide, a thalidomide analogue, is less toxic and better suited for long-term use.

Mechanism of action.— The precise mechanism of action of lenalidomide is unknown.⁴⁷ The drug possesses immunomodulatory and antiangiogenic properties. It inhibits secretion of pro-inflammatory cytokines and increases secretion of anti- inflammatory cytokines from peripheral blood mononuclear cells. Lenalidomide inhibits cell proliferation with varying effectiveness in some but not all cell lines. Of those tested, lenalidomide inhibited growth of Namalwa cells (a human B cell lymphoma cell line with a deletion of one chromosome 5) but was much less effective in inhibiting growth of other cell lines without chromosome 5 deletions. It inhibited expression of cyclooxygenase-2 (COX-2) but not COX-1 in vitro.⁴⁷

Adverse effects.—A total of 148 patients received at least one dose of 10 mg lenalidomide in a clinical trial. All patients experienced at least one adverse event. The most frequently reported events were related to blood and lymphatic system disorders, skin and subcutaneous tissue disorders, gastrointestinal pathology, and general disorders and administrative site conditions.

Thrombocytopenia and neutropenia were the most frequently reported adverse events.⁴⁸ The next most common included diarrhea, pruritus, rash, and fatigue. Eighty percent of patients required a dose delay or reduction during the major study for the indication. Thirty-four percent of patients required a second dose delay or reduction. Patients on lenalidomide therapy should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter, and may require dose interruptions and/or reduction. They may require use of blood product support and/or growth factors.

Patients should seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with Revlimid may lessen the potential for venous thromboembolic events. The decision to take prophylactic measures should be done carefully after assessing individual risk factors.

Since it is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects, Revlimid may cause fetal harm when administered to a pregnant female. Females of childbearing potential should be advised to avoid pregnancy while on Revlimid. Two effective contraceptive methods should be used throughout therapy, including during therapy interruptions and for at least 4 weeks after completing a course.

Drug interactions.—In vitro metabolism studies and nonclinical studies show that Revlimid is not metabolized by and does not inhibit or induce cytochrome P450 enzymes. This suggests that lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions in humans.

Indications and uses.—Revlimid is indicated for treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.

Dosage, administration, and availability.—The recommended starting dose of Revlimid is 10 mg daily. Patients should not break, chew or open the capsules. Dosing is continued or modified based upon clinical and laboratory findings.

Revlimid capsules contain 5 or 10 mg of lenalidomide. Because of its potential toxicity and to avoid fetal exposure to Revlimid, its manufacturer has limited the product’s availability to a restricted distribution program called “RevAssist.” The restrictive program requires patients, including female patients undergoing mandatory pregnancy testing, to provide informed consent before starting Revlimid. Physicians must check pregnancy tests, limit prescriptions to a one-month mail supply, and report any pregnancies to FDA. Along with the manufacturer, FDA will reevaluate the risk management plan when results of further animal testing for birth defects are completed.

NELARABINE (Arranon)

Leukemia

Formation and development of normal blood cells (hematopoiesis) is a closely regulated symphony of biological events that leads to proliferation and differentiation of hematopoietic stem cells, which then develop into mature peripheral blood cells. Acute leukemia results when one or more malignant events occur during an early stage in the hematopoietic process. Instead of proliferating and differentiating normally, the affected cells continue to proliferate but in an uncontrolled fashion. As a result, immature lymphoid cells (in acute lymphoid leukemia) or myeloid cells (in acute myeloid leukemia) called blasts that normally compose <5% of cells manufactured by the bone marrow, accumulate rapidly, and progressively replace normal cells within bone marrow. The outcome is diminished production of normal erythrocytes, leukocytes, and thrombocytes. This, in turn, leads to the familiar clinical complications of leukemia: anemia, infection, and hemorrhage. With time, the leukemic blasts enter the bloodstream and eventually invade normal organs; they concentrate in the lymph nodes, spleen, liver, and other vital tissues. Left untreated, acute leukemia is rapidly fatal with most patients dying within several months to a year of diagnosis.

Acute lymphoblastic leukemia (ALL) affects children, accounting for approximately one-fourth of cancer diagnoses among people younger than age 15 years, and is the second leading cause of death in children in this age group. Caucasian children are affected more frequently than African-American children. There is little difference in incidence rates by gender among children. In older age groups, ALL occurs more commonly in males. Its occurrence peaks between ages 2 and 10 years. It then undergoes a second, more gradual increase in frequency later in life.⁴⁹ An estimated 2,400 children and 1,200 adults are diagnosed with ALL in the United States each year. Approximately 700 of these patients have T–cell-ALL (T-ALL).⁵⁰ ALL can be divided into several forms based on cell surface antigen expression. The five most common forms are early pre-B-cell, pre-B-cell, B-cell, T-cell, and null-cell ALL. T-ALL is less common with increasing patient age, being truly rare in patients exceeding 60 years of age.⁵¹

Non-Hodgkin’s Lymphoma

Non-Hodgkin’s lymphomas are cancers that affect the lymphatic system, particularly lymphocytes. Lymphoblastic lymphoma (LBL) is an especially aggressive form of non-Hodgkin’s lymphoma that occurs more often in children than adults. Patients with predominantly nodal disease who have minimal or no involvement of bone marrow are frequently classified as having lymphoblastic lymphoma, whereas persons with more than 25% of neoplastic cells in the marrow are described as having lymphoblastic leukemia.^52,53 These distinctions are arbitrary and as a rule, reflect the stage of disease rather than different diagnoses. The pathological basis for this is not understood. Of an estimated 50,000 Americans diagnosed with non-Hodgkin’s lymphoma each year, approximately 900 have T-cell LBL (T-LBL).⁵⁰

There is significant biological and clinical overlap between cancers diagnosed as ALL and LBL. Some patients have predominantly lymphomatous involvement (eg, presence of a mediastinal [area between the two lobes of the lungs] mass or other solid lesion).⁵⁴ Most however have, or later, develop marrow involvement. In a similar fashion, patients who present with leukemia may have or develop extramedullary tumors. Both lymphoblastic leukemia and lymphoblastic lymphoma can therefore be considered the same disease with different clinical characteristics.⁵²

Arranon

The FDA approved a NME drug for use in treatment of two rare but very aggressive malignancies: T-ALL and T-LBL.^50,55 Before this agent’s approval, there was no standard of treatment for these patients and their prognosis was particularly poor.

Mechanism of action.—Arranon is a T-cell-selective cytotoxic deoxyguanosine prodrug that is demethylated by adenosine deaminase into ara-G, then mono-phosphorylated by deoxyguanosine kinase and deoxycytidine kinase, and subsequently converted to the active 5′-triphosphate, ara-GTP. Ara-GTP accumulates in leukemic blasts as a fraudulent nucleoside triphosphate where it competes with the native substrate for incorporation into DNA by DNA polymerase.^56,57 This disrupts DNA synthesis, thus inducing cellular apoptosis. Additional cytotoxic actions, including inhibition of RNA synthesis and ribonucleotide reductase, may contribute to the drug’s overall activity but these actions are not fully understood.^58,59

Adverse effects.—Arranon was evaluated for safety in Phase I and II clinical trials. The safety profile is based on data from 103 adults and 84 children. The most common adverse events in children included hematologic disorders (anemia, leukopenia, neutropenia, and thrombocytopenia). The most frequent nonhematologic adverse events reported were headache, vomiting, increased transaminase and bilirubin levels, and decreased potassium and albumin levels.

The most common adverse events in adults were fatigue; gastrointestinal disorders (nausea, diarrhea, vomiting, and constipation); hematologic disorders (anemia, neutropenia, and thrombocytopenia); respiratory disorders (cough and dyspnea); nervous system disorders (somnolence and dizziness); and fever. Blurred vision was reported in 4% of adult patients.

Arranon is a potent chemotherapeutic drug that has potentially significant toxic side effects. The product’s label contains a “boxed warning” (Figure 1) that describes its potential to cause neurotoxicity, the dose-limiting outcome. Common signs and symptoms of neurotoxicity include ataxia (loss of muscle coordination), confusion, convulsions, drowsiness, and tingling and/or numbness in the fingers and toes. Full recovery following severe neurologic toxicity may not occur with cessation of therapy. Patients treated previously or concurrently with intrathecal chemotherapy or previously with craniospinal irradiation may be at increased risks for neurologic damage.

Figure 1. Boxed WARNING for Arranon⁶⁰

Drug interactions.—Arranon and ara-G have been shown to not significantly inhibit the activities of the human hepatic cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4. Fludarabine (Fludara) administered by infusion does not affect the pharmacokinetics of Arranon, ara-G, or ara-GTP.

Indications and uses.—Arranon is indicated for treatment of patients with T-ALL and T-LBL whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens. This use is based on the induction of complete responses. The term complete response (or complete remission) is defined as the disappearance of all signs of cancer in response to treatment. Studies to confirm increased survival or other benefit from drug treatment have not been conducted.

Dosage, administration and availability.—The recommended pediatric dose is 650 mg/m² administered intravenously over 1 hour daily for 5 consecutive days, repeated every 21 days. The adult dose is 1,500 mg/m² administered intravenously over 2 hours on days 1, 3, and 5, repeated every 21 days.

The appropriate dose of Arranon should be transferred into polyvinyl chloride (PVC) infusion bags or glass containers and administered undiluted. The drug is stable in these bags and containers for up to 8 hours at 30^° C. The recommended duration of treatment has not been established. During clinical trials, treatment was generally continued until there was evidence of disease progression or unacceptable toxicity, or the patient became a candidate for bone marrow transplantation or no longer derived benefit from treatment. Appropriate measures (eg, hydration, urine alkalinization, and prophylaxis with allopurinol) must be instituted to prevent hyperuricemia or tumor lysis syndrome.^60,61

Patients with severe renal impairment (CL_CR <30 mg/dL) or severe hepatic impairment (bilirubin >3.0 mg/dL) should be monitored closely for toxicity when treated with Arranon. Immunocompromised patients should not receive vaccines containing live microbials. Because Arranon is cytotoxic, caution, including proper aseptic technique, should be used during handling and preparation. Wearing rubber gloves and other protective clothing to prevent skin contact is recommended.

Arranon is supplied as a clear, colorless, sterile solution for intravenous infusion. The solution contains 5 mg of nelarabine per mL.

DASATINIB

Chronic Myelogenous (Myeloid) Leukemia

The myeloid leukemias are a heterogeneous group of cancers characterized by infiltration of blood, bone marrow, and other tissues by neoplastic cells of the hematopoietic system. The estimated number of new myeloid leukemia cases in the United States in 2004 was 16,520. They consist of a number of malignancies that range from rapidly fatal to slowly growing. Based on their untreated course, the myeloid leukemias are designated acute or chronic. In the United States, chronic myelogenous leukemia (CML) is diagnosed in about 4,600 people annually.⁶² The age-adjusted incidence is higher in men than in women (2.0 versus 1.2). The incidence of CML increases slowly with age until the mid-40s, when it begins to rise rapidly (Figure 2).^63,64

Figure 2. Age-specific incidence rate of chronic myeloid leukemia (1995-1998) increases with age.⁶³

CML is characterized by a balanced translocation between the long arms of chromosomes 9 and 22, called the Philadelphia chromosome (Ph) abnormality.^65,66 At the clinical level, CML runs a biphasic or triphasic course.⁶⁷ Approximately 90% of patients are diagnosed in the chronic phase and have a median survival of close to 5 years. Unless the disease is controlled or eliminated, patents eventually transform to a terminal or blastic phase of CML. The prognosis for these patients is poor, with a median survival of 3–6 months. Two-thirds of cases go through an intermediate accelerated phase. Their median survival is 1–2 years. Although these three CML phases are distinct and well recognized, the criteria that define them vary greatly.⁶⁷

Progression of CML is associated with worsening symptoms. Unexplained fever, significant weight loss, increasing dose requirement of the drugs controlling the disease, bone and joint pain, bleeding, thrombosis, and infections suggest transformation into accelerated or blastic phases. Fewer than 10%–15% of newly diagnosed patients present with accelerated disease.⁶⁸

Sprycel

Sprycel was approved as an orphan drug for each of its indications.⁶²

Mechanism of action.—Dasatinib inhibits a variety of tissue kinases.⁶⁹ In vitro, the new drug is active in leukemic cell lines that are not sensitive to or have become resistant to imatinib mesylate (Gleevec). Dasatinib inhibits the progression of CML and ALL.

Adverse effects.—The majority of dasatinib-treated patients in premarketing clinical trials experienced adverse drug reactions some time during therapy. The most frequently reported adverse events included fluid retention events such as pleural effusion; gastrointestinal events including diarrhea, nausea, abdominal pain and vomiting; and bleeding episodes. The most frequently reported serious adverse events included pyrexia, pleural effusion, febrile neutropenia, gastrointestinal bleeding, pneumonia, thrombocytopenia, dyspnea, anemia, cardiac failure, and diarrhea.

Severe thrombocytopenia, neutropenia, and anemia are possible outcomes of therapy. They occur more frequently in patients with advanced CML than in chronic phase CML. Complete blood counts should be performed weekly for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression is generally reversible and usually managed by withholding Sprycel temporarily or with dose reduction.

In addition to thrombocytopenia, the drug causes platelet dysfunction in vitro. Severe CNS hemorrhage, including fatalities, occurred in 1% of patients. Severe gastrointestinal hemorrhage occurred in 7% of patients and generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 4% of patients.

Sprycel is associated with fluid retention, including pleural and pericardial effusion and pulmonary edema, and it can be severe. The agent als