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P T. 2012;37(1): 25-27, 55

Pharmaceutical Approval Update January 2012

Marvin M. Goldenberg PhD, RPh, MS

Ruxolitinib (Jakafi) Tablets

Manufacturer: Incyte Corp., Wilmington, Del.

Indication: Ruxolitinib (INC B018424) is intended for the treatment of myelofibrosis (MF), which causes anemia, fatigue, pain, and swelling of the spleen. The disease spurs abnormal blood cells to build up in bone marrow, forming thick scar tissue that slows the production of healthy blood cells. To make up for the shortage of blood cells, other organs, including the liver and the spleen, begin producing blood cells.

Drug Class: This kinase inhibitor has the chemical name of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate. The molecular weight is 404.36.

Uniqueness of Drug: Ruxolitinib is a well-tolerated, first-in-class Janus kinase 2 (JAK2) inhibitor with various potential clinical indications. It is the first product to be approved by the FDA for MF. It is an oral JAK1 and JAK2 inhibitor and a potent selective inhibitor of both JAK1 and JAK2 of the Janus kinase–Signal Transducer and Activator of Transcription (Jak–Stat) pathway.

Warnings and Precautions:

Hematological reactions. Ruxolitinib can cause hematological adverse reactions, including thrombocytopenia, anemia, and neutropenia. A complete blood count (CBC) must be performed before therapy with ruxolitinib is initiated.

If the platelet count is less than 200 × 109/L at the start of therapy, thrombocytopenia is more likely to develop during treatment. In clinical studies, thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding ruxolitinib. If indicated, platelet transfusions may be administered.

If anemia occurs during treatment, patients may require blood transfusions. Dose modifications of ruxolitinib may also be considered if anemia develops.

Neutropenia, defined as an absolute neutrophil count (ANC) of less than 0.5 × 109/L, is generally reversible and can be managed by temporarily withholding ruxolitinib. The CBC should be monitored as indicated and dosages adjusted as required.

Infections. The risk of serious bacterial, mycobacterial, fungal, and viral infections should be assessed. Active serious infections should be resolved before therapy with ruxolitinib begins. Physicians should carefully observe patients receiving ruxolitinib for signs and symptoms of infection and should initiate appropriate treatment promptly. Physicians should also inform patients about early signs and symptoms of herpes zoster and should advise them to seek treatment promptly.

Dosage and Administration:

Recommended starting dose. The initial dose of ruxolitinib is based on the platelet count (Table 1). Before therapy begins, a CBC and platelet count must be performed every 2 to 4 weeks until doses are stabilized and then as clinically indicated. Doses may be titrated based on safety and efficacy.

Dose modifications for thrombocytopenia. Treatment should be interrupted if the platelet count is below 50 × 109/L. After the platelet count recovers above this level, dosing may be restarted or increased after recovery of the count to acceptable levels. Table 2 presents the maximum allowable dose to be used in restarting therapy after a previous interruption.

Dose reductions. Reducing the dosage should be considered if the platelet count decreases, with the goal of avoiding dose interruptions for thrombocytopenia (Table 3).

Dose modifications based on response. If efficacy is considered insufficient and platelet and neutrophil counts are adequate, doses may be increased in 5-mg, twice-daily increments to a maximum of 25 mg twice daily. Doses should not be increased during the first 4 weeks of therapy and not more frequently than every 2 weeks. Treatment should be discontinued after 6 months if spleen size does not decrease and if symptoms show no improvement.

Based on limited clinical data, long-term maintenance at a dose of 5 mg twice daily has not resulted in responses. Continued use at this dose should be limited to patients for whom the benefits outweigh the potential risks. The dose may be increased if the following conditions persist: (1) patients have not achieved a reduction, from pretreatment baseline, in either a palpable spleen length of 50% or a 35% in spleen volume, as measured by computed tomography or magnetic resonance imaging; (2) the platelet count exceeds 125 × 109/L at 4 weeks and is never below 100 × 109/L; and (3) the ANC is higher than 0.75 × 109/L.

Commentary: Ruxolitinib inhibits Janus-associated kinases (JAKs) JAK1 and JAK2, which mediate the signaling of cytokines and growth factors that are important for dermatophoresis and immune function. The availability of ruxolitinib is a significant medical advancement for patients with MF, a debilitating disease.

MF is a myeloproliferative neoplasm associated with dysregulated JAK1 and JAK2 signaling. It is marked by an enlarged spleen, anemia, decreased white blood cell and platelet counts, and related symptoms. JAK1 and JAK2 help to regulate blood and immunological functioning.

The FDA’s approval of ruxolitinib was based on results from two randomized phase 3 trials—COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment (COMFORT-I and COMFORT-II). Treated patients experienced significant reductions in splenomegaly. In COMFORT-I, they also experienced improvements in symptoms (abdominal discomfort, pain under the left ribs, a feeling of fullness, night sweats, bone and muscle pain, and itching). Most patients taking placebo experienced worsening of these same parameters.

Ruxolitinib is another example of an increasing trend in oncology research and development whereby a detailed scientific understanding of the mechanisms of a disease allows a drug to be directed toward specific molecular pathways. The clinical studies that resulted in the drug’s approval focused on problems that patients with MF commonly encounter, including an enlarged spleen and pain.

The label for ruxolitinib has no boxed warnings, contraindications, or a requirement for a Risk Evaluation and Mitigation Strategy (REMS).

Sources: www.fda.gov; www.rxlist.com/jakafi-drug.htm; www.incyte.com; www.jakafi.com

Aflibercept (Eylea) Injection

Manufacturer: Regeneron Pharmaceuticals, Inc., Tarrytown, N.Y.

Indication: Aflibercept is indicated for the treatment of patients with neovascular (wet) age-related macular degeneration (AMD).

Drug Class: Produced in recombinant Chinese hamster ovary cells, aflibercept is a recombinant fusion protein formulated as an iso-osmotic solution for intravitreal injection. The drug consists of portions of human vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and VEGFR-2) extracellular domains, fused to the Fc (fragment, crystallizable) region of human immunoglobulin (IgG1). As a dimeric glycoprotein, aflibercept has a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an additional 15% of the total molecular mass. The total molecular weight is 115 kDa.

Uniqueness of Drug: VEGF-A and placental growth factor (PGF) are members of the VEGF family of angiogenic factors that can act as mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases, VEGFR-1 and VEGFR-2, which are present on the surface of endothelial cells. PGF binds only to VEGFR-1, which is also present on the surface of leukocytes. Activation of these receptors by VEGF-A can result in neovascularization and vascular permeability. Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PGF, inhibiting the binding and activation of these cognate VEGF receptors.

Warnings and Precautions:

Ocular problems. Intravitreal injections have been associated with endophthalmitis and retinal detachments. Proper aseptic injection technique must always be used when aflibercept is injected. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and appropriate management should be instituted.

Increased intraocular pressure. Acute increases in intraocular pressure have occurred within 60 minutes of intravitreal injections, including those of aflibercept. Sustained increases in intraocular pressure have also been reported after repeated intravitreal injections of VEGF inhibitors. Intraocular pressure and perfusion of the optic nerve head should be monitored and managed appropriately.

Thromboembolism. There is a risk of arterial thromboembolic events following the intravitreal use of VEGF inhibitors. These events may include nonfatal stroke, nonfatal myocardial infarction, vascular death, or death from unknown causes. The incidence in the VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW 1 and VIEW 2) trials during the first year was 1.8% (32 patients of 1,824) in the combined group of patients who received aflibercept.

Dosage and Administration: Aflibercept is indicated for ophthalmic intravitreal injection only and must be administered by a qualified physician. The recommended dose is 2 mg (0.05 mL or 50 μL), given by intravitreal injection every 4 weeks for the first 12 weeks, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks. Although aflibercept may be injected as frequently as 2 mg every 4 weeks, additional efficacy was not demonstrated when it was administered every 4 weeks when compared with every 8 weeks.

Aflibercept should be inspected visually prior to administration. If cloudiness, discoloration, or particulates are visible, the vial must not be used. With aseptic technique, the drug is injected with a 30-gauge × 1.5-inch needle. The glass vial is used one time only. Controlled aseptic conditions include surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum or equivalent. Adequate anesthesia and a topical broad–spectrum microbicide should be given prior to the injection.

Immediately after the injection, patients should be monitored to check for an elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, a sterile paracentesis needle should be available. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without delay.

Each vial should be used only for the treatment of a single eye. If treatment is needed for the other eye, a new vial should be used, and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before the drug is administered to the other eye. No special dosage modification is required in terms of patient age or sex.

A single-use glass vial provides 0.05 mL of a 40-mg/mL solution for intravitreal injection.

Contraindications: Aflibercept is not intended for patients with ocular or periocular infections, active intraocular inflammation, or a hypersensitivity to aflibercept or its excipients.

Commentary: Aflibercept is regarded as an important new competitor to ranibizumab (Lucentis, Genentech/Roche); it is given once every two months after three initial once-a-month injections, whereas ranibizumab is administered once every month, although some patients may require treatment only once every 3 months. Aflibercept costs $1,850 per treatment, whereas ranibizumab costs approximately $2,000 per treatment.

Of note, bevacizumab (Avastin, Genentech/Roche) was approved in 2004 for intravenous use in colorectal cancer. It is also used on an off-label basis, via eye injection, to treat wet AMD. The cost per intravitreal injection of bevacizumab ranges from about $20.00 to $60.00, according to the American Macular Degeneration Foundation.

All of these drugs are injected directly into the eye after the ocular surface has been numbed. The small needle is inserted near the corner of the eye, not the center. The physician asks the patient to look in the opposite direction to expose the injection site, which also allows the patient to avoid seeing the needle.

According to WebMD, some insurers, including Medicare, may prefer aflibercept’s cost effectiveness. The drug’s reduced dosage schedule calls for fewer follow-up treatments, which can range from $250 to $300 per office visit in addition to the cost of the drug. Although the FDA has ruled that the drug’s benefits outweigh its risks, adverse effects have included bleeding at the injection site, eye pain, cataracts, vitreous floaters, and elevated eye pressure.

Results reported in December were from the second year of studies in which patients were given therapy as needed. Patients receiving aflibercept gained an average of 7.6 letters on an eye chart after 96 weeks, compared with 7.9 letters with ranibizumab. Those receiving aflibercept had fewer injections in the second year, at 4.2 on average, compared with 4.7 for ranibizumab, not enough of a change to differentiate the medications significantly. Visual acuity gains were maintained over two years but showed little overall benefit when each drug was given as needed. These data may reduce aflibercept’s perceived differentiation from ranibizumab with respect to convenience and price.

Sources: www.fda.gov; www.webmd.com; http://daily-med.nlm.nih.gov/dailymed/drugInfo.cfm?id=56561; Business Week, December 6, 2011

Hemacord (Hematopoietic Progenitor Cells, Cord Blood)

Manufacturer: New York Blood Center, Inc., New York, N.Y.

Indication: Hemacord is used in unrelated donor hematopoietic progenitor cell (HPC) transplantation, along with an appropriate preparative regimen for hematopoietic and immunological reconstitution, in patients with disorders affecting the blood-forming system that are inherited, acquired, or a result of myeloablative treatment.

Drug Class: Hemacord contains HPCs from human cord blood, one of three sources of HPCs used in transplants; the other two are bone marrow and peripheral blood.

Uniqueness of Drug: After HPCs are infused into the patient, the cells migrate to the bone marrow, where they divide and mature. When the mature cells move into the bloodstream, they can partially or fully restore the number and function of many blood cells, including immune function.

Boxed Warning: There is a risk of graft-versus-host disease (GVHD), infusion reactions, graft failure, and engraftment syndrome; each of these is potentially life-threatening. Individuals receiving Hemacord require close monitoring.

Warnings and Precautions:

Allergic reactions and anaphylaxis. Allergic reactions, including bronchospasm, wheezing, angioedema, pruritus, and hives, may occur with the infusion of HPCs and cord blood.

Infusion reaction. Infusion reactions are expected to occur and may include nausea, vomiting, fever, rigors or chills, flushing, dyspnea, hypoxemia, chest tightness, hypotension, tachycardia, and bradycardia.

Graft-versus-host disease. Acute and chronic GVHD may occur in patients who have received Hemacord.

Engraftment syndrome. The syndrome is manifested as unexplained fever and rash in the peri-engraftment period. Patients may have unexplained weight gain, hypoxemia, and pulmonary infiltrates.

Graft failure. Primary graft failure, which may be fatal, is an inability to achieve an absolute neutrophil count (ANC) greater than 500/μL by day 42 after transplantation. Immunological rejection is the primary cause of graft failure.

Malignancies of donor origin. Patients who have undergone HPC transplantation may experience post-transplant lymphoproliferative disorder, manifested as a lymphoma-like disease favoring non-nodal sites. The disorder is usually fatal if it is not treated.

Transmission of serious infections. Infectious disease may occur because Hemacord is derived from human blood. Disease may be caused by known or unknown infectious agents.

Transmission of rare genetic diseases. Hemacord may result in the transmission of rare genetic diseases involving the hematopoietic system for which donor screening and testing have not been performed.

Dosage and Administration: This product is for intravenous use only. The recommended minimum dose is 2.5 × 107 nucleated cells/kg at cryopreservation. Multiple units may be required to achieve the appropriate dose. Matching for at least four of six HLA–A antigens, HLA–B antigens, and HLA–DRB1 alleles is recommended. Hemacord should be prepared by a trained health care professional. Each unit of Hemacord contains a minimum of 5.0 × 108 total nucleated cells with a minimum of 1.25 × 106 viable CD34+ cells, suspended in 10% dimethyl sulfoxide (DMSO) and 1% Dextran 40, at the time of cryopreservation.

Commentary: Hemacord is the first cord blood product to be approved in the U.S. and is the first licensed therapy for use in hematopoietic stem-cell transplantation in patients with disorders affecting the hematopoietic system. Cord blood transplants have been used to treat patients with certain blood cancers and some inherited metabolic and immune system disorders. Cord blood, which remains in the umbilical cord and the placenta after childbirth, is routinely discarded as biologic waste; however, in recent years, some patents with financial means and interest have been saving a sample of their newborn infant’s cord blood at a cord blood bank, and some public blood banks have begun to collect and store cryopreserved cord blood for public use.

Sources: www.fda.gov; www.nybloodcenter.org; www.medicalnewstoday.com

Tables

Proposed Starting Doses

Platelet Count Starting Dose
Greater than 200 x 109/L 20 mg orally twice daily
100 x 109/L to 200 x 109/L 15 mg orally twice daily

From Jakafi prescribing information.

Maximum Restarting Doses After a Safety Interruption*

Current Platelet Count Maximum Dose When Restarting Treatment*
Greater than or equal to 125 x 109/L 20 mg twice daily
100 to less than 125 x 109/L 15 mg twice daily
75 to less than 100 x 109/L 10 mg twice daily for at least 2 weeks; if stable, may increase to 15 mg twice daily
50 to less than 75 x 109/L 5 mg twice daily for at least 2 weeks; if stable, may increase to 10 mg twice daily
Below 50 x 109/L Continue hold

*Maximum doses are displayed. When restarting, begin with a dose at least 5 mg twice daily below the dose at interruption.

From Jakafi prescribing information.

Dosing Recommendations for Thrombocytopenia

Dose at the Time of Platelet Decline
25 mg twice daily 20 mg twice daily 15 mg twice daily 10 mg twice daily 5 mg twice daily
Platelet count New dose New dose New dose New dose New dose
100 to less than 125 x 109/L 20 mg twice daily 15 mg twice daily No change No change No change
75 to less than 100 x 109/L 10 mg twice daily 10 mg twice daily 10 mg twice daily No change No change
50 to less than 75 x 109/L 5 mg twice daily 5 mg twice daily 5 mg twice daily 5 mg twice daily No change
Less than 50 x 109/L Hold Hold Hold Hold Hold

From Jakafi prescribing information.