Pocket Drug Guide

Posts Tagged ‘United States’

Following the entrance of the protein tyrosine kinase inhibitor imatinib (Novartis’ s Gleevec/Glivec) into the chronic myelogenous leukemia marketplace in 2001, the agent dramatically transformed the market, and protein tyrosine kinase inhibitors have dominated research and development in the field ever since. Since 2001, imatinib has entirely replaced interferon-a as the agent against which all potential newcomers are measured. Several agents that were trialed against interferon-a prior to the launch of imatinib have had to be reevaluated for synergism with imatinib or for activity in imatinib-refractory patients — indeed, the high and durable response rates imatinib has achieved have caused several companies to discontinue development of competing therapies. However, imatinib’s shortcomings define the nature and extent of unmet needs in the treatment of chronic myelogenous leukemia.

The leaders among the emerging therapies for chronic myelogenous leukemia are the protein tyrosine kinase inhibitors BMS-354825 and AMN-107, under development by Bristol-Myers Squibb and Novartis, respectively. Other novel promising agents include the heat-shock protein (HSP) inhibitors, peptide vaccines, farnesyl transferase inhibitors (FTIs), and hypomethylating agents. TABLE:Emerging Therapies in Development for Chronic Myelogenous Leukemia lists the emerging therapies’ stages of development.

Other drugs in development for the treatment of chronic myelogenous leukemia include rapamycin analogues, histone deacetylase inhibitors (HDACIs) such as suberoylanilide hydrox-amic acid (SAHA), and anti-bcl-2 antisense oligonucleotides.

A preclinical study has reported that the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, synergized with imatinib against BCR-ABL-positive myeloid and lymphoid cells and increased survival in a murine chronic myelogenous leukemia model. In addition, rapamycin + imatinib combinations inhibited imatinib-resistant mutants of BCR-ABL.

The possibility of combining HDACIs with the HSP-90 antagonist 17-AAG was raised in a recent study as a novel strategy against BCR-ABL-positive leukemias, including those resistant to imatinib.

Companies developing agents for chronic myelogenous leukemia may apply for orphan drug status for their molecule in any of the major markets. Orphan drug status was introduced in 1983 to give pharmaceutical companies a financial incentive to develop products to treat rare diseases. In the United States, a condition is considered rare if it affects fewer than 200,000 people in the country. Manufacturers of compounds with orphan drug status receive several benefits: seven years of market exclusivity if the product is subsequently approved, a federal tax credit for clinical research costs, exemption from the FDA registration fee, and protocol assistance. They may also be eligible for additional grants. The introduction of orphan drug status has dramatically increased the number of drugs being developed to treat rare conditions.

TABLE . Emerging Therapies in Development for Chronic Myelogenous Leukemia

Compound	Development Phase3	Marketing Company
Protein tyrosine kinase inhibitors
BMS-354825
United States	II	Bristol-Myers Squibb
Europe	II	Bristol-Myers Squibb
Japan	II	Bristol-Myers Squibb
AMN-107
United States	I	Novartis
Europe	I	Novartis
Japan	—	—
Heat-shock protein inhibitors
17-AAG
United States	lb	Kosan Biosciences/NCI/UK Institute of Cancer Research
Europe	—	—
Japan	—	—
Vaccines
AG-858 (HSPPC-70-C)
United States	II	Antigenics
Europe	II	Antigenics
Japan	—	—
PR1 peptide antigen
United States	II	M.D. Anderson Cancer Center
Europe	—	—
Japan	—	—
BCR-ABL fusion peptide vaccine
United States	II	Memorial Sloan-Kettering Cancer Center
Europe	—	—
Japan	—	—
Farnesyl transferase inhibitors
Tipifarnib (R-115777; Zarnestra)
United States	I	Janssen Pharmaceutica/Johnson & Johnson
Europe	—	—
Japan	—	—
Lonafarnib (Sch-66336; Sarasar)		Schering-Plough
United States	I
Europe	—	—
Japan	—	—
Hypomethylating agents
Decitabine (DAC)
United States	II	SuperGen/MGI Pharma
Europe	—	—
Japan	—	—
Antineoplastic agents
Homoharringtonine (Ceflatonin)
United States	II	ChemGenex
Europe	—	—
Japan	—	—
Apoptosis stimulators
Arsenic trioxide (Trisenox)
United States	II	Cell Therapeutics
Europe	—	—
Japan	—	—

^aAgent may be in later stages of development for other indications.

The long median survival of patients with chronic-phase chronic myelogenous leukemia means that initial response rates to investigational drugs are frequently used as surrogate measures of efficacy in clinical trials. These initial response rates have historically been the ability to achieve a complete hematologic response (a white blood cell count between 4,000 and 11,000 per mm³) or complete cytogenetic response (the absence of cells expressing the Philadelphia chromosome). However, because of the success of imatinib at achieving these endpoints, measuring molecular response (a reduction in quantities of BCR-ABL transcripts, as detected by polymerase chain reaction [PCR], is becoming increasingly important for evaluating novel therapies. A complete molecular response occurs when there is no evidence of BCR-ABL transcripts, indicating disease eradication.

Overview

Protein tyrosine kinases (PTKs) are enzymes that catalyze the phosphorylation of tyrosine residues. These enzymes are involved in cellular signaling pathways and regulate key cell functions such as proliferation, differentiation, anti-apoptotic signaling, and neurite outgrowth. Unregulated activation of these enzymes, through mechanisms such as point mutations or overexpression, can lead to various forms of cancer as well as to benign proliferative conditions. More than 70% of the known oncogenes and protooncogenes involved in cancer encode PTKs.

A number of protein tyrosine kinase inhibitors have been developed and approved for cancer treatment. These include inhibitors of c-Abl (imatinib, for treatment of chronic myelogenous leukemia); HER2 (trastuzumab [Genentech/Roche's Herceptin], for treatment of breast cancer); vascular endothelial growth factor receptor (bevacizumab [Genentech/Roche's Avastin], for treatment of metastatic colorectal cancer); and the epidermal growth factor receptor (EGFR) gefitinib (AstraZeneca’s Iressa, also known as cetuximab (ImClone/Merck & Co./BMS’s Erbitux), for treatment of lung and colorectal cancer, respectively.

Mechanism Of Action

The rationale for developing tyrosine kinase inhibitors for the treatment of cancer is based on the observation that tyrosine kinase enzymes are critical components of the cellular signaling apparatus and are regularly mutated or otherwise deregulated in human malignancies. Novel tyrosine kinase inhibitors are designed to exploit the molecular differences between tumor cells and normal tissues. In chronic myelogenous leukemia, affected cells have a consistent cytogenetic abnormality, the Philadelphia chromosome, which carries a BCR-ABL fusion gene encoding a tyrosine kinase oncoprotein. Imatinib mesylate is a specific inhibitor of this oncoprotein.

Imatinib

Imatinib mesylate (Novartis’s Gleevec/Glivec, formerly STI-571) was first launched in the United States in May 2001 for the treatment of blastic- and accelerated-phase chronic myelogenous leukemia and chronic-phase disease after failure of interferon-a therapy. Imatinib had previously been awarded fast-track status for the myeloid blastic phase indication of chronic myelogenous leukemia and granted orphan drug designation in the United States, European Union, and Japan. In December 2002, the FDA approved the product for first-line therapy in all phases of chronic myelogenous leukemia, after data from the imatinib arm of the International Randomized Study of Interferon Versus ST-1571 (IRIS; discussed subsequently) showed high cytogenetic response rates and delay in disease progression, suggesting that imatinib improves long-term survival. The dose of 400 mg per day of imatinib administered orally, the same dose used in the IRIS trial, is considered standard therapy for patients with newly diagnosed chronic myelogenous leukemia in the chronic phase. In February 2002, the FDA also approved imatinib for the treatment of inoperable and metastatic malignant gastrointestinal stromal tumors. The product is also being investigated for the potential treatment of other cancers that express tyrosine kinases, including acute lymphocytic leukemia and certain solid tumors.

Imatinib is a 2-phenylamino-pyrimidine derivative that specifically inhibits the tyrosine kinase activity of the ABL proteins c-ABL and BCR-ABL. The BCR-ABL fusion gene present in chronic myelogenous leukemia encodes an oncoprotein, p210BCR-ABL, that has dysregulated tyrosine kinase activity that is central to the pathogenesis of chronic myelogenous leukemia. Imatinib competitively inhibits the interaction of adenosine triphosphate (ATP) with these oncoproteins, thereby lessening their ability to phosphorylate and activate downstream target proteins.

The initial approval of imatinib was based on data from Phase II studies involving approximately 1,230 patients in 32 centers located in five countries. The trial endpoints included hematologic and cytogenetic response rates. In one study, a total of 532 patients with late chronic-phase chronic myelogenous leukemia in whom previous therapy with interferon-a had failed were treated with 400 mg of oral imatinib daily. Imatinib induced MCRs in 60% (69% of these patients displayed a cytogenetic response) and CHRs in 95% of the patients. The time to onset of an major cytogenetic response ranged from 2.4 months to 19 months, and the median time to a CHR was 0.7 months. After a median follow-up of 18 months, chronic myelogenous leukemia had not progressed to the accelerated or blastic phases in an estimated 89% of patients, and 95% of the patients were still alive. Only 2% of patients discontinued treatment because of drug-related adverse events, and no treatment-related deaths occurred.

Data from some ongoing Phase III IRIS trials demonstrated superior response rates in imatinib-treated patients compared with interferon-a. The IRIS study was the largest study of chronic myelogenous leukemia patients ever conducted, enrolling 1,106 patients (553 randomized to each treatment arm) with newly diagnosed Ph-positive chronic myelogenous leukemia between June 2000 and January 2001 in 16 countries. The study compared imatinib at 400 mg per day with interferon-a plus subcutaneous low-dose cytarabine (LDAC) (IFN+LDAC) as first-line treatments; patients were allowed to cross over to the other treatment arm if they experienced loss of response, lack of response, or intolerance to the treatment. Patients were evaluated for hematologic and cytogenetic responses, toxic effects, and rates of progression.

After a median follow-up, the estimated rate of an major cytogenetic response at 18 months was 87% in the imatinib group and 35% in the IFN+LDAC-treated group. The estimated rates of cytogenetic response were 76% and 14%, respectively. At 18 months, the estimated rate of freedom from progression to accelerated or blastic-phase chronic myelogenous leukemia was 97% in the imatinib group and 91% in the combination-therapy group. Imatinib was better tolerated than IFN+LDAC. It is worth noting that 89% of patients receiving IFN+LDAC had already switched to imatinib therapy after a median of only 8 months into the study. Therefore, the survival benefit with imatinib compared with IFN+LDAC has not yet become apparent with long-term follow-up because most patients treated with IFN+LDAC are benefiting early on from the added sequential imatinib therapy.

An additional follow-up to the IRIS trial at 42 months confirmed durable response with first-line imatinib therapy while demonstrating the effect of cytogenetic response on long-term outcomes. Of newly diagnosed patients treated with imatinib, 98% had achieved CHR, while 91% had achieved an major cytogenetic response, and 84% had achieved a cytogenetic response. For patients who had achieved cytogenetic response and a thousandfold (3 log) or greater reduction in BCR-ABL transcript level (i.e., a molecular response) at 12 months, the probability of remaining progression-free was 98% at 42 months. This probability compared with 90% for patients with cytogenetic response and less than a thousandfold reduction in BCR-ABL transcript level, and 75% for patients who had not achieved cytogenetic response. Responses to imatinib were found to be durable at the 42-month follow-up; an estimated 91% of patients maintained CHR, 91% of patients maintained major cytogenetic response, and 87% of patients maintained cytogenetic response.

A follow-up study monitored the molecular response for a median of 42 months in all 28 patients enrolled in the IRIS trial in Australia and New Zealand who commenced imatinib as their first-line therapy. The study’s aim was to determine if the BCR-ABL levels continued to decrease after 24 months. A cytogenetic response (approximately equivalent to a greater than 2-log reduction of BCR-ABL) was achieved in 24 of the 28 patients. Of the four patients without a cytogenetic response, all had disease progression, and in one patient a BCR-ABL mutation was detected, followed by rapid progression to blastic-phase disease. The data demonstrate that, although the frequency of achieving an major molecular response increased between 12 and 42 months, most of the improvement occurred between 12 and 24 months. Thirteen patients achieved an major molecular response by 12 months, and all 13 achieved a 4-log reduction (equivalent to undetectable levels of BCR-ABL transcripts) at 42 months. These results suggest that, in patients achieving an major molecular response by 12 months, leukemic cell mass is still decreasing after 3.5 years of imatinib therapy.

Common side effects of imatinib treatment are superficial edema, nausea, and muscle cramps. Some patients may experience severe toxicity, leukopenia, thrombocytopenia, and anemia. The most common adverse events experienced in the IRIS trial were hematologic and hepatic toxicities and included severe (NCI grades 3/4) neutropenia (16.2%), anemia (4.0%), thrombocytopenia (9.3%), and elevated liver enzymes (5.4%). Other drug-related adverse events occurred in 15.8% of patients.

Another study, conducted by researchers at the M.D. Anderson Cancer Center in Houston, Texas examined the optimal dose of imatinib therapy. In this trial, 222 previously untreated early chronic-phase chronic myelogenous leukemia patients were split into two groups. One group of patients was treated with the 400 mg daily dose of imatinib, while another group was treated with 800 mg daily. Patients in the higher-dose group had an estimated progression-free survival rate of 99% at 12 months compared with 92% in the standard dose group. Researchers concluded that the 800 mg daily imatinib dose resulted in higher rates of CCRs and MMRs. Extramedullary toxicity (toxicity outside the bone marrow) was similar in the two groups, but myelosuppression was more common with the higher dose. At 12 months, the median actual dose for the high-dose group was still 800 mg daily, with 36% of evaluable patients having required dose reduction, compared with 14% of those treated with the standard dose.

Acquired resistance to imatinib among patients with chronic-phase disease appears to be rare and can often be overcome by increasing the dose. In a follow-up study, 261 patients with chronic myelogenous leukemia in chronic-phase post-interferon-a failure received an escalated daily dose of 600-800 mg of imatinib orally after demonstrating a poor response or relapse at the standard dose (400 mg daily). Among patients treated for hematologic resistance or relapse, 65% achieved a complete or partial hematologic response. Among patients treated for cytogenetic resistance or relapse, 56% achieved a complete or major cytogenetic response.

In contrast, 70% of patients in myeloid blast crisis exhibit resistance to imatinib. Furthermore, all patients in lymphoid blast crisis relapse within six months of responding to imatinib. This resistance appears to arise from a variety of mechanisms, including acquired mutations in the ABL kinase domain, BCR-ABL overexpression, P-glycoprotein overexpression reducing the cellular uptake of imatinib, selection of preexisting mutant cells, and possibly, excessive degradation of the BCR-ABL protein.

Several studies have shown that imatinib is not as effective in the treatment of accelerated and blastic-phase chronic myelogenous leukemia as it is in the treatment of chronic-phase disease. A Phase II study investigated the hematologic and cytogenetic responses of 260 patients in myeloid blast crisis treated with 400-600 mg imatinib daily. Imatinib induced hematologic responses in 52% of patients and sustained hematologic responses lasting at least four weeks in 31% of patients, including CHRs in 8%. In patients with a sustained response, the estimated median response duration was 10 months. Imatinib induced MCRs in 16% of patients, and 7% of the responses were complete. Median survival time was 6.9 months. Drug-related adverse events led to discontinuation of therapy in 5% of patients, most often because of cytopenia, skin disorders, or gastrointestinal reactions.

Another Phase II study involving 235 patients showed that imatinib 400-600 mg daily induced hematologic and cytogenetic responses in accelerated-phase chronic myelogenous leukemia. Imatinib induced a hematologic response in 82% of patients and sustained hematologic responses lasting at least four weeks in 69%, and complete responses in 34%. The rate of major cytogenetic response was 24%; complete responses were achieved by 17%. Estimated 12-month progression-free and overall survival rates were 59% and 74%, respectively. In comparison with 400 mg, imatinib doses of 600 mg led to more cytogenetic responses (28% compared with 16%), longer duration of response (79% compared with 57% at 12 months), time to disease progression (67% compared with 44% at 12 months), and overall survival (78% compared with 65% at 12 months) with no clinically relevant increase in toxicity.

Several groups have investigated the combination of imatinib plus LDAC using the hypothesis that resistance to imatinib would be less frequent. The chronic myelogenous leukemia French Group performed a Phase II trial to determine the safety and tolerability of the combination in 30 previously untreated patients in chronic-phase chronic myelogenous leukemia. Treatment was administered in 28-day cycles. Patients were treated continuously with imatinib at a dose of 400 mg daily. LDAC was given on days 14 to 28 of each cycle at an initial dose of 20 mg/m²/day via subcutaneous injection. Adverse events were frequently observed: grade 3 or 4 hematologic toxicities and nonhematologic toxicities occurred in 53% and 23% of patients, respectively. At 6 months, 100% of patients achieved a CHR, and the cumulative incidence of cytogenetic response at 12 months was 83%. The researchers concluded that the combination was safe and promising, given the rates of response.

The STI-571 Prospective International Randomized Trial (SPIRIT) is a Phase III study underway to compare imatinib monotherapy, imatinib plus cytarabine, and imatinib plus interferon-a as first-line treatment in randomized, newly diagnosed chronic myelogenous leukemia patients.

Overview

Immunotoxins use MAb technology conjugated to natural toxins. Monoclonal antibodies are well established in cancer therapy. Immunotoxins have a lack of encouraging data in non-Hodgkin’s lymphoma, but their activity in blood-based tumors versus solid tumors may prove more efficacious.

Mechanism Of Action

Immunotoxins comprise peptides, usually an antibody or growth factor, which are linked to toxins such as diphtheria toxin, Pseudomonas exotoxin, or ricin. This “magic bullet” mechanism is designed to target the toxic moiety to a specific cell by binding the growth factor/antibody portion of the immunotoxin to its cell surface receptor. Upon internalization, the toxin is cleaved into an active form and causes cell death.

Denileukin Diftitox

Ligand Pharmaceuticals is developing denileukin diftitox (Ontak) for the treatment of chronic lymphocytic leukemia. Phase II trials are underway in the United States. This agent has already been launched in the United States and preregis-tered in Western Europe for the treatment of cutaneous T-cell lymphoma.

Denileukin diftitox is an interleukin-2 (IL-2) diphtheria toxin fusion protein; it is designed to direct the cytocidal action of diphtheria toxin to cells that express the IL-2 receptor. The human IL-2 receptor exists in three forms: low (CD25), intermediate (CD122/CD132), and high (CD25/CD122/CD132) affinity, the last of which is expressed on activated T and B lymphocytes and activated macrophages.

Researchers presented data from a Phase II trial in which heavily pretreated, fludarabine-refractory chronic lymphocytic leukemia patients received denileukin diftitox at a dose of 18 µg/kg/day or 9 µg/kg/day (if older than 70) intravenously for 5 days every 21 days. The mean age of patients enrolled in this study was 61.8 years and included 14 males and 4 females with Rai stages I (n = 2), II (n = 6), and IV (n = 10) who had received a mean of 4.5 prior treatments. Eleven out of 12 patients who received three or more courses of denileukin diftitox showed a reduced chronic lymphocytic leukemia cell count, and 6 of the 11 showed a >95% reduction. Seven of 12 patients showed a reduction in all lymph node diameters, with 1 patient showing 60% and another 80% shrinkage. Pre- and post-bone marrow biopsies performed on 11 patients showed a reduction in chronic lymphocytic leukemia marrow index; 7/11 had>50% reduction, including >98% in 3 patients.

In the study, denileukin diftitox produced 2/12 (17%) PRs and 7/12 (58%) minimal responses. Progression-free intervals ranged from 1 to more than 19 months. Toxicities were mild to moderate and included asymptomatic transient transaminasemia, fever, hypoalbuminemia, nausea, vomiting, elevated creatinine kinase, and vascular leak syndrome. The results suggest this agent has some biologic activity in this difficult-to-treat group of patients.

Previous published data have reported that immunotoxins directed against CD25 are more effective in treating malignancies where the expression of surface CD25 is high, such as in hairy-cell leukemia. Research has determined that chronic lymphocytic leukemia cells can be sensitized to CD25-directed immunotoxins by treating them with an agent that upregulates CD25 expression. A follow-up study is investigating denileukin diftitox therapy in combination with bexarotene (Ligand’s Tagretin), a retinoid X receptor (RXR) selective agonist known to upregulate IL-2 receptor expression.

Another study of denileukin diftitox therapy also presented data on a small number of heavily pretreated fludarabine-refractory patients. Their median age was 63, and patients had received three to eight prior therapies. Of the five evaluable patients, the median number of denileukin diftitox cycles received was three. Therapy was stopped after one cycle because of grade 4 hepatitis, diarrhea, and disseminated herpes simplex with fatal pneumonia and after two cycles because of grade 4 vascular leak with microangiopathy/cardiac tamponade or lack of efficacy. Other toxicities included grade 1 and 2 fatigue and myalgias; grade 4 anorexia; and grade 1, 2, and 4 raised liver function. Two of the five patients achieved a PR, both of which were ongoing at 12+ months, and two achieved minor responses (1 month and ongoing at 6+ months). CD25-positive and -negative patients were treated, and PR was observed in both groups. Furthermore, therapy with denileukin diftitox resulted in reduced lymphocytosis (median pre = 55 and post = 3.7) and a more normalized range of hemoglobin, neutrophils, and platelets.

Overview

The subject if immune surveillance as a defense against cancer has been debated since the 1950s. Knowledge of the genetic basis of cancer and immune processes has expanded significantly since that time and allowed researchers to manipulate tumor-specific characteristics as targets for the immune system. The idea of activating a specific immune response against cancer is an attractive one, and scientific research in this area is making its way into the clinic.

Mechanism Of Action

The immune system has developed a safety mechanism that allows it to mount appropriate responses to pathogens while maintaining tolerance to self-tissue. When this tolerance breaks down, autoimmunity occurs. The safety mechanism works by allowing only a specific subset of cells known as antigen-presenting cells (APCs) to induce an immune response by delivering two signals. The primary signal comprises an antigen bound to a major histocom-patibility (MHC) molecule, which engages the T-cell-receptor (TCR) complex on the surface of the responding T cell. The secondary, or costimulatory, signal results when molecules on the surface of the APC interact with their ligands on the T-cell surface. These initial steps must occur to drive an immune response; the delivery of one signal without the other can result in anergy (a state of nonre-sponsiveness). In cancer, it is thought that the immune system ignores malignant cells because one or both signals are missing.

Xcellerate

Xcyte Therapies and the University of Chicago were developing Xcellerate, a cocktail of immunostimulatory antibody-coated beads, which are used to stimulate patients’ T cells ex vivo before being reinfused. Xcellerate is in Phase I/II studies for prostate cancer, multiple myeloma, and chronic lymphocytic leukemia in the United States. Xcyte technologies has eventually sold this technology to Invitrogen.

Inadequate or impaired antigen-presentation and/or the delivery of costimulatory signals appear to play a role in the failure of the immune system to detect and eradicate cancer cells. This scenario is particularly true in chronic lymphocytic leukemia, where the number of circulating T cells is reduced and those that do exist can be anergic (nonresponsive) due to the tumor burden. Xcellerate aims to overcome these problems of immune inaction by delivering such signals ex vivo. Blood is collected from the patients and sent to Xcyte Therapies’ cell manufacturing facility, where Xcellerate-activated T cells are generated by stimulation with CD3 (part of the TCR complex) and CD28 (costimulatory signal) antibody-coated beads. The product is then returned and administered in an outpatient setting.

Three clinical trials in the United States are investigating Xcellerate. A Phase I trial in hormone-refractory prostate cancer patients has been completed, and Phase I/II trials in multiple myeloma and chronic lymphocytic leukemia are ongoing.

In 2003, at ASH, researchers presented data from the Phase I/II study of Xcellerated T cells in chronic lymphocytic leukemia patients. Eleven patients received varying doses of activated T cells. There were no grade 3 or 4 infusion toxicities. Lymph node and spleen size fell by more than 50% in 10/11 patients, although this decline was not associated with a corresponding fall in circulating lymphocyte count. Further follow-up is needed to determine the clinical significance of these data.

ISF-154

ISF-154 is a personalized, cellular therapy being developed by the University of California at San Diego (UCSD) and Tragen for B-cell malignancies. It is in Phase II trials for chronic lymphocytic leukemia in the United States.

B cells are one of the three types of professional APCs, but chronic lymphocytic leukemia B cells are known to be poor at presenting antigen because of their lack of surface costimulatory molecules. In an attempt to overcome this defect and potentially induce an immune response against the malignant cells themselves, ISF-154 therapy involves collecting chronic lymphocytic leukemia cells from the patient and transducing them with CD40L, a critical molecule for T-cell activation, using a recombinant adenovirus vector. These transduced cells are then readministered to the patient.

Phase II trial data were presented at ASH in 2003. In this multidose trial, seven patients received five courses of 3  —  6 x 10⁸ ISF-154 transduced cells given at two-week intervals, and trial endpoints aimed to evaluate safety and relative tumor load reduction. All patients had intermediate -or high-risk disease classified by the modified Rai system. Six of seven patients received all five courses of therapy; one patient withdrew after suffering grade II adverse events consisting primarily of flu-like symptoms after the second course of therapy. All patients (7/7) responded to therapy, experiencing transient falls in B-cell counts and lymph node size reductions of more than 50%. Durable responses were achieved in 5/6 patients who received all five courses of therapy. Two of these five patients achieved a PR; a third patient’s disease declined progressively over six months as the circulating B-cell count fell by 60% following the last infusion.

Rituximab (Rituxan, MabThera) is under development by Biogen Idee and Genentech in collaboration with Roche, Chugai, and Zenyaku Kogyo. This antibody is in Phase III clinical trials in the United States and Europe.

Rituximab is a mouse/human chimeric MAb directed against the cluster of differentiation (CD) 20 molecule. CD20 is a calcium channel that interacts with the B-cell immunoglobulinreceptor complex and is expressed on both normal and malignant B cells, making it an ideal target for monoclonal antibodies therapy in B-cell disorders. After binding to CD20, rituximab is thought to deplete B cells in a number of ways, including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and alteration of calcium flux and factors involved in apoptosis. This antibody has been launched for the treatment of relapsed or refractory low-grade or follicular, CD20-positive B-cell non-Hodgkin’ s lymphoma (B-NHL).

Rituximab is under investigation in many chronic lymphocytic leukemia clinical trials both as a single agent and in combination with chemotherapy as well as in first- and subsequent-line settings.

The role for rituximab as a single agent in chronic lymphocytic leukemia is controversial. Previous studies showed an overall response rate of only 11% and 25%, comparing poorly with the rate of 40-60% reported for follicular NHL. However, a recent Nordic multicenter study yielded improved results. Twenty-four chronic lymphocytic leukemia patients of median age 57 (47-72) with active disease (3 Binet A, 7 Binet B, 14 Binet C) who had previously been heavily treated with a variety of chemotherapy regimens were given the standard dose of 375 mg/m² rituximab once weekly for four doses. The primary objectives this study addressed were response rate, quality, and duration; secondary objectives were to analyze the feasibility and tolerability of rituximab therapy.

Eight of 23 evaluable patients (35%) achieved a partial response (PR), with a median duration of 12.5 weeks. A drop of at least 50% in blood lymphocyte count occurred in 17/21 (81%) patients who had pretreatment lymphocytosis, and 10 patients achieved a normal blood lymphocyte count (< 3 x 10⁹ L^_1). Of the 15 patients who did not achieve a PR with rituximab, 9 had at least a 50% drop in lymphocyte count and 3 achieved a normal count.

TABLE. Emerging Therapies in Development for Chronic Lymphocytic Leukemia

Compound	Development Phase	Marketing Company
Monoclonal antibodies
Rituximab (Rituxan, MabThera)
United States	III	Biogen Idec/Genentech
Europe	III	Roche/Chugai/Zenyaku Kogyo
Japan	—	—
Lumiliximab (IDEC-152)
United States	II	Biogen Idee
Europe	—	—
Japan	—	—
Antisense oligonucleotides
Oblimersen (Genasense)
United States	Ill	Genta/Aventis
Europe	—	—
Japan	—	—
Cell-cycle inhibitors
Alvocidib (Flavopiridol)
United States	II	National Cancer Institute
Europe	III	—
Japan	—	—
Immunostimulatory therapies
Xcellerate
United States	I/I I	Invitrogen (formerly with Xcyte Technology)
Europe	—	—
Japan	—	—
ISF-154
United States	II	Tragen/University of California at San Diego
Europe	—	—
Japan	—	—
Immunotoxins
Denileukin diftitox (Ontak)
United States	II	Ligand Pharmaceuticals
Europe	—	—
Japan	—	—
Apoptosis inducers
SDX-101
United States	Ib/lla	Salmedix
Europe	—	—
Japan	—	—
Motexafin gadolinium (Xcytrin)
United States	II	Pharmacyclics
Europe	—	—
Japan	—	—
Selective apoptotic antineoplastic drugs
OSI-461
United States	Ila	OSI Pharmaceuticals
Europe	—	—
Japan	—	—

Seventy-five percent of patients experienced rituximab-related side effects, half of which were related to the first infusion only. The most common toxicities were World Health Organization (WHO) grade 1/2 chills and grade 2 fever. In previous studies, the severe infusion-related toxicities reported had been specifically linked to a high tumor burden. Mainly mild/moderate side effects were observed in this study, even in patients with extremely high lymphocytosis (223 x 10⁹ L^_1). This study demonstrates that single-agent rituximab does have some activity in heavily pretreated chronic lymphocytic leukemia patients, although the response is minor and of short duration.

The reasons rituximab is more effective in NHL than in chronic lymphocytic leukemia are unclear. Circulating soluble CD20 and a high tumor burden, both of which “mop up” rituximab, are potential mechanisms/states by which the antibody is rapidly cleared from the blood; this theory is supported by the observation of altered pharmacokinetics and increased response rates with higher doses of rituximab in chronic lymphocytic leukemia. In addition, chronic lymphocytic leukemia cells have a much lower density of surface CD20 than do NHL cells, although no correlation between density and response to therapy has been found.

Rituximab has been used as a first-line, single-agent therapy, and limited clinical data suggest it may be more effective than as second- or third-line therapy. In one trial, treatment-naive patients with stage II — IV small lymphocytic lymphoma or chronic lymphocytic leukemia received 375 mg/m² rituximab weekly for four doses. Patients who achieved an objective response (PR or complete response [CR]) or stable disease at reevaluation after six weeks continued maintenance courses of rituximab using the standard four-week schedule every six months for a maximum of four courses. Twenty-two of forty-three patients (51%) had an objective response at week 6, and the remaining patients had stable disease.

Twenty-eight patients (65%) went on to receive maintenance rituximab therapy. With a median follow-up of 24 months, the response rate was 58% (9% CR). Median progression-free survival (PFS) was 19 months with a one- and two-year actuarial PFS of 63% and 49%, respectively. Two patients had a reversible grade 3 infusion-related toxicity with the first course of rituximab. The increase in overall response rate is encouraging, but the small CR indicates that single-agent rituximab will not result in long-term survival in chronic lymphocytic leukemia.

Treatment for chronic lymphocytic leukemia is generally reserved for patients with symptoms of advanced disease, although rituximab therapy may be effective in early-stage disease for those at risk of progression. The overall response rate in 21 evaluable patients with Rai stage 0-11 and beta-2 microglobulin levels >2 mg/dL was 90% (19% CR, 19% nodular PR [nPR], 48% PR). The clinical significance of these results is unclear because a longer follow-up is required to analyze time to progression and long-term survival.

The dose and schedule of administration for single-agent rituximab therapy as both first and subsequent lines of therapy are under investigation in dose-escalation studies in an attempt to increase response rates. Researchers have reported using doses of up to 2,000 mg/m²/week in four patients. Such studies are ongoing to optimize clinical responses.

The most active area of research involving rituximab is in combination with chemotherapy. A randomized Phase II study of fludarabine in combination with concurrent rituximab versus sequential rituximab was conducted in 104 previously untreated chronic lymphocytic leukemia patients. The treatment schedule for sequential therapy involved patients receiving 25 mg/m² fludarabine for 5 days, repeated every 28 days for six cycles. Four weekly doses of 375 mg/m² rituximab were administered to patients who achieved stable disease or better, following a two-month rest period and restaging. The concurrent schedule followed the same pattern as the sequential schedule, with the addition of rituximab to each fludarabine cycle. It is important to note that patients receiving concurrent administration received 11 doses of rituximab (seven in combination with fludarabine and four as consolidation after this therapy) compared with only 4 doses in the sequential arm.

Concurrent administration of these two agents demonstrated superior response rates when compared with the sequential arm (47% CR versus 28% CR, 43% PR versus 49% PR, respectively). Neutropenia was more common in the concurrent arm, but infectious complications occurred at similar frequencies in both schedules. Additional data presented at the American Society of Hematology (ASH) meeting in 2003 determined that adding rituximab to fludarabine did not significantly increase the risk of infection.

This encouraging study establishes that concurrent administration of rituximab and fludarabine produces CR rates superior to those achieved with fludarabine alone. To date, the impact of rituximab on improving progression-free survival and overall survival compared with fludarabine monotherapy has not been analyzed in a randomized trial. A retrospective comparison with data from 179 patients enrolled in the North American Intergroup Study CALGB 9011 who received fludarabine monotherapy showed that CR, PR, and two-year performance-free and overall survival rates were significantly superior in the fludarabine/rituximab group.

The triple-drug regimen fludarabine/cyclophosphamide/rituximab (FCR) is also under intense investigation. In one study, 202 previously untreated chronic lymphocytic leukemia patients received FCR (25 mg/m²/day F for three days; 250 mg/m²/day C for three days; 375-500 mg/m² R on day 1). Results showed 68% CR, 18% nPR, and 14% PR. The study also analyzed patients for the presence of minimal residual disease (minimal residual disease) and found that the FCR regimen produced a high level of minimal residual disease-negative complete remissions. A longer follow-up will determine whether minimal residual disease-negative CR is more durable than minimal residual disease-positive CR.

At the 2003 ASH meeting, the results of a sequential FCR program also were presented. Thirty treatment-naive chronic lymphocytic leukemia patients received six cycles of standard fludarabine therapy, then 3 g/m² cyclophosphamide every three weeks for three cycles, and finally standard rituximab therapy. CR and PR rates of 57% and 29% (10% nPR and 19% PR), respectively, were achieved.

The FCR regimen has also succeeded in patients with relapsed or refractory chronic lymphocytic leukemia. In one trial, 179 patients who had already received between one and three courses of therapy were treated with FCR and achieved responses of 25% CR, 16% nPR, and 32% PR. Minimal residual disease (analyzed by polymerase chain reaction) was absent in 33% of CR patients. Therapy was well tolerated, and 62% of patients completed four or more cycles of this regimen. Forty-one percent of patients experienced fever and chills with the first rituximab infusion, and a minority experienced hypotension, nausea, and dyspnea (6%, 9%, and 3%, respectively). Hematologic toxicities included neutropenia in 30% of cycles and thrombocytopenia in 12%.

A comparative, retrospective analysis of patients treated with fludarabine (plus or minus prednisone), fludarabine/cyclophosphamide, or FCR demonstrated increased CR, overall response, and median survival in patients treated with FCR.

The purine analogue pentostatin (SuperGen Warner-Lambert’s Nipent) has shown significant activity and minimal toxicity when combined with cyclophos-phamide in chronic lymphocytic leukemia patients. In one trial, rituximab was added to this combination (known as the PCR regimen) and administered to previously untreated chronic lymphocytic leukemia patients. Preliminary data on 15 patients presented at ASH 2003 revealed 40% CR, 13% complete clinical response, and 47% PR. Most toxicities were grade 1 or 2, although eight patients suffered grade 3 anemia and hypotension and one patient developed grade 4 sinus bradycardia.

In another trial, 20 patients with relapsed or refractory disease were treated with the PCR regimen; the response rates were 20% CR, 10% nPR, and 50% PR. Grade 3/4 neutropenia occurred in 45% of patients, grade 3/4 thrombocytopenia in 5%, and infections in 15%. Preliminary data suggest this regimen is well tolerated, but further analysis is needed to determine both response rates and toxicity profiles compared with those associated with fludarabine-containing regimens.

The combination of rituximab and another MAb, alemtuzumab is under investigation for relapsed and refractory chronic lymphocytic leukemia. Nine patients underwent treatment with this combination, and preliminary data showed a 44% CR and 23% PR rate. Nonhematologic toxicities were grade 2 or less, and infection occurred in 44% of patients. Another study presented at ASH 2003 failed to show any complete or partial remissions in 11 patients with relapsed or refractory chronic lymphocytic leukemia who were treated with alemtuzumab and rituximab in combination. Further investigation into the combination of these antibodies is needed to determine their potential efficacy.

In an attempt to improve upon the success seen in FCR, the M.D. Anderson Cancer Center is pioneering a trial examining a regimen consisting of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (known as the CFAR regimen). Only two relapsed/refractory patients have completed all courses, and both achieved PRs. Four patients on continuing therapy were evaluated after three courses, and responses included one CR, one nPR, and two PRs. Seven patients came off therapy because of treatment failure (n = 2), infection (n = 1), noncompliance (n = 1), or at their own request (n = 2); one death occurred as a result of disease-related liver failure. Early analysis indicates good response with substantial but expected toxicities.

Rituximab enjoys extensive off-label usage in the United States, mainly in the first- and second-line chronic lymphocytic leukemia settings in combination with chemotherapy. In Europe, however, the use of rituximab is restricted by a lack of reimbursement owing to its experimental status and high cost.

Three major staging systems exist for the classification of chronic lymphocytic leukemia. (These systems are described in TABLE.Common Staging Systems Used in the Treatment of Chronic Lymphocytic Leukemia).

The original Rai system, published in 1975, consists of stages 0-IV and is based on the presence of lymphadenopa-thy, organomegaly, and cytopenias, demonstrating a correlation between Rai stage and survival. This system was later modified from the five-tier system to a three-tier system that categorizes patients as having a low, intermediate, or high risk of disease progression.

TABLE.Common Staging Systems Used in the Treatment of Chronic Lymphocytic Leukemia

System	Stage	Definition
Rai staging system	0	Lymphocytosis only
	I	Lymphocytosis and lymphadenopathy
	II	Lymphocytosis, spleen or liver enlargement
	III	Lymphocytosis and anemia (hemoglobin <11 g/dL)
	IV	Lymphocytosis and thrombocytopenia (platelet count < 100,000 mL)
Modified Rai staging system	Low risk of progression	Rai stage 0
	Intermediate risk of progression	Rai stage I or II
	High risk of progression	Rai stage III or IV
Binet staging system	A	Lymphocytosis, with enlargement of <3 lymphoid areas3; no anemia or thrombocytopenia
	B	Lymphocytosis, with enlargement <3 lymphoid areas
	C	Lymphocytosis and either anemia (hemoglobin <10 g/dL) or thrombocytopenia (platelet count <100,000/mL), or both

a. The following lymphoid areas are included: cervical, axillary, inguinal (whether unilateral or bilateral), spleen, and liver.

The Binet classification system (A, B, C) was devised based on a retrospective analysis of disease burden that draws a correlation between the number of nodal groups involved with disease and bone marrow failure. The National Cancer Institute (NCI)’s guidelines for chronic lymphocytic leukemia state that the major distinctions and benefits of the Binet system derive from its recognition that (1) a predominantly splenic form of the disease may have a better prognosis in the Binet system than in the Rai systems, (2) patients with comorbid anemia or thrombocytopenia have a similar prognosis, and (3) the presence of either of these two conditions can be grouped in the same stage rather than in separate stages.

Although both the Rai and Binet systems group patients according to their risk of progression, the early stages of disease do not correspond well between the two systems. Binet’s good prognosis group, A, includes twice as many patients as Rai’s stage 0 because it includes all Rai stage 0, two-thirds of Rai stage I, and one-third of Rai stage II. The original and modified Rai systems are used throughout the United States; all three systems are used in Europe, although physicians quote Binet more frequently. The overlap among staging systems has made the comparison of clinical trials using different staging systems difficult.

Although the Rai and Binet staging systems each give general indications as to a patient’s prognosis, survival within each stage can vary significantly, particularly in those patients with Binet stage A and Rai stage 0. As many as 30% of these patients have “smoldering” chronic lymphocytic leukemia, which progresses slowly and never requires therapy; other patients have more progressive disease that will eventually require treatment and may be fatal. The median survival of patients with Rai stage 0 exceeds 12 years and may reach 20 years with a 10-year overall survival rate of 70-75%. Patients with Rai stage I and II have a median survival of 8-10 years and 5-8 years, respectively, whereas recent data show a median survival of 5 years and longer in Rai stage III and IV patients.

Brand Name: Rapamune
Active Ingredient: sirolimus
Indication: The prevention of acute kidney rejection following transplantation
Company Name: Wyeth-Ayerst Laboratories
Availability: By prescription only

Introduction

The U.S. Food and Drug Administration’s (FDA) Subcommittee of the Antiviral Drugs Advisory Committee on Immunosuppressive Drugs voted unanimously 27 July 1999 that Rapamune® (sirolimus) is safe and effective for the prevention of acute kidney rejection following transplantation. If final approval is ultimately given by the FDA, Rapamune would be the first of a new class of immunosuppressive agents developed to treat transplant patients. Rapamune is a product of Wyeth-Ayerst Laboratories, the pharmaceutical division of American Home Products Corporation.

Kidney transplantation is the most common type of transplant procedure in the U.S., with over 12,000 transplants occurring in 1998. To help minimize the risk of organ rejection, transplant patients are given a life-long regimen of immunosuppressive agents. These drugs are intended to lower the body’s normal immune response allowing the transplanted organ to remain functional.

Many patients require retransplants in part because of organ failure due to toxicities; this need for repeat organ transplants only compounds the organ shortage. For example, there are more than 40,000 patients in the U.S. awaiting kidney transplants. However, only about 12,000 kidneys were available for use in 1998. These organ shortages have increased the importance of organ transplants being successful and the need for new therapies that can help decrease the incidence of rejection episodes.

Rapamune (sirolimus) was first developed as a potential antifungal agent, called rapamycin. When testing the antifungal properties of rapamycin in the 1970′s, researchers discovered that it caused suppression of the immune system and abandoned it as an antifungal agent. The drug then demonstrated the ability to halt the growth of cancerous tumors, but attempts to develop an intravenous formula of rapamycin proved futile. In the 1980′s, researchers focused their attention on rapamycin’s immunosuppressive properties. Subsequent clinical trials demonstrated that rapamycin could more effectively and safely lower the risk of chronic rejection of kidney transplants.

How it Works

When an organ is transplanted, the recipient’s immune system recognizes the new organ as foreign and attacks it. The attack causes a build-up of scar tissue, associated with chronic rejection, on the transplanted organ. Rapamune (sirolimus) reduces the risk of chronic rejection by suppressing the immune system, hence weakening its attack.

Rapamune (sirolimus): Clinical Study Results

Two clinical trials, one conducted in the United States and one involving patients from nine countries, demonstrated Rapamune’s efficacy versus standard treatment and versus placebo.

The U.S. study was randomized, double-blinded, comparative, and race-stratified. It involved 38 centers and included 719 kidney transplant patients. Patients were randomized to receive a combination of cyclosporin, a steroid, and Rapamune 2 mg or 5 mg or the standard treatment of cyclosporin, a steriod, and azathioprine. The primary endpoint was efficacy failure. 18.7% and 16.8% of the patients receiving 2 mg and 5 mg of Rapamune, respectively, reached endpoint; whereas, 32.3% of the patients receiving standard therapy experienced endpoint.

The second study included 576 patients and compared Rapamune (sirolimus) to placebo. Except for the control group that received cyclosporin, a steroid, and placebo, patients in the international trial received the same drug treatments as the patients in the above-mentioned trial. 30%, 25.6%, and 47.7% of patients who were administered Rapamune 2 mg, Rapamune 5 mg, and placebo, respectively, experienced endpoint. The large differences in the results of the U.S. trial and the international trial could be attributable to the differing methodologies of the studies. The U.S. study eliminated high-risk patients that may have been included in the international trial.

What the Patient Should Know

Rapamune (sirolimus) is administered orally (2 mg or 5 mg) in combination with cyclosporin and a steriod to avoid transplant rejection. Patients receiving this treatment are under strict medical supervision.

Brand Name: Antagon
Active Ingredient: ganirelix acetate
Indication: aid in artificial fertilization (inhibits premature luteinizing horomone (LH) surges in women undergoing controlled ovarian hyperstimulation)
Company Name: Organon, Inc.

Introduction

In the United States, infertility affects 6.1 percent of American women and their partners. Each year, about 2.7 million couples seek medical help for fertility problems. Latest data released by the American Society for Reproductive Medicine indicated that in 1996 65,800 cycles of assisted reproduction treatment were started. That same year, 20,000 babies were born with the help of assisted reproductive techniques, of whom 14,054 were born after In Vitro Fertilization (IVF). Antagon reduces total treatment time per IVF cycle from four weeks to about 10 days.

Gonadotriphin releasing hormone (GnRH) is released in the healthy body in pulses and stimulates the synthesis and secretion of LH and follicle-stimulating hormone (FSH). The pulses are observed as rises in serum luteinizing horomone (LH). At midcycle, a substantial increase in GnRH release results in an LH surge. This surge results in the commencement of ovulation, resumption of meiosis in the oocyte, and luteinization.

Assisted reproduction treatment involves the administration of gonadotropins. Antagon (ganirelix acetate) blocks the luteinizing horomone (LH) surge in women undergoing controlled ovarian hyperstimulation (COH). Improperly controlled ovarian hyperstimulation can result in massive ovarian cysts, aseites, pleural effusion, thrombosis, and hypoproteinaemia.

How It Works

Antagon (ganirelix acetate) competitively blocks the GnRH receptors on the pituitary gonadotroph and the subsequent transduction pathway. It induces a rapid, reversible suppression of gonadotropin secretion. Pituitary LH and FSH levels fully recover within 48 hours of discontinuation of Antagon use.

Antagon (ganirelix acetate): Clinical Study Results

Two clinical studies demonstrated the safety and efficacy of Antagon (ganirelix acetate). Both studies followed similar procedures although they differed in design. On day 2 or 3 of the natural menstrual cycle, the administration of exogenous recombinant FSH 150 IU daily was initiated. Antagon adminstration was begun on the morning of day 7 or 8. Both drugs were administered until at least 3 follicles were 17 mm or greater in diameter. At that time, human chorionic gonadotrophin (hCG) was administered and Antagon and exogenous recombinant FSH were discontinued. Oocyte retrieval, in vitro fertilization, or intracytoplasmatic sperm injection was then performed.

A multicenter, double-blind, randomized study was conducted to determine the most effective dose of Antagon in the prevention of LH surges in women undergoing COH with recombinant follicle-stimulating hormone (FSH). The highest pregnancy and implantation rates were achieved with the 250 ucg dose of Antagon. A multicenter, randomized, open-label study examined follicular phase treatment with Antagon 250 ucg, using luteal phase GnRH agonist as a reference treatment. A total of 463 patients were treated with Antagon by subcutaneous injection once daily starting on day 6 of recombinant follicle-stimulating hormone (FSH) treatment. Premature luteinizing horomone (LH) surges occurred in less than 1% of patients prior to hCG administration.

What the Patient Should Know

The following adverse events were reported: gynecological abdominal pain, fetal death, headache, ovarian hyperstimulation syndrome, vaginal bleeding, injection site reaction, nausea, and gastrointestinal abdominal pain. If the patient becomes pregnant, Antagon should be discontinued.

Brand Name: Zaditor
Active Ingredient: ketotifen fumarate
Indication: Provides temporary relief from itching of the eye due to allergic conjunctivitis
Dosage Form(s): opthalmic solution, 0.025%
Company Name: Ciba Vision
Availability: Not approved for marketing as of Aug 99

Introduction

Following a priority review, Zaditor (ketotifen) was approved by the FDA on July 2, 1999. The priority review was granted because, as an antihistamine for ocular itching, Zaditor is in a different class from other currently approved ocular itching drugs. Ketotifen capsules are marketed by Novartis, Ciba’s parent company, outside the United States for the systemic treatment of bronchial allergies and asthma.

How it Works

Zaditor (ketotifen) is a histamine antagonist and mast cell stabilizer. This dual activity prevents mast cell degranulation, which limits the release of inflammatory mediators; secondly, the mediators from cells involved from hypersensitivity reactions are directly inhibited by ketotifen. Other currently approved drugs for this indication rely primarily on the direct inhibition of the activity of histamine and other inflammatory mediators in the eye.

Zaditor (ketotifen): Clinical Study Results

Although the systemic use of ketotifen has been well documented for the management of allergies and related bronchospastic disorders, there is little published information about the clinical activity of the drug in eye drop formulation. No specific results of clinical studies are noted in the direction circular for Zaditor (ketotifen), and a Medline search did not identify any clinical studies that used this drug. However, in vitro studies have shown the antihistaminic activity of ketotifen to be equal to that of emedastine and more than 5,000 times more potent than that of brompheniramine.

Published results of a clinical trial using a 0.1% ophthalmic preparation of ketotifen found a 91% effectiveness rate in reducing conjunctivitis caused by pollinosis, and this effect was typically evident within the first three days of treatment.

The recommended dose is one drop in the affected eye every 8 to 12 hours, thereby providing relatively convenient twice or three-times-a-day dosing.

What the Patient Should Know

Worsening of conjunctival irritation, headaches, and rhinitis were the most commonly reported adverse events during the controlled clinical studies of Zaditor (ketotifen). However, the occurrences were generally mild. In an effort to avoid contamination of the dropper tip and solution, the tip of the dropper should not touch the eyelids or surrounding areas. Also, the bottle should be kept tightly closed when not being used. Contact lenses should not be inserted for at least 10 minutes after using Zaditor (ketotifen). Zaditor is not intended to treat irritation due to contact lenses, and contact lenses should not be used if the eye is red.