Pharmaceutical Approval Update June 2017
Manufacturer: Novartis Pharmaceuticals, East Hanover, New Jersey
Date of Approval: March 13, 2017
Indication: Ribociclib is a cyclin-dependent kinase (CDK) inhibitor indicated in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) advanced or metastatic breast cancer.
Drug Class: CDK4/6 inhibitor
Uniqueness of Drug: Breast cancer is the second most common cancer among women in the United States, and the American Cancer Society estimates that more than 250,000 women will be diagnosed with invasive breast cancer in 2017. Ribociclib is approved as a first-line treatment for HR+/HER2− metastatic breast cancer in combination with an aromatase inhibitor.
Warnings and Precautions:
QT interval prolongation. Monitor patients’ electrocardiograms (ECGs) and electrolytes (potassium, calcium, phosphorus, magnesium) prior to initiation of treatment with ribociclib. Repeat ECGs at approximately day 14 of the first cycle and at the beginning of the second cycle, and as clinically indicated. Monitor electrolytes at the beginning of each cycle for six cycles, and as clinically indicated.
Avoid the use of ribociclib in patients who already have or who are at significant risk of developing QTc prolongation, including patients with long QT syndrome, uncontrolled or significant cardiac disease (including recent myocardial infarction, congestive heart failure, unstable angina, and brady-arrhythmias), and electrolyte abnormalities. Avoid using ribociclib with drugs known to prolong the QTc interval and/or strong cytochrome P450 3A inhibitors as this may lead to prolongation of the QTcF interval. Based on the observed QT prolongation during treatment, ribociclib may require dose interruption, reduction, or discontinuation.
Hepatobiliary toxicity. Increases in serum transaminase levels have been observed. Perform liver function tests (LFTs) before initiating treatment with ribociclib. Monitor LFTs every two weeks for the first two cycles, at the beginning of each subsequent four cycles, and as clinically indicated.
Neutropenia. Perform a complete blood count (CBC) before initiating therapy with ribociclib. Monitor CBC every two weeks for the first two cycles, at the beginning of each subsequent four cycles, and as clinically indicated.
Embryo-fetal toxicity. Based on findings from animal studies and upon the drug’s mechanism of action, ribociclib can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus and to use effective contraception during therapy.
Dosage and Administration: Ribociclib tablets are taken in combination with letrozole. The recommended starting dose is 600 mg (three 200-mg tablets) of ribociclib taken once daily with or without food for 21 consecutive days followed by seven days off treatment. Patients should take their dose of ribociclib and letrozole at the same time each day, preferably in the morning. Dose interruption, reduction, and/or discontinuation may be required based on individual safety and tolerability.
Commentary: The Food and Drug Administration’s approval of ribociclib was based on a randomized, double-blind, placebo-controlled, international clinical trial in postmenopausal women with HR+/HER2− advanced or metastatic breast cancer who had received no prior therapy for advanced disease. Patients (N = 668) were randomized to receive ribociclib plus letrozole (n = 334) or placebo plus letrozole (n = 334). Ribociclib 600 mg or placebo was administered orally once daily for 21 consecutive days (followed by seven days off), along with letrozole 2.5 mg administered orally once daily for 28 days. Treatment continued until disease progression or unacceptable toxicity. The addition of ribociclib reduced the risk of progression or death by 44% during follow-up. Median progression-free survival was 25.3 months for the ribociclib/letrozole combination compared with 16 months for letrozole alone. The most common adverse reactions observed in 20% or more of patients taking ribociclib were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain.
Sources: Novartis Pharmaceuticals, Kisqali prescribing information
Manufacturer: US WorldMeds LLC, Louisville, Kentucky
Date of Approval: March 21, 2017
Indication: Safinamide is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease (PD) experiencing “off” episodes. It has not been shown to be effective as monotherapy for the treatment of PD.
Drug Class: Monoamine oxidase type B (MAO-B) inhibitor
Uniqueness of Drug: PD is the second most common chronic progressive neurodegenerative disorder in the elderly after Alzheimer’s disease. PD affects an estimated seven to 10 million patients worldwide, of whom one million are in the United States. Safinamide is the first new drug in a decade approved for the treatment of PD.
Warnings and Precautions:
Hypertension. Safinamide may cause hypertension or exacerbate existing hypertension. Monitor for hypertension if safinamide is prescribed concomitantly with sympathomimetic medications, including prescription or nonprescription nasal, oral, and ophthalmic decongestants and cold remedies.
Serotonin syndrome. Concomitant use of safinamide with MAO inhibitors, antidepressants, or opioid drugs may cause serotonin syndrome and is contraindicated.
Falling asleep during activities of daily living. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), safinamide should be discontinued. If patients continue taking safinamide, advise them to avoid driving and other potentially dangerous activities.
Dyskinesia. Safinamide may cause dyskinesia or exacerbate pre-existing dyskinesia. Reducing the patient’s daily levodopa dosage or the dosage of other dopaminergic drugs may mitigate dyskinesia.
Hallucinations/psychotic behavior. Patients with major psychotic disorders should not be treated with safinamide because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone. In addition, treatments for psychosis that antagonize the effects of dopaminergic medications may exacerbate the symptoms of Parkinson’s disease. Consider dosage reduction or stopping the medication if a patient develops hallucinations or psychotic-like behaviors while taking safinamide.
Impulse control/compulsive behaviors. Patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including safinamide, that increase central dopaminergic tone. In some cases, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about compulsive behaviors while on this medication. Consider dose reduction or stopping the medication if a patient develops such urges while taking safinamide.
Withdrawal-emergent hyperpyrexia and confusion.
A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone.
Retinal pathology. Monitor periodically for visual changes in patients with a history of retinal/macular degeneration, uveitis, inherited retinal conditions, family history of hereditary retinal disease, albinism, retinitis pigmentosa, or any active retinopathy (e.g., diabetic retinopathy).
Dosage and Administration: The recommended starting dosage of safinamide is 50 mg administered orally once daily (at the same time of day), without regard to meals. After two weeks, the dosage may be increased to 100 mg once daily, based on individual need and tolerability. Daily dosages of safinamide greater than 100 mg have not been shown to provide additional benefit, and higher dosages increase the risk for adverse reactions. Safinamide has been shown to be effective only in combination with levodopa/carbidopa. If a dose is missed, the next dose should be taken at the same time the next day. Safinamide 100 mg should be tapered by decreasing the dose to 50 mg for one week before stopping the medication.
Commentary: The efficacy of safinamide in treating PD was shown in a clinical trial with 645 participants who were also taking levodopa and were experiencing “off” time. Those receiving safinamide experienced more beneficial “on” time, when Parkinson’s symptoms are reduced, without dyskinesia, compared with those receiving a placebo. The increase in “on” time was accompanied by a reduction in “off” time and better scores on a measure of motor function assessed during “on” time than before treatment. In another clinical trial of 549 participants, the patients who had safinamide added to their levodopa treatment had more “on” time without troublesome uncontrolled involuntary movement compared with those taking a placebo and also had better scores on a measure of motor function assessed during “on” time than before treatment. The most common adverse reactions were dyskinesia, falls, nausea, and insomnia.
Sources: US WorldMeds LLC, Xadago prescribing information
Manufacturer: EMD Serono, Inc., Rockland, Massachusetts
Date of Approval: March 23, 2017
Indication: Avelumab is indicated for the treatment of adults and children 12 years of age and older with metastatic Merkel cell carcinoma (MCC). This indication received accelerated approval based on tumor response and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Drug Class: Programmed death-1/programmed death ligand-1 inhibitor
Uniqueness of Drug: According to the National Cancer Institute, about 1,600 people in the United States are diagnosed with MCC. Avelumab helps the immune system to fight this rare form of skin cancer once it has spread to other parts of the body.
Warnings and Precautions:
Immune-mediated pneumonitis. Withhold avelumab for moderate pneumonitis; permanently discontinue for severe, life-threatening, or recurrent moderate pneumonitis.
Immune-mediated hepatitis. Monitor patients for changes in liver function. Withhold for moderate hepatitis; permanently discontinue for severe or life-threatening hepatitis.
Immune-mediated colitis. Withhold avelumab for moderate or severe colitis; permanently discontinue for life-threatening or recurrent severe colitis.
Immune-mediated endocrinopathies. Withhold avelumab for severe or life-threatening endocrinopathies.
Immune-mediated nephritis and renal dysfunction. Withhold avelumab for moderate or severe nephritis and renal dysfunction; permanently discontinue for life-threatening nephritis or renal dysfunction.
Infusion-related reactions. Interrupt or slow the rate of infusion for mild or moderate infusion-related reactions. Stop the infusion and permanently discontinue avelumab for severe or life-threatening infusion-related reactions.
Embryo-fetal toxicity. Avelumab can cause fetal harm. Advise the patient of the potential risk to a fetus and to use effective contraception.
Dosage and Administration: The recommended dose of avelumab is 10 mg/kg administered as an intravenous infusion over 60 minutes every two weeks until disease progression or unacceptable toxicity. Premedicate patients with an antihistamine and acetaminophen prior to the first four infusions of avelumab. Premedication should be administered for subsequent avelumab doses based upon clinical judgment and presence/severity of prior infusion reactions.
Commentary: The approval of avelumab was based on a single-arm, 88-patient study in which one-third of participants saw their tumors shrink partially or completely. The 86% of patients who responded were still seeing results with therapy six months later. The most common adverse reactions (reported in 20% or more of patients) were fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, and peripheral edema.
Sources: EMD Serono, Inc., Bavencio prescribing information