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Pharmaceutical Approval Update August 2016
Manufacturer: AbbVie, Inc., North Chicago, Illinois
Date of Approval: April 11, 2016
Indication: Venetoclax is an oral BCL-2 inhibitor indicated for treating patients with chronic lymphocytic leukemia (CLL) with 17p deletion (as detected by a Food and Drug Administration–approved test) who have received at least one prior therapy.
Drug Class: Antiapoptotic protein inhibitor
Uniqueness of Drug: CLL with 17p deletion is highly correlated with unfavorable outcomes with current standard treatments, making patients with this abnormality very high-risk. Venetoclax is a new agent with a different mechanism that is selective and orally bioavailable as a small-molecule inhibitor of BCL-2, an antiapoptotic protein. Overexpression of BCL-2 has been demonstrated in CLL cells, where it mediates tumor cell survival and has been associated with resistance to chemotherapeutics. Venetoclax helps restore the apoptosis process by binding directly to the BCL-2 protein, displacing proapoptotic proteins and triggering mitochondrial outer membrane permeabilization and the activation of caspases. In nonclinical studies, venetoclax has demonstrated cytotoxic activity in tumor cells that overexpress BCL-2.
Warnings and Precautions:
Tumor lysis syndrome (TLS). TLS, including fatal events and adrenal failure requiring dialysis, has occurred in previously treated CLL patients with a high tumor burden. Venetoclax can cause a rapid reduction in tumors and therefore poses a risk for TLS in the initial five-week ramp-up phase. Blood chemistry changes consistent with TLS require prompt management. These can occur as early as six to eight hours following the first dose and at each subsequent dose increase. The TLS risk continues based on multiple factors, including tumor burden and comorbidities. Reduced renal function (creatinine clearance of less than 80 mL/min) further increases the risk. The risk should be assessed in all patients. Patients should be pre-medicated with antihyperuricemics and provided with adequate hydration. As the overall TLS risk increases, more intensive measures (i.e., intravenous hydration, frequent monitoring, and/or hospitalization) should be undertaken. Coadministration of venetoclax with strong or moderate cytochrome P450 3A (CYP3A) inhibitors and P-glycoprotein inhibitors increases venetoclax exposure and may increase TLS risk. Perform tumor burden assessments, including radiographic evaluation, and assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) in all patients and correct pre-existing abnormalities prior to initiation of venetoclax treatment. The risk may decrease as tumor burden decreases.
Neutropenia. Grade 3 or 4 neutropenia occurred in 41% of venetoclax-treated patients. Monitor complete blood counts throughout treatment and interrupt dosing or reduce the dose for severe neutropenia. Consider supportive measures, including antimicrobials and growth factors (e.g., granulocyte colony-stimulating factor).
Immunization. Live attenuated vaccines should not be administered prior to, during, or after venetoclax treatment. Wait until B-cell recovery occurs. The safety and efficacy of immunization with live attenuated vaccines during or following venetoclax treatment have not been studied.
Embryo-fetal toxicity. Based on animal data, venetoclax may cause embryo-fetal harm when administered to a pregnant woman. If a woman becomes pregnant during treatment, she should be apprised of the potential hazard to the fetus.
Dosage and Administration: Assess patient-specific factors for risk level of TLS and provide prophylactic hydration and antihyperuricemics to patients prior to the first venetoclax dose. Recommended TLS prophylaxis is based on tumor burden from clinical trial data. Administer venetoclax according to a weekly ramp-up schedule over five weeks as follows: week 1, 20 mg; week 2, 50 mg; week 3, 100 mg; week 4, 200 mg; and week 5 and beyond, 400 mg. This ramp-up schedule is designed to gradually reduce tumor burden and decrease TLS risk. Patients should take the tablets whole and with a meal and water at about the same time each day. The tablets should not be chewed, crushed, or broken prior to ingestion.
Commentary: Venetoclax efficacy was determined in an open-label, single-arm, multicenter clinical trial of CLL patients with 17p deletion (n = 106) who had received at least one prior therapy. Patients received venetoclax via a weekly ramp-up schedule starting at 20 mg and ramping to 50 mg, 100 mg, 200 mg, and finally 400 mg once daily. Patients continued to receive venetoclax 400 mg orally once daily until disease progression or unacceptable toxicity. Venetoclax efficacy was evaluated by overall response rate as assessed by an independent review committee using the International Workshop for Chronic Lymphocytic Leukemia updated National Cancer Institute–sponsored working group guidelines (2008). The most common adverse reactions of any grade occurring in 20% or more of patients were anemia, diarrhea, fatigue, nausea, neutropenia, thrombocytopenia, and upper respiratory tract infection. Serious adverse reactions were reported in 44% of patients. The most frequent serious adverse reactions (2% or greater occurrence) were pneumonia, febrile neutropenia, pyrexia, autoimmune hemolytic anemia, anemia, and TLS.
Sources: AbbVie, Inc., Venclexta prescribing information
Riboflavin 5′-Phosphate in 20% Dextran Ophthalmic Solution and Riboflavin 5′-Phosphate Ophthalmic Solution (Photrexa Viscous and Photrexa)
Manufacturer: Avedro, Inc., Waltham, Massachusetts
Date of Approval: April 15, 2016
Indication: Photrexa Viscous and Photrexa are indicated for use in corneal collagen cross-linking in combination with the KXL system for the treatment of progressive keratoconus.
Drug Class: Topical photoenhancer
Uniqueness of Drug: Keratoconus is a progressive thinning and distortion of the cornea. It is the most common corneal dystrophy in the U.S., affecting approximately one in 2,000 Americans. It causes the cornea to bulge from its normal symmetrical shape, creating an abnormal curvature that changes corneal optics, producing blurred and distorted vision, which is difficult to correct with lenses. This progressive thinning and weakening can result in significant visual loss and may lead to corneal transplantation. Photrexa Viscous, Photrexa, and the KXL system are the first and only approved therapeutic treatment for progressive keratoconus.
Warnings and Precautions:
Ulcerative keratitis. Ulcerative keratitis (corneal ulcers) can occur. Monitor for resolution of epithelial defects.
Dosage and Administration: The solution is administered drop by drop by an ophthalmologist using a slit lamp and irradiation with the KXL system following corneal debridement under topical anesthesia.
Commentary: The safety and efficacy of riboflavin ophthalmic solution/UVA irradiation for performing corneal collagen cross-linking was evaluated in three prospective, 12-month, randomized, parallel-group, open-label, sham-controlled trials. The trials were sham-controlled for the first three months. Study 1 enrolled 58 patients, and study 2 enrolled 147 patients, all with progressive keratoconus. In each of these trials, patients had one “study eye” in which they received either riboflavin ophthalmic solution or a “sham” (placebo) treatment and one nonstudy eye. Patients were evaluated on day 1, week 1, and months 1, 3, 6, and 12. At month 3 or later, patients had the option of receiving CXL treatment in both the sham study eyes and nonstudy eyes and were followed up for 12 months from the time of receiving the CXL treatment. Approximately 56% and 89% of the sham study eyes in patients with progressive keratoconus received CXL treatment by month 3 and month 6, respectively. The average patient age was 33 years old. The maximum corneal curvature (Kmax) was assessed at baseline, and at months 1, 3, and 12 in each study.
The CXL-treated eyes showed increasing improvement in Kmax from month 3 through month 12. In the CXL-treated eyes, progressive keratoconus patients had an average Kmax reduction of 1.4 diopter and 1.7 diopter in study 1 and study 2, respectively, at month 12. The sham eyes had an average increase of 0.5 diopter and 0.6 diopter in study 1 and study 2, respectively, at month 12. The most common ocular adverse reactions in any CXL-treated eyes were corneal opacity, punctate keratitis, corneal striae, corneal epithelium defect, eye pain, reduced visual acuity, and blurred vision.
Sources: Avedro Inc.; Photrexa Viscous and Photrexa prescribing information
Manufacturer: Acadia Pharmaceuticals, Inc., San Diego, California
Date of Approval: April 29, 2016
Indication: Pimavanserin is indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease (PD) psychosis.
Drug Class: Atypical antipsychotic
Uniqueness of Drug: Pimavanserin is the first and only approved treatment for this indication. It has no appreciable binding affinity for dopamine, histamine, muscarinic, or adrenergic receptors. It is a selective inverse agonist and antagonist at serotonin 5-HT2A receptors and serotonin 5-HT2C receptors.
It is estimated that 40% of PD patients have psychosis, characterized by delusions and hallucinations.
Warnings and Precautions:
Boxed warning. There is increased mortality in elderly patients with dementia-related psychosis treated with anti-psychotic drugs, such as pimavanserin. Pimavanserin is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with PD psychosis.
QT interval prolongation. Pimavanserin increases the QT interval. Its use should be avoided with other drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval.
Drug interactions. When pimavanserin is administered with strong cytochrome P450 (CYP) 3A4 inhibitors (e.g., clarithromycin, indinavir, or ketoconazole), reduce the pimavanserin dose by half. When pimavanserin is administered with strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, or St. John’s wort), patients should be monitored for reduced efficacy, and an increase in the pimavanserin dose may be needed.
Renal and hepatic impairment. Pimavanserin requires no dosage adjustment in patients with mild-to-moderate renal impairment. However, it is not recommended in patients with severe renal impairment or severe hepatic impairment.
Dosage and Administration: The recommended pimavanserin dose is 34 mg, taken as two 17-mg tablets once daily, with or without food.
Commentary: The efficacy of pimavanserin was demonstrated in a six-week, randomized, placebo-controlled, parallel-group, outpatient study. One hundred ninety-nine patients were randomized in a 1:1 ratio and given once-daily pimavanserin or placebo. Patients were 40 years of age and older with a diagnosis of PD for at least one year before study entry along with psychotic symptoms (hallucinations and/or delusions) that started after the PD diagnosis and that were severe and frequent enough to warrant treatment with an antipsychotic. Patients were required to have a mini-mental state examination score of 21 or higher and to be able to self-report symptoms. Most patients were already on PD medications, which were required to be stable for at least 30 days prior to beginning the study and were to remain constant throughout the study period. The PD-adapted Scale for the Assessment of Positive Symptoms (SAPS-PD) was used to evaluate pimavanserin efficacy. SAPS-PD total scores range from 0 to 45 with higher scores reflecting greater illness severity. A negative change in score indicates improvement. Primary efficacy was evaluated based on change from baseline to week 6 in SAPS-PD total score. Pimavanserin 34 mg (n = 95) was statistically significantly superior to placebo (n = 90) in decreasing the frequency and/or severity of hallucinations and delusions in patients with PD psychosis as measured by central, independent, and blinded raters using the SAPS-PD scale. An effect on both hallucinations and delusions was seen.
Sources: Acadia Pharmaceuticals, Inc., Nuplazid prescribing information