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Pharmaceutical Approval Update October 2014
Manufacturer: Gilead Sciences, Foster City, California
Date of Approval: July 23, 2014
Indications: Idelalisib is indicated for the treatment of:
- Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other comorbidities
- Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies
- Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies
Drug Class: Idelalisib is a kinase inhibitor that targets the phosphatidylinositol 3-kinase, PI3Kδ.
Uniqueness of Drug: Idelalisib induces apoptosis and inhibits proliferation in cell lines derived from malignant B cells and in primary tumor cells. Idelalisib inhibits several cell signaling pathways, including B-cell receptor (BCR) signaling and CXCR4 and CXCR5 signaling, which are involved in trafficking and homing of B cells to the lymph nodes and bone marrow. Treatment of lymphoma cells with idelalisib results in inhibition of chemotaxis and adhesion and reduced cell viability.
Warnings and Precautions:
Hepatotoxicity. Fatal or serious hepatotoxicity occurred in 14% of idelalisib patients. Elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than five times the upper limit of normal have occurred. These findings were generally seen in the first 12 weeks of treatment and were reversible with dose interruption. After resumption of treatment at a lower dose, ALT and AST elevations recurred in 26% of patients. Discontinue idelalisib for recurrent hepatotoxicity; avoid concurrent use with other drugs that may cause liver toxicity.
Severe diarrhea or colitis. Across clinical trials, severe diarrhea or colitis occurred in 14% of idelalisib patients. Diarrhea can occur at any time. Avoid concurrent use of idelalisib with other drugs that cause diarrhea. Diarrhea due to idelalisib responds poorly to antimotility agents. Median time to resolution ranged from one week to one month across trials following interruption of idelalisib therapy and, in some cases, use of corticosteroids.
Pneumonitis. Serious and sometimes fatal pneumonitis occurred in patients treated with idelalisib. Patients taking this medication who present with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on a radiological exam, or a decline of more than 5% in oxygen saturation should be evaluated for pneumonitis. If pneumonitis is suspected, interrupt idelalisib until the etiology of the pulmonary symptoms has been determined. Patients with pneumonitis thought to be caused by idelalisib have been treated by discontinuing idelalisib and administering corticosteroids.
Intestinal perforation. Serious and fatal intestinal perforation has occurred in patients using idelalisib. At the time of perforation, some patients had moderate-to-severe diarrhea. Advise patients to promptly report new or worsening abdominal pain, chills, fever, nausea, or vomiting. Discontinue idelalisib permanently in patients who have intestinal perforation.
Severe cutaneous reactions. One case of toxic epidermal necrolysis occurred in a study of idelalisib in combination with rituximab and bendamustine. Other severe or life-threatening (grade 3 or higher) cutaneous reactions have been reported in idelalisib patients. Watch for the development of severe cutaneous reactions and discontinue idelalisib if they occur.
Anaphylaxis. Serious allergic reactions, including anaphylaxis, have been reported with idelalisib. In patients who have serious allergic reactions, discontinue idelalisib permanently and institute appropriate supportive measures.
Neutropenia. Treatment-emergent grade 3 or 4 neutropenia occurred in 31% of idelalisib patients across clinical trials. Monitor blood counts at least every two weeks for the first three months of therapy, and at least weekly in patients while neutrophil counts are less than 1.0 Gi/L.
Embryo-fetal toxicity. Based on findings in animals, idelalisib may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy or if the patient becomes pregnant while taking it, the patient should be apprised of the potential hazard to a fetus. Advise females of reproductive potential to avoid becoming pregnant while using idelalisib. If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after the last dose of the medication.
Dosage and Administration: The recommended maximum starting dose is 150 mg administered orally twice daily. Treatment should be continued until disease progression or unacceptable toxicity.
Commentary: Zydelig was granted traditional approval to treat patients with CLL. It became the fifth drug with a breakthrough designation by the Food and Drug Administration (FDA) to be approved, and the third drug with this designation to be approved for CLL. Accelerated approval was granted for FL and SLL based on overall response rate, but improvement in patient survival or disease-related symptoms has not been established. Continued approval for these indications may be contingent upon verification of clinical benefit in confirmatory trials.
Peginterferon Beta-1a (Plegridy)
Manufacturer: Biogen Idec, Inc., Cambridge, Massachusetts
Date of Approval: August 15, 2014
Indication: Plegridy is indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS).
Drug Class: The mechanism by which Plegridy exerts its effects in MS patients is unknown.
Uniqueness of Drug: Although peginterferon beta-1a belongs to a popular class of medications approved for relapsing forms of MS, it is the first “pegylated” form of this interferon. Pegylation involves attaching a polyethylene glycol to the interferon molecules. This process increases the circulation time, which enables the interferon to maintain biological effects in the body for longer periods and allows for less frequent dosing.
Warnings and Precautions:
Hepatic injury. Severe hepatic injury, including hepatitis, autoimmune hepatitis, and rare cases of severe hepatic failure, have been reported with interferon beta. Asymptomatic elevation of hepatic transaminases has also been reported, and in some patients has recurred upon resumption of interferon beta. Elevations in hepatic enzymes and hepatic injury have been observed with the use of Plegridy in clinical studies. The incidence of increases in hepatic transaminases was greater in patients taking Plegridy than in those taking placebo. Monitor patients for signs and symptoms of hepatic injury.
Depression and suicide. Depression, suicidal ideation, and suicide occur more frequently in patients receiving interferon beta than in patients receiving placebo. Advise patients to tell their health care provider immediately about any symptom of depression or suicidal ideation. If a patient develops depression or other severe psychiatric symptoms, consider stopping treatment with Plegridy.
Seizures. Seizures are associated with the use of interferon beta. Exercise caution when administering Plegridy to patients with a seizure disorder.
Anaphylaxis and other allergic reactions. These are rare complications of treatment with interferon beta. People who had serious allergic reactions with Plegridy recovered promptly after treatment with antihistamines or corticosteroids. Discontinue the drug if a serious allergic reaction occurs.
Injection-site reactions. Such reactions, including injection-site necrosis, can occur with the use of subcutaneous interferon beta. Decisions to discontinue therapy following necrosis at a single injection site should be based on the extent of the necro sis. For patients who continue therapy with Plegridy after injection site necrosis has occurred, avoid administration of the drug near the affected area until it is fully healed. If multiple lesions occur, discontinue Plegridy until healing occurs.
Congestive heart failure. Congestive heart failure, cardiomyopathy, and cardiomyopathy with congestive heart failure occur in patients receiving interferon beta. Monitor patients with significant cardiac disease for worsening of their cardiac condition during initiation and continuation of treatment with Plegridy.
Decreased peripheral blood counts. Interferon beta can cause decreased peripheral blood counts in all cell lines, including rare instances of pancytopenia and severe thrombocytopenia. Compared to placebo, there were no significant differences in red blood cell counts in patients treated with Plegridy. Monitor patients for infections, bleeding, and symptoms of anemia. Monitor complete blood cell counts, differential white blood cell counts, and platelet counts during treatment with Plegridy. Patients with myelosuppression may require more intensive monitoring of blood cell counts.
Autoimmune disorders. Multiple organs have been targeted by autoimmune disorders; idiopathic thrombocytopenia, hyperthyroidism, hypothyroidism, and autoimmune hepatitis have been reported with interferon beta. If patients develop a new autoimmune disorder, consider stopping Plegridy.
Dosage and Administration: The recommended dosage of Plegridy is 125 micrograms injected subcutaneously every 14 days. Patients should be titrated over 29 days to the recommended dosage and advised to rotate sites for subcutaneous injections. Prophylactic and concurrent use of analgesics and/or antipyretics may prevent or ameliorate flu-like symptoms sometimes experienced during treatment.
Commentary: Inteferon beta has proven to be successful in treating MS symptoms with a well-established safety profile. Plegridy will combine these benefits with its less frequent administration schedule because of the new pegylated formulation, increasing convenience for MS patients. Although Plegridy is in the same class as other interferon beta medications, its relative effectiveness has not been established with other MS therapies.
Manufacturer: Merck, Whitehouse Station, New Jersey
Date of Approval: August 13, 2014
Indication: Suvorexant is indicated for the treatment of insomnia characterized by difficulties with sleep onset, sleep maintenance, or both.
Drug Class: Suvorexant is an orexin receptor antagonist.
Uniqueness of Drug: The orexin neuropeptide signaling system is a central promoter of wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive. Antagonism of orexin receptors may also underlie such potential adverse effects as narcolepsy and cataplexy. Genetic mutations in the orexin system in animals result in hereditary narcolepsy; loss of orexin neurons has been reported in humans with narcolepsy.
Warnings and Precautions:
Central nervous system (CNS) depressant effects and daytime impairment. Suvorexant is a CNS depressant that can impair daytime wakefulness even when used as prescribed. Prescribers should monitor for somnolence and CNS depressant effects, but impairment can occur without symptoms and may not be detected by an ordinary clinical exam. CNS depressant effects may persist in some patients up to several days after suvorexant is discontinued. Suvorexant can impair driving skills and may increase the risk of falling asleep while driving. Discontinue or decrease the dose in patients who drive if daytime somnolence develops. The risk of next-day impairment, including impaired driving, increases if suvorexant is taken with less than a full night of sleep remaining, taken at a higher-than-recommended dose, co-administered with other CNS depressants, or co-administered with other drugs that increase blood levels of suvorexant. Patients should be cautioned against driving and other activities requiring complete mental alertness if suvorexant is taken in these circumstances.
Need to evaluate for comorbid diagnoses. Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, treatment of insomnia should be initiated only after careful evaluation of the patient. The failure of insomnia to remit after seven to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness. Worsening of insomnia or the emergence of new cognitive or behavioral abnormalities may result from an unrecognized underlying psychiatric or physical disorder, and can emerge during treatment with hypnotic drugs such as suvorexant.
Abnormal thinking and behavioral changes. Cognitive and behavioral changes (e.g., amnesia, anxiety, hallucinations, and other neuropsychiatric symptoms) have been associated with the use of hypnotics. Complex behaviors such as “sleep-driving” (driving while not fully awake), preparing and eating food, making phone calls, or engaging in sexual activity, with amnesia after the event, have been associated with the use of hypnotics in hypnotic-naïve and hypnotic-experienced persons. The use of alcohol and other CNS depressants may increase the risk of such behaviors. Discontinuation of suvorexant should be strongly considered for patients who report any complex sleep behavior.
Worsening of depression/suicidal ideation. In clinical studies, a dose-dependent increase in suicidal ideation was observed in patients taking suvorexant as assessed by questionnaire. Immediately evaluate patients with suicidal ideation or any new behavioral sign or symptom. In primarily depressed patients treated with sedative-hypnotics, worsening of depression and suicidal thoughts and actions (including completed suicides) have been reported. Suicidal tendencies may be present in such patients, and protective measures may be required. Intentional overdose is more common among these patients; therefore, the lowest number of tablets that is feasible should be prescribed for the patient at any one time. The emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
Patients with compromised respiratory function. Suvorexant’s effect on respiratory function should be considered if the drug is prescribed to patients with compromised respiratory function. Suvorexant has not been studied in patients with severe obstructive sleep apnea or severe chronic obstructive pulmonary disease.
Sleep paralysis, hypnagogic/hypnopompic hallucinations, and cataplexy-like symptoms. Sleep paralysis (an inability to move or speak for up to several minutes during sleep–wake transitions) and hypnagogic/hypnopompic hallucinations (including vivid and disturbing perceptions by the patient) can occur with suvorexant use. Prescribers should explain the nature of these events to patients when prescribing the medication. Symptoms similar to mild cataplexy can occur, with risk increasing with the dose of suvorexant. Such symptoms can include periods of leg weakness lasting from seconds to a few minutes, can occur both at night and during the day, and may not be associated with an identified triggering event.
Dosage and Administration: The recommended dose for suvorexant is 10 mg, taken no more than once per night, within 30 minutes of going to bed, and with at least seven hours remaining before the planned time of awakening. The lowest effective dose should be used for the patient.
Commentary: Belsomra is the first orexin receptor antagonist approved by the FDA for insomnia. This novel class of medication takes a new approach to the treatment of insomnia. Traditional medications have typically caused sleepiness by enhancing inhibitory neurotransmitters in the brain. Orexins promote wakefulness and arousal, and as a result, orexin receptor antagonists are used to promote sleepiness. As a more targeted sleep aid, Belsomra will be expected to cause fewer side effects.