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P T. 2010 August; 35(8): 475–478.
PMCID: PMC2935647

Pharmaceutical Approval Update

Marvin M. Goldenberg, PhD, RPh, MS

Cabazitaxel (Jevtana) Injection

Manufacturer: Sanofi-Aventis, Bridgewater, N.J.

Indication: Cabazitaxel is used in combination with prednisone for the treatment of patients with hormone-refractory metastatic prostate cancer who have previously received regimens containing docetaxel (Taxotere, Sanofi-Aventis).

Drug Class: This antineoplastic agent belongs to the taxane class and is prepared by semisynthesis with a precursor extracted from yew needles. The chemical name is (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3[(tertbutoxycarbonyl)amino-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9oxo-5,20-epoxytax-11-en-2-yl benzoate–propan-2-one(1:1). The molecular formula is C45H57NO14 • C3H6O, and the molecular weight is 894.01.

Uniqueness of Product: A microtubule inhibitor, cabazitaxel binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly. This leads to the stabilization of microtubules, which results in the inhibition of mitotic and interphase cellular functions.

Boxed Warning: Deaths from neutropenia have been reported. In order to monitor the occurrence of neutropenia, all patients should undergo frequent blood cell counts. Cabazitaxel should not be given to patients if neutrophil counts are 1,500 cells/mm3 or below.

Severe hypersensitivity reactions can include generalized rash or erythema, hypotension, and bronchospasm. The infusion should be discontinued immediately, and appropriate therapy should be administered. Patients should receive pre-medication with a histamine-2 (H2) antagonist and a corticosteroid. Cabazitaxel must not be given to patients with a history of severe hypersensitivity reactions to this product or to other drugs formulated with polysorbate 80.

Warnings and Precautions: Neutropenic deaths have been reported. Blood counts should be monitored often to determine whether granulocyte–colony-stimulating factor (G–CSF) or a dosage modification is needed. Primary prophylaxis with G–CSF should be considered in patients with high-risk clinical features.

Severe hypersensitivity reactions can occur. Patients should receive premedication with a corticosteroid and an H2-antagonist. The infusion should be stopped immediately if hypersensitivity is observed.

Mortality related to diarrhea has been reported. The patient should be rehydrated and treated with an antiemetic and anti-diarrheal agents as needed. If the patient is experiencing grade 3 or higher diarrhea, the dose should be modified.

Renal failure, including cases with fatal outcomes, has been reported. The cause should be identified and managed aggressively.

In a clinical trial, patients 65 years of age or older were more likely to experience fatal outcomes not related to disease progression and certain adverse reactions, including neutropenia and febrile neutropenia. Close monitoring is indicated.

Hepatic impairment is likely to increase cabazitaxel levels. The drug should not be given to patients with hepatic impairment. Patients with impaired hepatic function were excluded from the randomized clinical trial.

Fetal harm can result when cabazitaxel is administered to pregnant women.

Dosage and Administration: The individual dosage, based on calculation of the body surface area, is 25 mg/m2. The drug is given as a one-hour intravenous (IV) infusion every three weeks in combination with oral prednisone 10 mg, given daily throughout treatment.

Patients should receive premedication at least 30 minutes before each dose with the following IV agents to reduce the risk and severity of hypersensitivity: an antihistamine (dexchlorpheniramine 5 mg, or diphenhydramine 25 mg or an equivalent antihistamine); a corticosteroid (dexamethasone 8 mg or equivalent); and an H2-antagonist (ranitidine 50 mg or equivalent steroid). Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed.

Cabazitaxel should be administered under the supervision of a qualified physician experienced in the use of antineoplastic medicinal products.

Infusion containers containing polyvinyl chloride (PVC) and polyurethane infusion sets should not be used to prepare or administer the infusion solution.

The injection and the diluent vials contain an overfill to compensate for liquid loss during preparation. The final cabazitaxel solution should be administered intravenously as a one-hour infusion at room temperature. An in-line filter of 0.22 microns (μm) of nominal pore size is used during administration. The final infusion solution should be used immediately. However, in-use storage time can be longer under specific conditions, such as for eight hours under ambient conditions (including the one-hour infusion) or for a total of 24 hours if the solution is refrigerated (including the one-hour infusion).

Jevtana 60 mg/1.5 mL is supplied as a kit and contains 60 mg of cabazitaxel in 1.5 mL of polysorbate 80, a diluent for the injection contains approximately 5.7 mL of 13% weight for weight (w/w) ethanol in water for injection.

Commentary: Prostate cancer remains the second most common cause of death from cancer in the U.S. Approximately 217,800 new cases of prostate cancer are expected to be detected in 2010. It is anticipated that nearly 32,100 men will die from prostate cancer in 2010.

Prostate cancer is a hormonally sensitive disease that can be controlled for long periods with androgen-deprivation therapy or chemical castration. When the disease stops responding to this therapy, it can be difficult to treat. The FDA has approved the chemotherapy agent cabazitaxel (Jevtana) to be used in conjunction with the steroid prednisone for patients with hormone-refractory prostate cancer. Cabazitaxel is the first drug to be approved for prostate cancer that has progressed during or after therapy with docetaxel (Taxotere), and it has been moved forward under the FDA’s expedited review program. This is the only FDA-approved regimen that significantly improves overall survival in patients with hormone-refractory metastatic prostate cancer who have received a docetaxel regimen.

Sources: http://products.sanofi-aventis.us/jevtana/jevtana.pdf; www.accessdata.fda.gov/drugsatfda_docs/label/2010/201023lbl.pdf

Aztreonam for Inhalation Solution (Cayston)

Manufacturer: Gilead Sciences, Foster City, Calif.

Indication: Aztreonam for inhalation solution is a monobactam antibacterial agent used for improving respiratory symptoms in cystic fibrosis (CF) patients with Pseudomonas aeruginosa infection. The drug’s safety and effectiveness have not been established in pediatric patients younger than seven years of age, patients with a forced expiratory volume in 1 second (FEV1) of between 25% and 75% predicted, or patients with Burkholderia cepacia infection.

Drug Class: The active ingredient is aztreonam, a monobactam antibacterial. The monobactams differ structurally from beta-lactam antibiotics (e.g., penicillins, cephalosporins, carbapenems) because of their monocyclic nucleus. This nucleus contains several side chains; sulfonic acid in the 1-position activates the nucleus, an aminothiazolyl oxime side chain in the 3-position confers specificity for aerobic gram-negative bacteria, including Pseudomonas species; and a methyl group in the 4-position enhances beta-lactamase stability.

Aztreonam is designated chemically as (Z)-2-[[[(2-amino-4-thiazolyl)[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]carbamoyl]methylene]amino]oxy]-2-methylpropionic acid.

Uniqueness of Drug: Aztreonam exhibits activity in vitro against gram-negative aerobic pathogens, including P. aeruginosa. It binds to penicillin-binding proteins of susceptible bacteria, which leads to inhibition of bacterial cell wall synthesis and death of the cell. Aztreonam activity is not decreased in the presence of lung secretions in patients with CF.

Warnings and Precautions:

Allergic reactions. Severe allergic reactions have been reported following administration of aztreonam for injection to patients with no known history of exposure to this product. Allergic reactions with facial rash, facial swelling, and throat tightness have also been reported in clinical trials. If an allergic reaction occurs, the drug should be stopped and appropriate treatment should be initiated.

Caution is advised if patients have a history of beta-lactam allergy, although in clinical trials no severe allergic reactions were reported in patients with a known beta-lactam allergy who received aztreonam. A history of allergy to beta-lactams, such as penicillins, cephalosporins, and carbapenems, may be a risk factor, because cross-reactivity may occur.

Bronchospasm. Bronchospasm is a complication associated with nebulized therapies, including aztreonam. A reduction of 15% or more in FEV1 immediately following administration of the study medication was observed in 3% of patients receiving aztreonam after pretreatment with a bronchodilator.

Decreases in FEV1 after a two-day cycle. In clinical trials, patients with increases in FEV1 during a 28-day course of aztreonam were sometimes treated for pulmonary exacerbations when FEV1 declined after the treatment period. Health care providers should consider the patient’s baseline FEV1 and the presence of other symptoms when evaluating whether post-treatment changes in FEV1 are caused by a pulmonary exacerbation.

Development of drug-resistant bacteria. Prescribing aztreonam in the absence of known P. aeruginosa infection in patients with CF is unlikely to provide benefit and increases the risk of the development of drug-resistant bacteria.

Dosage and Administration: The recommended dose for both adults and pediatric patients seven years of age and older is one single-use vial (75 mg of aztreonam), reconstituted with 1 mL of sterile diluent and administered three times per day for a 28-day course, followed by 28 days without aztreonam therapy. The dosage is not based on weight or adjusted for age. Doses should be taken at least four hours apart.

The Altera Nebulizer System is used to administer aztreonam (Cayston) by inhalation. Patients should use a bronchodilator before receiving therapy. Aztreonam should not be administered with any other nebulizer, and it should not be mixed with any other drugs in the nebulizer handset.

Aztreonam should be administered immediately after reconstitution. The product should not be reconstituted until a dose is ready to be given. One amber glass vial containing the drug and one diluent ampule from the carton should be used.

Commentary: Cystic fibrosis is a chronic, debilitating genetic condition that affects the respiratory and digestive systems of approximately 70,000 people worldwide, including 30,000 people in the U.S. Chronic respiratory tract infection with P. aeruginosa contributes to the decline in pulmonary function, which is often associated with morbidity and mortality among these patients.

Expert clinicians indicate that inhaled antibiotic therapy is the standard of care for the treatment of chronic pseudomonal infection in people living with CF. As new inhaled antibiotic treatment options such as Cayston become available, it is important that head-to-head clinical trial data comparing different approaches be generated to determine the optimal treatment.

In a head-to-head phase 3 clinical trial that compared aztreonam inhalation solution with tobramycin inhalation solution (Tobi, Novartis) in 268 CF patients with P. aeruginosa, one of the co-primary endpoints of non-inferiority for mean percentage change in FEV1% predicted was achieved after 28 days of treatment. Patients receiving Cayston had a mean increase in FEV1% predicted from baseline to day 28 of 8.35%, compared with 0.55%, for patients receiving tobramycin, thus meeting the statistical definition of superiority. Safety results were similar for both arms of the study, with a lower incidence of cough in patients receiving aztreonam.

Results from this study suggest that Cayston may represent an important advance in anti-pseudomonal therapy for patients with CF.

Source: www.cayston.com/media/Cayston_prescribe_info.pdf

Denosumab (Prolia) Injection

Manufacturer: Amgen, Thousand Oaks, Calif.

Indication: Denosumab is indicated for postmenopausal women with osteoporosis who have a high risk for fracture. High-risk patients are defined as those with a history of osteoporotic fracture or multiple risk factors for fracture or those who have not responded to or are intolerant of other available osteoporosis therapies. In postmenopausal patients with osteoporosis, denosumab has been found to reduce the incidence of vertebral, nonvertebral, and hip fractures.

Drug Class: Denosumab has an approximate molecular weight of 147 kilodaltons (kD) and is produced in genetically engineered mammalian (Chinese hamster ovary) cells.

Uniqueness of Drug: Denosumab is a human immunoglobulin G2 (IgG2) monoclonal antibody with affinity and specificity for the human receptor activator of nuclear factor kappa-B ligand (RANKL).

Warnings and Precautions:

Hypocalcemia and mineral metabolism. Hypocalcemia may be exacerbated by the use of denosumab. Pre-existing hypocalcemia must be corrected before patients receive denosumab. In patients predisposed to hypocalcemia and disturbances of mineral metabolism, clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended. Examples of mineral disturbances include a history of hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of the small intestine, and severe renal impairment (a creatinine clearance [CrCl] of below 30 mL/minute or current dialysis).

Hypocalcemia following denosumab administration is a significant risk in patients with severe renal impairment. All patients with severe renal impairment, including those receiving dialysis, should be informed about the symptoms of hypocalcemia and the importance of maintaining adequate calcium and vitamin D levels. All patients should take calcium and vitamin D supplements.

Serious infections. In a clinical trial of more than 7,800 women with postmenopausal osteoporosis, serious infections leading to hospitalization were reported more frequently in the denosumab patients than in those receiving placebo. Serious skin infections, as well as infections of the abdomen, urinary tract, and ear, were more common in patients treated with denosumab. Endocarditis was also reported more frequently in the denosumab subjects. The incidence of opportunistic infections was balanced between placebo and denosumab groups, and the overall incidence of infections was similar between the treatment groups. Patients should be urged to seek prompt medical attention if they experience signs or symptoms of severe infection, including cellulitis.

Patients taking concomitant immunosuppressant agents and patients with an impaired immune system may be at an increased risk of serious infections. Clinicians should consider the risk–benefit profile in these patients before they prescribe denosumab. If a serious infection develops while a patient is receiving denosumab, the clinician should assess the need for continued denosumab therapy.

Dermatological adverse reactions. In a study of more than 7,800 postmenopausal women with osteoporosis, epidermal and dermal adverse events such as dermatitis, eczema, and rash occurred at a significantly higher rate with denosumab than with placebo. Most of these events were not specific to the injection site.

Jaw osteonecrosis. Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction or local infection with delayed healing. ONJ has been reported in patients receiving denosumab. The clinician should perform a routine oral examination before initiating denosumab. A dental examination with appropriate preventive dentistry should be considered before denosumab is prescribed for patients with risk factors for ONJ, such as (1) invasive dental procedures (tooth extraction, dental implants, oral surgery), (2) a diagnosis of cancer, (3) concomitant therapies (chemotherapy, corticosteroids), (4) poor oral hygiene, and (5) a comorbid disorder (a periodontal or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). Good oral hygiene practices should be maintained during treatment with denosumab.

For patients requiring invasive dental procedures, the clinical judgment of the treating physician or oral surgeon should guide the management plan of each patient based on individual risk–benefit assessment.

Patients who are thought to have ONJ or who develop ONJ during denosumab therapy should be under the care of a dentist or an oral surgeon. Extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of denosumab therapy should be considered according to each patient’s risk–benefit assessment.

Suppression of bone turnover. In clinical trials in women with postmenopausal osteoporosis, denosumab resulted in significant suppression of bone remodeling, as evidenced by markers of bone turnover and bone histomorphometry. The significance of these findings and the effects of long-term treatment with denosumab are unknown. The long-term consequences of the degree of suppression of bone remodeling observed with denosumab may contribute to adverse outcomes such as ONJ, atypical fractures, and delayed fracture healing. Patient should be monitored for these consequences.

Dosage and Administration: The recommended dose of denosumab is 60 mg, administered as a single subcutaneous (SQ) injection once every six months in the upper arm, upper thigh, or abdomen. All patients should take 1,000 mg of calcium daily and at least 400 IU of vitamin D daily.

If a dose of denosumab is missed, the injection should be given as soon as the patient is available. Thereafter, injections are given every six months from the date of the last injection.

The prefilled denosumab syringe should be visually inspected for particulate matter and discoloration prior to administration whenever the solution and container are available for inspection by the clinician. The solution should not be used if it is discolored or cloudy or if it contains many particles or foreign particulate matter.

To administer denosumab from the single-use vial, the clinician uses a 27-gauge needle to withdraw and inject the 1-mL dose. The vial should not be re-entered; it should be discarded along with any liquid remaining in the vial.

Dosage forms and strengths are 1 mL of a 60-mg/mL solution in a single-use prefilled syringe and 1 mL of a 60-mg/mL solution in a single-use vial.

Commentary: Denosumab is a fully human monoclonal antibody that specifically targets a ligand (RANKL), which binds to the RANKL receptor, a key mediator of osteoclast formation, function, and survival. Denosumab is being studied for conditions other than osteoporosis, such as treatment-induced bone loss, bone metastases, multiple myeloma, and rheumatoid arthritis, as well as for bone loss associated with hormone ablation in men with prostate cancer who are at an increased risk of fractures. Denosumab is also awaiting FDA approval in women undergoing hormone ablation for breast cancer and bone loss in men undergoing androgen-deprivation therapy for nonmetastatic prostate cancer.

With the key osteoporosis drug products expected to lose patent protection in the next few years, denosumab’s approval is an important event for Amgen. Denosumab will compete primarily with Merck’s Fosamax (alendronate), GlaxoSmith-Kline’s Boniva (ibandronate), Procter & Gamble’s Actonel (risedronate), and Eli Lilly’s Evista (raloxifene) and Forteo (teriparatide) for a share of the billion-dollar osteoporosis market.

Source: http://pi.amgen.com/united_states/prolia/prolia_pi.pdf


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