Pharmaceutical Approval Update August 2017
Manufacturer: Shionogi, Inc., Florham Park, New Jersey
Date of Approval: March 23, 2017
Indication: Naldemedine is indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain.
Drug Class: Opioid antagonist
Uniqueness of Drug: This is the second orally available opioid antagonist for treating OIC. However, naldemedine is the first oral opioid antagonist issued as a Schedule II controlled substance due to its structural similarity to naltrexone. Methylnaltrexone bromide (Relistor, Salix Pharmaceuticals), approved as an oral tablet in July 2016, is also indicated for treating OIC in adult patients with chronic noncancer pain.
Warnings and Precautions:
Gastrointestinal (GI) perforation. Cases of GI perforation have been reported while using other peripherally acting opioid antagonists in patients with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the GI tract, such as peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative GI tract malignancies, or peritoneal metastases. When prescribing naldemedine, take into account the overall risk–benefit profile in patients with these conditions or with other conditions that might lead to impaired GI tract wall integrity (e.g., Crohn’s disease). Monitor patients for the development of severe, persistent, or worsening abdominal pain, and discontinue naldemedine in patients who develop this symptom.
Opioid withdrawal. Clusters of symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, increased lacrimation, hot flush/flushing, pyrexia, sneezing, feeling cold, abdominal pain, diarrhea, nausea, and vomiting have occurred in patients treated with naldemedine. Patients with blood–brain barrier breakdown may be at increased risk for opioid withdrawal or reduced analgesia. The overall risk–benefit profile should be taken into account when using naldemedine in these patients. These and all patients should be monitored for symptoms of opioid withdrawal.
Drug interactions. Avoid concomitant use of strong cytochrome P450 (CYP) 3A inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because they decrease naldemedine concentrations. Avoid concomitant use of other opioid antagonists due to the potential for additive effects and an increased risk of opioid withdrawal. Patients should be monitored for adverse reactions with concomitant use of moderate (e.g., fluconazole, atazanavir, aprepitant) and/or strong (e.g., itraconazole, clarithromycin, ritonavir) CYP3A4 inhibitors, due to their ability to increase naldemedine concentrations. Patients should also be monitored for adverse reactions when naldemedine is coadministered with P-glycoprotein inhibitors (e.g., amiodarone, captopril, cyclosporine).
Contraindications: Due to the potential for GI perforation, naldemedine is contraindicated in patients with known or suspected GI obstruction and in patients at increased risk of recurrent obstruction. Naldemedine is also contraindicated in patients with a history of hypersensitivity to the drug. Reactions have included bronchospasm and rash.
Dosage and Administration: In adults, the recommended dose of naldemedine is 0.2 mg once daily with or without food. Patients receiving opioids for less than four weeks may be less responsive to naldemedine. If the opioid pain medication is discontinued, naldemedine should also be discontinued.
Commentary: Naldemedine was evaluated in two replicate 12-week, randomized, double-blind, placebo-controlled trials (study 1, N = 547; and study 2, N = 553). Naldemedine increased the frequency of spontaneous bowel movements (SBMs) weekly from baseline to the last two weeks of the 12-week treatment period. In addition, naldemedine increased the mean frequency of complete SBMs per week from baseline to the last two weeks of the 12-week treatment period. Naldemedine also improved the frequency of straining associated with SBMs. The most common adverse reactions experienced by patients receiving treatment compared with placebo-treated patients were abdominal pain (8% versus 2%), diarrhea (7% versus 2%), gastroenteritis (2% versus 1%), and nausea (4% versus 2%).
Sources: Shionogi, Inc., Symproic prescribing information; Salix Pharmaceuticals, Relistor prescribing information; and Food and Drug Administration, Symproic approval letter
Manufacturer: Teva Pharmaceuticals USA, Inc., North Wales, Pennsylvania
Date of Approval: April 3, 2017
Indication: Deutetrabenazine is indicated for the treatment of chorea associated with Huntington’s disease (HD).
Drug Class: Vesicular monoamine transporter 2 (VMAT2) inhibitor
Uniqueness of Drug: The precise mechanism by which deutetrabenazine exerts its antichorea effects is unknown, but it is believed to be related to its effect as a reversible depletor of monoamines such as dopamine, serotonin, norepinephrine, and histamine from nerve terminals. The major circulating metabolites of deutetrabenazine, alpha-dihydrotetrabenazine (α-HTBZ) and beta-dihydrotetrabenazine (β-HTBZ), are reversible inhibitors of VMAT2, resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores.
Deutetrabenazine, previously granted orphan drug status by the Food and Drug Administration, is the first deuterated product approved by the agency. Deutetrabenazine is the second product approved for HD, a rare and fatal neurodegenerative disorder affecting more than 35,000 people in the United States. Chorea is one of the most obvious physical manifestations of HD, occurring in approximately 90% of patients. Chorea significantly impacts patients’ functionality and activities of daily living. This is the first new treatment for HD chorea in nearly a decade.
Warnings and Precautions:
Boxed warning: depression and suicidal thoughts and behavior (suicidality). When considering the use of deutetrabenazine, the risk of suicidality should be balanced against the need for chorea treatment. All deutetrabenazine-treated patients should be monitored for new or worsening depression or suicidality. If these occur and do not resolve, discontinuation of treatment should be considered. Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with the drug and should be instructed to immediately report concerning behaviors to the treating physician. Patients with HD who express suicidal ideation should be evaluated immediately. Caution should be utilized when treating patients with a history of suicide attempts, suicidal ideation, or depression.
Clinical worsening and adverse events. HD is progressive and is characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time. Deutetrabenazine may worsen mood, cognition, rigidity, and functional capacity. Prescribers should periodically re-evaluate the need for deutetrabenazine in patients by assessing its effect on chorea and possible adverse effects, including sedation/somnolence, depression and suicidality, parkinsonism, akathisia, restlessness, and cognitive decline. Sometimes it may be difficult to distinguish between adverse reactions and HD progression. Decreasing the deutetrabenazine dose or stopping it may help distinguish the difference. In some patients, the underlying chorea may improve over time, decreasing the need for deutetrabenazine.
Neuroleptic malignant syndrome (NMS). Although NMS has not been reported with deutetrabenazine, it has been reported with other drugs that reduce dopamine transmission. Clinicians should be alerted to the signs and symptoms associated with NMS, including hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. Additional signs may include elevated creatinine phospho kinase, myoglobinuria, rhabdomyolysis, and acute renal failure. If NMS occurs, deutetrabenazine should be discontinued immediately. NMS recurrence has been reported with drug therapy resumption; therefore, if deutetrabenazine treatment is needed after NMS recovery, patients should be closely monitored for signs of recurrence.
Akathisia, agitation, restlessness, and parkinsonism. Deutetrabenazine may increase the risk of akathisia, agitation, restlessness, and parkinsonism in patients with HD. Dose reduction or discontinuation may be necessary.
Sedation and somnolence. Sedation is a dose-limiting side effect of deutetrabenazine. Until patients are aware of how the drug affects them, they should not perform activities requiring mental alertness to maintain safety. This includes driving a motor vehicle and/or operating hazardous machinery.
QTc prolongation. Tetrabenazine, a closely related VMAT2 inhibitor, causes an approximate 8-msec increase in the corrected QT (QTc) interval; therefore, a clinically relevant QT prolongation may occur in some patients treated with deutetrabenazine who are poor metabolizers of cytochrome P450 (CYP) 2D6 or are taking a strong CYP2D6 inhibitor. Deutetrabenazine use should be avoided in combination with other known QTc-prolonging drugs, such as antipsychotics (e.g., chlorpromazine, haloperidol, thioridazine), antibiotics (e.g., moxifloxacin), and class 1A (e.g., quinidine, procainamide) and class III anti-arrhythmics (e.g., amiodarone, sotalol).
Hyperprolactinemia. Although serum prolactin levels were not measured in the Austedo trials, tetrabenazine has been shown to elevate prolactin levels. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, which is an important factor if deutetrabenazine is being considered for a patient with previously detected breast cancer. Chronic increases in serum prolactin levels can cause low estrogen levels, which are associated with an increased risk of osteoporosis. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be performed, and deutetrabenazine discontinuation should be considered.
Possible long-term ophthalmic effects. Deutetrabenazine and its metabolites bind to melanin-containing tissues, which could accumulate over time. Ophthalmological or microscopic examination of the eye was not conducted in the chronic toxicity studies, and ophthalmological monitoring in humans was inadequate to exclude the possibility of injury after long-term exposure.
Contraindications. Deutetrabenazine is contraindicated in patients who are suicidal, or who have untreated or inadequately treated depression. It should not be used in patients with congenital long QT syndrome or in patients with a history of cardiac arrhythmias. Deutetrabenazine is contraindicated in patients with hepatic impairment, due to the results of tetrabenazine clinical trials. In these trials, the exposure to deuterated dihydro metabolites α-HTBZ and β-HTBZ was up to 40% greater in patients with hepatic impairment, and the mean tetrabenazine peak concentration in patients with hepatic impairment was up to 190-fold higher than in healthy individuals. Deutetrabenazine should not be prescribed for patients already taking tetrabenazine or for those taking monoamine oxidase inhibitors or reserpine. Concomitant use with dopamine antagonists or antipsychotics can increase the risk for parkinsonism, NMS, and akathisia. Sedating drugs, including alcohol, can cause additive somnolence or worsened sedation.
Dosage and Administration: The recommended starting dose of deutetrabenazine is 6 mg once daily. It should be titrated up at weekly intervals by 6 mg daily to a tolerated dose that reduces chorea, up to a maximum recommended daily dosage of 48 mg (24 mg twice daily). Total daily doses of at least 12 mg should be given as two divided doses. It should be administered with food and swallowed whole. If patients are being switched from tetrabenazine, discontinue tetrabenazine and start deutetrabenazine the next day. See the full prescribing information for Austedo for the dose conversion table from tetrabenazine to this agent. The maximum recommended dosage of deutetrabenazine in poor CYP2D6 metabolizers is 18 mg twice daily (a total daily dose of 36 mg).
Commentary: The efficacy of deutetrabenazine for treating HD chorea was established in a multicenter, randomized, double-blind, placebo-controlled trial in 90 ambulatory patients with manifest chorea associated with HD. The total maximal chorea scores for patients who received deutetrabenazine showed a statistically significant improvement of approximately 4.4 units from baseline to the maintenance period (average of week 9 and week 12), compared with approximately 1.9 units in the placebo group. In a patient-rated global impression assessment, 51% of deutetrabenazine-treated patients rated their symptoms at the end of treatment as “improved” or “much improved,” compared with 20% of placebo-treated patients. In a physician-rated clinical global impression of change, 42% of deutetrabenazine-treated patients were rated as “improved” or “much improved,” compared with 13% of placebo-treated patients. The most common side effects of deutetrabenazine in clinical trials were sedation, diarrhea, tiredness, and dry mouth.
Sources: Teva, Austedo prescribing information
Manufacturer: Samsung Bioepis Co. Ltd., Incheon, Korea
Date of Approval: April 21, 2017
Indication: Renflexis is indicated for the treatment of moderately to severely active Crohn’s disease (CD) in adults and children, and for adults with ulcerative colitis (UC), rheumatoid arthritis (RA) in combination with methotrexate, active ankylosing spondylitis (AS), psoriatic arthritis (PsA), and chronic severe plaque psoriasis.
Drug Class: Tumor necrosis factor (TNF)-alpha inhibitor
Uniqueness of Drug: Renflexis is the first Samsung Bioepis product approved for marketing in the United States, and is the second biosimilar to Remicade (infliximab, Janssen Biotech) approved in the U.S.
Warnings and Precautions:
Boxed warning: increased risk of infection. Renflexis carries an increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis), and infections due to other opportunistic pathogens. Renflexis should not be administered during an active infection. If a Renflexis-treated patient develops an infection, he or she should be carefully monitored, and Renflexis should be stopped if the infection becomes serious. Prior to starting treatment, patients should be tested for latent TB and if positive, TB treatment should be started prior to starting Renflexis. All Renflexis-treated patients should be monitored for the development of active TB, even if their initial latent TB test was negative. For patients who reside or travel in regions where mycoses are endemic, invasive fungal infections should be suspected if patients develop a serious systemic illness. Empiric antifungal therapy should be considered for these patients.
Boxed warning: lymphoma and other malignancies. These malignancies, some fatal, have been reported in children and adolescents treated with TNF blockers, including infliximab products. Fatal hepatosplenic T-cell lymphoma has been reported post-marketing in patients treated with TNF blockers, including infliximab products. Almost all of these patients had received azathioprine or 6-mercaptopurine along with a TNF blocker at or prior to diagnosis. The majority of cases were reported in patients with CD or UC; most were adolescent or young adult males.
Demyelinating disease. During Renflexis treatment, exacerbation or new onset of demyelinating disease may occur.
Lupus-like syndrome. Lupus-like syndrome may occur during Renflexis treatment. Treatment should be discontinued if this syndrome develops.
Hepatitis B virus (HBV) reactivation. Prior to starting Renflexis, patients should be tested for HBV infection. HBV carriers should be monitored during and for several months after therapy. If reactivation occurs, Renflexis should be stopped and HBV antiviral therapy should be given.
Hepatotoxicity. Rare severe hepatic reactions may occur, some fatal or necessitating liver transplantation. Renflexis should be discontinued if patients develop jaundice and/or marked liver enzyme elevations.
Heart failure. New onset or worsening of heart failure symptoms may occur.
Cytopenias. Advise patients to seek immediate medical attention if signs and symptoms develop, and consider stopping Renflexis.
Hypersensitivity. Serious infusion reactions, including anaphylaxis or serum sickness-like reactions, may occur during Renflexis treatment.
Live vaccines or therapeutic infectious agents. These agents should not be given with Renflexis. All pediatric patients should be brought up to date with all vaccinations prior to initiating Renflexis treatment. There should be a waiting period of at least six months following birth before the administration of live vaccines to infants that have been exposed in utero to infliximab products.
Contraindications. Renflexis doses greater than 5 mg/kg are contraindicated in patients with moderate-to-severe heart failure. Use of Renflexis is also contraindicated in any patient with a previous severe hypersensitivity reaction to any infliximab products, a known hypersensitivity to Renflexis inactive ingredients, or a known hypersensitivity to any murine proteins.
Dosage and Administration: Renflexis is administered by intravenous infusion over a period of at least two hours. Patient dose varies by indication and patient weight.
Adult CD: 5 mg/kg at weeks 0, 2, and 6, then every eight weeks. Some adult patients who initially respond to treatment may benefit from a dose increase to 10 mg/kg if they later lose their response.
Pediatric CD, UC, PsA, and plaque psoriasis: 5 mg/kg at weeks 0, 2, and 6, then every eight weeks.
RA: Given with methotrexate, 3 mg/kg at weeks 0, 2, and 6, then every eight weeks. Some patients may benefit from increasing the dose to 10 mg/kg or by receiving treatment every four weeks.
AS: 5 mg/kg at weeks 0, 2, and 6, then every six weeks.
Commentary: The approval of Renflexis was based on the review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrate Renflexis is biosimilar to Remicade. The most common side effects of Renflexis include infections (e.g., upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain.
Source: Samsung Bioepsis Co. Ltd., Renflexis prescribing information