Unless otherwise specified, the information in the following summaries applies to adults, not children. Consult a pharmacist or the package insert for information on drug safety during pregnancy and breastfeeding. Consult a pharmacist, the prescribing information, or a current and comprehensive drug reference for more details on precautions, drug interactions, and adverse reactions for all these drugs.
ANTIVIRAL AGENTS
Remdesivir
The first drug to be approved for the treatment of COVID-19.
Few, if any, events have dominated the attention of the world in recent years more than the COVID-19 pandemic. Remdesivir (Veklury - Gilead) exhibits activity against SARS-CoV-2, the virus that causes COVID-19, and is the first drug to be approved for the treatment of this infection. It may also be active against certain other coronaviruses. Prior to its full approval, remdesivir was available for use in hospitalized patients under the provisions of a US FDA Emergency Use Authorization (EUA).
Remdesivir is an adenosine nucleotide prodrug that is converted to its active form which inhibits SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), which is essential for viral replication. Following administration, it is distributed into cells where it is metabolized to a nucleoside monophosphate intermediate by carboxyesterase 1 and/or cathepsin A. This intermediate is subsequently phosphorylated by cellular kinases to form the pharmacologically active nucleoside triphosphate metabolite. Remdesivir triphosphate acts as an analogue of adenosine triphosphate (ATP) and competes with high selectivity over the natural ATP substrate for incorporation into nascent RNA chains.
Remdesivir is administered I.V. and is indicated for adults and pediatric patients (12 years of age and older and weighing at least 40 kg) for the treatment of COVID-19 requiring hospitalization. It should only be administered in a hospital setting or in a healthcare setting capable of providing acute care.
The effectiveness of remdesivir was evaluated in three clinical trials in patients hospitalized with mild-to-severe COVID-19. The primary goal of the largest trial was time to recovery, with recovery defined as either being discharged from the hospital or being hospitalized but not requiring supplemental oxygen and no longer requiring ongoing medical care. The median time to recovery was 10 days for the remdesivir group compared with 15 days for the placebo group. The likelihood of clinical improvement at Day 15 was also statistically significantly higher in the remdesivir group. The overall 29-day mortality was 11% for the remdesivir group compared with 15% for the placebo group, but this difference was not statistically significant. In other studies in patients with moderate or severe COVID-19, 5-day and 10-day courses of treatment with remdesivir were compared. The clinical improvement with the 5-day regimen was similar to or better than the outcomes with the 10-day regimen, and the 5-day regimen is recommended for most patients with COVID-19 who are candidates for treatment.
A study sponsored by the World Health Organization (WHO) failed to demonstrate a statistically significant difference in mortality between the group of patients treated with remdesivir and the group receiving standard of care, an outcome that is consistent with the results of the study described above. However, the WHO trial was not designed to assess outcomes such as time to recovery.
The administration of remdesivir in younger children and also in a nebulized formulation are being evaluated. However, these are not labeled indications or formulations at this time.
The most common adverse events experienced with remdesivir (and the incidence with a 5-day course of treatment) include nausea (5%), increased AST (3%), and increased ALT (2%). Hepatic lab testing should be performed in all patients before starting therapy, and during therapy as clinically appropriate. Treatment with remdesivir should be discontinued if ALT elevation is accompanied by signs or symptoms of liver inflammation.
Hypersensitivity reactions, including infusion-related and anaphylactic reactions, have been reported with the use of remdesivir. The occurrence of infusion-related reactions may be reduced with a slower infusion rate, but the maximum infusion time should not exceed 120 minutes. Limited data in women, as well as studies in animals, suggest that remdesivir is safe for use during pregnancy. The effectiveness and safety of remdesivir have not been established in pediatric patients younger than 12 years or weighing less than 40 kg.
The pharmacokinetic characteristics of remdesivir have not been evaluated in patients with renal impairment. However, the formulations include the excipient betadex sulfobutyl ether sodium that is renally cleared and accumulates in patients with decreased renal function. All patients should have an estimated glomerular filtration rate (eGFR) determined prior to starting treatment, and the use of remdesivir is not recommended in patients with an eGFR less than 30 mL per minute.
Cell culture studies have demonstrated an antagonistic effect of chloroquine on the intracellular metabolic activation and antiviral activity of remdesivir. Accordingly, the concurrent use of remdesivir with chloroquine or hydroxychloroquine is not recommended.
Remdesivir is administered via I.V. infusion over a period of 30 to 120 minutes. For most patients, a single loading dose of 200 mg of remdesivir is administered on Day 1, followed by daily maintenance doses of 100 mg from Day 2 through Day 5. For patients who do not demonstrate clinical improvement, treatment may be extended for up to 5 additional days. For patients requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation, the recommended duration of treatment is 10 days.
Remdesivir is supplied in two formulations for I.V. use. Single-dose vials containing 100 mg of the drug as a lyophilized powder should be reconstituted by adding 19 mL of Sterile Water for Injection. The vial should be shaken for 30 seconds and the contents of the vial allowed to settle for 2 to 3 minutes. If the contents of the vial are not completely dissolved, this procedure should be repeated as necessary until the contents of the vial are completely dissolved and a clear solution results. The reconstituted product should be immediately diluted in a 100 mL or 250 mL 0.9% sodium chloride infusion bag from which a volume of 40 mL or 20 mL of diluent should have been removed from the infusion bag for the 200 mg loading dose of remdesivir or a 100 mg maintenance dose, respectively. The prepared infusion solution is stable for 24 hours at room temperature or 48 hours when refrigerated.
Remdesivir is also supplied as an injection in single-dose vials containing 100 mg of the drug in 20 mL of solution. The vials should be stored in a refrigerator. When the medication is to be administered, the vial should equilibrate at room temperature and the contents then diluted in an infusion bag containing 250 mL of 0.9% sodium chloride from which 40 mL or 20 mL of diluent should have been removed as described above. With both formulations, the infusion bag should be gently inverted 20 times to mix the solution, but should not be shaken. The product labeling should be consulted for additional information regarding the preparation and administration of remdesivir.
Fostemsavir tromethamine
A prodrug that treats HIV-1 in patients that have a multidrug-resistant infection
Most patients with HIV-1 infection can be successfully treated with a combination of two or more antiretroviral agents. However, some patients have multidrug-resistant infection that is associated with a high risk of complications and death. Fostemsavir tromethamine (Rukobia - Viiv) is a prodrug that is hydrolyzed to the active moiety, temsavir, which is an HIV-1 attachment inhibitor. Temsavir binds directly to the gp120 subunit within the HIV-1 envelope glycoprotein gp160 and selectively inhibits the interaction between the virus and cellular CD4 receptors, thereby preventing attachment. Temsavir also can inhibit gp120-dependent post-attachment steps required for viral entry into host cells. Its mechanism of action is most similar to that of ibalizumab (Trogarzo) that is a post-attachment HIV-1 inhibitor which was approved in 2018 and is administered I.V.
Fostemsavir is administered orally in combination with other antiretrovirals for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations. It was evaluated in a placebo-controlled trial in which most patients had been treated for more than 15 years with five or more HIV treatment regimens. A primary efficacy endpoint was a significant decrease in the viral load (HIV-RNA), and 65% of the patients experienced this endpoint at Day 8 of treatment, compared with 19% in the placebo group.
The adverse events most often reported in the clinical study of fostemsavir include nausea (10%), diarrhea (4%), and headache (4%). Elevations in hepatic transaminases have been observed in patients who are co-infected with hepatitis B virus (HBV) or hepatitis C virus (HCV), with some of these elevations being associated with hepatitis B reactivation, particularly in patients who were withdrawn from anti-hepatitis therapy. Immune reconstitution syndrome has also been reported in patients treated with combination antiretroviral therapy, including fostemsavir, and patients may develop an inflammatory response to indolent or residual opportunistic infections (for example, Mycobacterium avium infection, tuberculosis).
Higher than recommended dosages of fostemsavir have been reported to significantly prolong the QT interval of the electrocardiogram, and caution should be exercised when the new agent is used in patients with a history of QT interval prolongation or who are being treated concurrently with other agents known to prolong the QT interval (for example, moxifloxacin, ziprasidone).
Experience with fostemsavir in pregnant women is very limited although the results of studies in animals suggest that adverse developmental effects are not likely to occur. Pregnant women who are treated with the new drug should be registered in the Antiretroviral Pregnancy Registry at 1-800-258-4263. Breastfeeding is not recommended because of the potential for HIV-1 transmission. The effectiveness and safety of fostemsavir in pediatric patients have not been evaluated.
Following oral administration, fostemsavir is rapidly converted to temsavir and the parent drug is generally not detectable in the plasma. Its absolute bioavailability is 27%, and approximately one-half and one-third of a dose are excreted in the urine and feces, respectively. Dosage adjustment is not necessary in patients with hepatic or renal impairment.
Temsavir is a substrate of CYP3A, esterases, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP), and drugs that are inducers or inhibitors of these pathways may affect temsavir plasma concentrations. Strong CYP3A inducers (for example, carbamazepine, rifampin, St. John's wort, enzalutamide, mitotane) may significantly decrease temsavir plasma concentrations which can result in the loss of virologic response, and concurrent use is contraindicated.
Temsavir is an inhibitor of organic anion-transporting polypeptide (OATP)1B1 and OATP1B3, as well as BCRP. It may increase the exposure of the HCV antiviral agents grazoprevir and voxilaprevir and increase the possibility of hepatic transaminase elevations. An alternative HCV regimen should be used if possible. Temsavir may also increase the activity of ethinyl estradiol and it is recommended that the daily dose of this estrogen should not exceed 30 mcg. Temsavir has been reported to increase the plasma concentration of rosuvastatin, and, when used concurrently, the lowest possible starting dose of a statin should be used.
The recommended dosage of fostemsavir is 600 mg twice a day with or without food. Fostemsavir tromethamine is supplied in extended-release tablets in an amount equivalent to 600 mg of fostemsavir. The tablets may have a slight vinegar-like odor and should be swallowed whole, and not be chewed, crushed, or split.
ANTIBACTERIAL AGENT
Cefiderocol
An innovative cephalosporin that belongs to a special class of antibiotics
Resistance to penicillins, cephalosporins, and carbapenems has increased because certain bacteria are able to produce extended-spectrum beta-lactamases and carbapenemases that break the beta-lactam ring and inactivate beta-lactam antibacterial agents. New beta-lactam antibacterial agents, alone or combined with a beta-lactamase inhibitor (for example, ceftolozane/tazobactam [Zerbaxa], ceftazidime/avibactam [Avycaz]), have been developed that are effective against some resistant Gram-negative bacteria, but some patients experience serious infections that are multidrug resistant and for which treatment options are very limited.
Cefiderocol (Fetroja - Shionogi) is a cephalosporin antibacterial agent that is most similar structurally to cefepime and ceftazidime. However, it contains a catechol substituent that results in it functioning as a siderophore that binds to extracellular free ferric iron. Via a siderophore uptake mechanism, cefiderocol is actively transported across the outer cell membrane of bacteria that is thought to increase activity within bacterial cells. It binds to penicillin-binding proteins and exhibits bactericidal activity by inhibiting cell wall biosynthesis.
Cefiderocol is administered I.V. and was initially approved in 2019 for use in patients 18 years of age and older who have limited or no alternative treatment options for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex. It has demonstrated in vitro activity against certain carbapenemase-producing Gram-negative bacteria.
Cefiderocol was evaluated in a trial in patients with cUTIs in which it was compared with imipenem/cilastatin, and for which efficacy was assessed as a composite of microbiological eradication and clinical cure. Efficacy was demonstrated in 73% of patients treated with the new drug, compared with 55% of those treated with imipenem/cilastatin. In another study in patients with infections caused by carbapenem-resistant bacteria, the effectiveness of cefiderocol was similar (approximately 50%) to the best-available treatment (most often colistin-based combination regimens).
In September 2020, the indications for cefiderocol were revised to delete the phrase, "who have limited or no alternative treatment options" and to add a second indication for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens.
In addition to cUTIs and HABP/VABP, ceftolozane/tazobactam, ceftazidime/avibactam, and imipenem/cilastatin/relebactam (Recarbrio) are also indicated for the treatment of complicated intra-abdominal infections (cIAIs) caused by susceptible organisms. For the treatment of cIAIs, the first two products are used in combination with metronidazole. However, cIAIs are not a labeled indication for cefiderocol at the present time.
As with other beta-lactam antibacterial agents, cefiderocol has caused hypersensitivity reactions and cross-hypersensitivity may occur in patients with a history of penicillin allergy. Its use is contraindicated in patients with a known history of severe hypersensitivity to the new agent or other beta-lactam antibacterial drugs.
The most commonly experienced adverse events reported in clinical studies with cefiderocol in the treatment of cUTIs include diarrhea (4%), infusion site reactions (4%), constipation (3%), and rash (3%). In the study in patients with HABP/VABP in which it was compared with meropenem, the adverse events reported most often with cefiderocol were elevations in liver function tests (16%), hypokalemia (11%), and diarrhea (9%). Clostridioides difficile-associated diarrhea has been reported and should be considered in all patients who experience diarrhea during or soon following treatment. Central nervous system adverse events including seizures have been reported with cefiderocol and other cephalosporins, and caution must be exercised in patients with a history of epilepsy and/or have impaired renal function.
An increase in all-cause mortality was observed in patients with carbapenem-resistant Gram-negative infections treated with cefiderocol (25% at Day 28) than in patients treated with best-available therapy (18% at Day 28). The cause(s) of the increased mortality has not been established.
Cefiderocol has not been evaluated in pregnant women, but studies in animals, as well as the clinical experience with other cephalosporins, suggest that adverse developmental outcomes are not likely to be associated with its use. The effectiveness and safety of the new agent in pediatric patients have not been established.
Cefiderocol is minimally metabolized and primarily excreted via the kidneys. Exposure is increased in patients with impaired renal function, and the dosage should be reduced in patients with a creatinine clearance less than 60 mL/min. Because increased clearance of the drug has been observed in patients with a creatinine clearance greater than 120 mL/min, an increased dosage is recommended in these patients. Dosage adjustment is not necessary in patients with impaired hepatic function.
False-positive results in dipstick tests (urine proteins, ketones, occult blood) have been reported in patients treated with cefiderocol, and alternative clinical lab methods of testing should be used to confirm positive tests.
Cefiderocol is administered by I.V. infusion over a period of 3 hours, and the recommended dosage is 2 g every 8 hours for 7 to 14 days, with the duration of treatment being guided by the patient's clinical status. The product labeling should be consulted for the dosage recommendations for patients with a creatinine clearance less than 60 mL/min, or greater than 120 mL/min.
Cefiderocol as a lyophilized powder is supplied in single-dose vials containing 1 g of the drug. The vials should be stored in a refrigerator. The powder should be reconstituted with 10 mL of either 0.9% Sodium Chloride Injection or 5% Dextrose Injection, and the vial should be gently shaken. The final volume of the reconstituted solution is approximately 11.2 mL. For the usual recommended dose of 2 g, the entire contents of two vials should be withdrawn and further diluted in an infusion bag containing 100 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
ANALGESIC
Oliceridine fumarate
An I.V. opioid agonist for adults in whom alternative treatments are inadequate
Morphine is the standard for the treatment of acute severe pain. No other medication is more effective in relieving pain although the extent of analgesia is related to the dosage used. The risks of addiction, abuse/misuse, respiratory depression, and other adverse events with morphine are cause for the continued search for new drugs that are highly effective analgesics but have fewer and/or different risks.
Oliceridine fumarate (Olinvyk - Trevena) is a full opioid agonist that is relatively selective for the mu-opioid receptors. It is administered I.V. and is indicated for use in adults for the management of acute pain severe enough to require an I.V. opioid analgesic and for whom alternative treatments are inadequate. Its use should be reserved for patients for whom nonopioid analgesics, opioid combination products, or other safer treatments have not provided adequate analgesia or are not expected to do so, or have not been tolerated or are not expected to be tolerated.
The effectiveness of oliceridine was evaluated in two placebo- and morphine-controlled studies in patients with moderate to severe acute pain following surgery. The analgesic efficacy response rates for oliceridine were significantly higher than in those receiving placebo, but lower than in those receiving morphine.
Treatment emergent adverse events were reported in 86% of the patients treated with a dosage of oliceridine up to the recommended maximum dosage of 27 mg a day, compared with 96% of the patients treated with morphine and 73% of those receiving placebo. The most commonly experienced adverse events (and the incidence with oliceridine, morphine, and placebo, respectively) include nausea (52%, 70%, 35%), vomiting (26%, 52%, 10%), headache (26%, 30%, 30%), dizziness (18%, 25%, 11%), constipation (14%, 14%, 9%), hypoxia (12%, 17%, 3%), and pruritus (9%, 19%, 6%). The incidence of gastrointestinal (GI) adverse events such as nausea and vomiting is lower than with morphine, and this may be an advantage for oliceridine in patients with a history of serious GI disorders or who are at increased risk of experiencing such. However, the most important risks with the use of oliceridine are generally similar to those with morphine and other opioid analgesics used for the treatment of acute severe pain.
The labeling for oliceridine includes boxed warnings regarding the risks of addiction, abuse, and misuse; life-threatening respiratory depression; neonatal opioid withdrawal syndrome; and concomitant use with benzodiazepines or other central nervous system depressants. Oliceridine is contraindicated in patients with significant respiratory depression and in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment. Oliceridine is also contraindicated in patients with known or suspected GI obstruction, including paralytic ileus.
If it is used in patients with chronic pulmonary disease, patients who are older adult, cachectic, or debilitated, or patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness, treatment must be closely monitored.
The new agent may prolong the QT interval although the extent of this response has not been studied with the use of total cumulative daily doses greater than 27 mg. Accordingly, the cumulative daily dose should not exceed 27 mg. It may also increase the frequency of seizures in patients with seizure disorders, cause severe hypotension, and possibly adrenal insufficiency.
As with the opioid analgesics, oliceridine is classified in Schedule II under the provisions of the Controlled Substances Act. Reversal of its effects with naloxone has not been established in humans, but some of its pharmacologic effects have been shown to be reversed in animals. Therefore, an opioid antagonist should be administered for clinically significant respiratory or circulatory depression resulting from overdosage of oliceridine. Because the duration of the reversal action is expected to be less than that of oliceridine, the patient should be closely monitored until spontaneous respiration is reliably reestablished.
Oliceridine may cause adverse developmental effects if it is used during pregnancy, and prolonged use may result in neonatal opioid withdrawal syndrome. The effectiveness and safety of oliceridine in pediatric patients have not been established.
Oliceridine is extensively metabolized, primarily via the CYP2D6 and CYP3A4 pathways. Approximately 70% of a dose is excreted as metabolites in the urine, with the remainder eliminated in the feces. Dosage adjustment is not necessary in patients with renal impairment. In patients with mild or moderate hepatic impairment, the initial dose does not need to be reduced, but these patients may require less frequent dosing. Caution must be exercised in patients with severe hepatic impairment; reducing the initial dose should be considered, and subsequent doses should be given only after a careful review of the patient's severity of pain and overall clinical status.
The action of oliceridine may be increased in patients who are CYP2D6 poor metabolizers or are being treated with a moderate to strong CYP2D6 inhibitor (for example, paroxetine, bupropion), and patients may require less frequent dosing of the analgesic. The action of the new drug may also be increased by the concomitant use of a moderate to strong CYP3A4 inhibitor (for example, clarithromycin, ketoconazole), but is decreased by the use of CYP3A4 inducers (for example, carbamazepine, phenytoin). The use of oliceridine in patients being treated with a serotonergic drug (for example, selective serotonin reuptake inhibitors) may increase the risk of serotonin syndrome, and concurrent use with an anticholinergic drug may increase the risk of urinary retention and/or severe constipation. Mixed agonist/antagonist and partial agonist opioid analgesics (for example, butorphanol, nalbuphine, pentazocine, buprenorphine) must be avoided in patients treated with oliceridine because they may reduce the analgesic effects of the new drug and/or precipitate withdrawal symptoms.
Oliceridine is only administered I.V., and an initial 1 mg dose is approximately equipotent to a 5 mg dose of morphine. The recommended initial dose is 1.5 mg, and the onset of the analgesic action is expected within 2 to 5 minutes. Supplemental doses of 0.75 mg can be administered beginning 1 hour after the initial dose and hourly thereafter as needed. Single doses greater than 3 mg should not be administered, and the cumulative total daily dose should not exceed 27 mg. For patient-controlled analgesia (PCA), the initial dose can be followed by access to patient demand doses with a 6-minute lockout. The recommended demand dose is 0.35 mg although a demand dose of 0.5 mg may be considered if the potential benefit outweighs the risk. The use of oliceridine for more than 48 hours has not been evaluated in controlled trials.
The new analgesic is supplied as an injection in vials containing oliceridine fumarate in an amount equivalent to 1 mg of oliceridine per mL. Single-dose vials that contain 1 mg/mL and 2 mg/2 mL are available, as are vials for single-patient use that contain 30 mg/30 mL. The latter formulation is for patient-controlled analgesia (PCA) use only.
AGENT FOR MULTIPLE SCLEROSIS
Ozanimod
A new treatment for relapsing forms of MS
Multiple sclerosis (MS) is the most common immune-mediated inflammatory demyelinating disease of the central nervous system. MS affects approximately 400,000 people in the US. It occurs more often in women than in men, and most individuals first experience symptoms between the ages of 20 and 40 years.
Relapsing-remitting MS (RRMS), the most common form of the disease, accounts for approximately 85% of all MS diagnoses. It is characterized by episodes of worsening function (relapses) followed by recovery periods (remissions) of varying duration. Most patients experience some degree of persistent disability that gradually worsens over time. In some of these patients, disability progresses independent of relapses, representing an extension of the disease designated as secondary progressive MS (SPMS). SPMS may be characterized by reduced ambulation necessitating a walking aid or wheelchair, as well as bladder dysfunction and cognitive decline. Active SPMS is one of the relapsing forms of MS, but many patients subsequently stop experiencing new relapses although disability continues to worsen, a phase designated as not active SPMS. Approximately 15% of patients with MS have primary progressive MS (PPMS), characterized by steadily worsening function from onset of symptoms, sometimes without relapses and remissions.
Ozanimod (Zeposia - Celgene) is the third sphingosine-1-phosphate (S1P) receptor modulator to be marketed in the US, joining fingolimod (Gilenya) and siponimod (Mayzent). These agents are administered orally and block the capacity of lymphocytes to egress from lymph nodes, thereby reducing the number of lymphocytes in peripheral blood and their migration into the CNS. Fingolimod exhibits activity at S1P receptors 1, 3, 4, and 5, whereas siponimod and ozanimod bind with high affinity to S1P receptors 1 and 5. The more selective binding of the latter two agents is thought to reduce the risk of cardiac adverse events.
Ozanimod is indicated for the treatment of relapsing forms of MS, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. The labeled indication for the three S1P receptor modulators is the same, except that fingolimod is indicated for patients age 10 years and older.
The effectiveness of ozanimod was demonstrated in two clinical trials in which it was compared with interferon beta-1a (administered I.M.). The primary endpoint of the studies was the annualized relapse rate during the period of the studies. Additional outcome measures included the evaluation of brain lesions and the time to disability progression. In both studies, the annualized relapse rate and accumulation of brain lesions were statistically significantly lower in patients treated with ozanimod compared with patients treated with interferon beta-1a. However, there was no statistically significant difference in disability progression between the two groups.
Adverse events most often experienced with ozanimod in the clinical trials included upper respiratory infection (26%), hepatic transaminase elevations (10%), hypertension (4%), orthostatic hypotension (4%), urinary tract infection (4%), and back pain (4%). The types of risks associated with ozanimod are generally similar to those of fingolimod and siponimod, although there are certain differences among the agents.
Initiation of ozanimod treatment may result in a transient decrease in heart rate and atrioventricular (AV) conduction delays. It is contraindicated in patients with Mobitz type II second-degree or third-degree AV block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker. It is also contraindicated in patients who have experienced a myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III or IV heart failure within the last 6 months, as well as in patients with severe untreated sleep apnea. Caution should be exercised in patients also being treated with other medications that lower heart rate (for example, beta-blockers) or prolong the QT interval (for example, class Ia or class III antiarrhythmic drugs, moxifloxacin, ziprasidone).
To reduce the risk of bradycardia and other cardiac complications, treatment with ozanimod should be initiated with a low dose and titrated upward. With the use of fingolimod, comprehensive cardiovascular monitoring (for example, for bradycardia) is recommended for 6 hours after the first dose for all patients, and similar monitoring is recommended for siponimod in patients with certain cardiovascular disorders (for example, sinus bradycardia, history of myocardial infarction). The opportunity to use ozanimod without first-dose monitoring is an advantage for the new agent.
Because the S1P receptor modulators may cause small increases in BP with continuing treatment, BP should be periodically monitored. These agents may also cause a decline in pulmonary function, and spirometric evaluation of respiratory function should be performed if clinically indicated. Some patients have experienced elevated aminotransferases, and liver function tests should be monitored. If significant liver injury is confirmed, treatment should be discontinued. Macular edema was reported in 0.3% of patients treated with ozanimod in the clinical trials, and an ophthalmic evaluation should be conducted in patients who experience any change in vision during the period of treatment. The risk of macular edema is increased in patients with diabetes or a history of uveitis.
Ozanimod causes a reduction in peripheral blood lymphocyte count to 45% of baseline values, and suppression of immune function may increase the risk of infection. Complete blood cell counts including lymphocyte count should be determined before initiation of treatment, and starting treatment in patients with an active infection should be delayed until the infection is resolved. Although the overall rate of infection was similar (35%) between patients treated with ozanimod and those receiving interferon beta-1a, the new drug increased the risk of upper respiratory tract infections and urinary tract infections. Cases of cryptococcal meningitis and herpes zoster have been reported. Patients without a confirmed history of varicella (chickenpox) or without documentation of vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV before initiating treatment with ozanimod. Because the elimination of ozanimod following discontinuation of treatment may take up to 3 months, monitoring for infections should be continued throughout this period.
Progressive multifocal leukoencephalopathy, a potentially fatal opportunistic infection of the brain caused by the JC virus, has been rarely reported with the use of fingolimod and other therapies for MS. The risk of this, as well as other infections, is increased in immunocompromised patients including those being treated with antineoplastic agents or with other immune-modulating or immunosuppressive therapies including corticosteroids. Concurrent use with immunosuppressants may result in an additive effect on the immune system, and caution should be exercised when initiating other drugs up to 4 weeks after the last dose of ozanimod. Initiating treatment with ozanimod following treatment with alemtuzumab is not recommended.
If administration of a live attenuated vaccine is required, it should be administered at least 1 month prior to initiating treatment with ozanimod, and the use of such a vaccine should be avoided during or within 3 months after treatment with ozanimod. Vaccinations may be less effective if administered during ozanimod treatment.
Adverse developmental effects may occur if ozanimod is administered during pregnancy, and women of childbearing potential should use effective contraception during and for 3 months after stopping concurrent treatment. The S1P receptor modulators have been identified in the milk of lactating animals, and their use in breastfeeding women is best avoided. The effectiveness and safety of ozanimod in pediatric patients have not been established.
Following oral administration, ozanimod is metabolized to active metabolites via multiple enzymatic pathways. Approximately 26% of a dose is recovered in the urine and 37% in the feces, primarily as inactive metabolites. Dosage adjustment is not necessary in patients with renal impairment, but its use in patients with hepatic impairment is not recommended. The exposure of one of the major active metabolites of ozanimod is approximately 50% lower in smokers than in nonsmokers.
The major active metabolites of ozanimod are substrates for the CYP2C8 metabolic pathway. Their activity may be increased by the concurrent use of a strong CYP2C8 inhibitor (for example, gemfibrozil), and decreased by the concurrent use of a CYP2C8 inducer (for example, rifampin); concomitant use is not recommended. Inhibitors of BCRP (for example, cyclosporine, omeprazole) may increase exposure of certain active metabolites of ozanimod and their concurrent use should be avoided.
The concurrent use of ozanimod with a monoamine oxidase type B (MAO-B) inhibitor (for example, selegiline) may increase the exposure of the active metabolites of the new drug, and certain metabolites may also inhibit MAO. Coadministration of the new drug with an MAO inhibitor (for example, selegiline, phenelzine, linezolid) is contraindicated, and at least 14 days should elapse between the discontinuation of ozanimod and initiation of treatment with an MAO inhibitor. MAO in the gastrointestinal tract and liver provides protection from the pressor effects of exogenous amines such as tyramine. Patients should be advised against consumption of foods containing a large amount of tyramine (that is, more than 150 mg) while being treated with ozanimod. The use of a serotonergic or adrenergic drug may increase BP, and concurrent use with ozanimod is not recommended.
Unlike siponimod, the activity of ozanimod is not altered in patients who are poor CYP2C9 metabolizers, and CYP2C9 genotype testing is not necessary before initiating treatment with ozanimod.
Ozanimod hydrochloride is supplied in capsules in amounts equivalent to 0.23 mg, 0.46 mg, and 0.92 mg of ozanimod. Treatment should be initiated with a 7-day titration-0.23 mg once a day on Days 1-4, 0.46 mg once a day on Days 5-7, and 0.92 mg once a day on Day 8 and thereafter. If a dose is missed during the first 2 weeks of treatment, therapy should be restarted using the titration regimen. If treatment is discontinued, the possibility of severe exacerbation (for example, disability) of disease should be considered.
In early 2021, the FDA approved the fourth S1P receptor modulator, ponesimod (Ponvory - Janssen) for use in adults. It has the same labeled indications as those of the other three agents.
ANTIEPILEPTIC DRUG
Cenobamate
Indicated for treating partial-onset seizures in adults
Approximately 3 million adults and almost 500,000 children in the US have epilepsy. Focal seizures, also called partial or partial-onset seizures, are the most common type of epilepsy in adults and affect a limited or localized area of the brain, but can spread to other parts of the brain (that is, secondary generalized seizures). Monotherapy with a single antiepileptic drug (AED) often does not provide adequate management of the seizure disorder for many patients and the use of two or more AEDs is often necessary. However, multiple-drug therapy is frequently challenging because the medications may cause similar CNS adverse events and also interact with each other via pharmacokinetic mechanisms. Levetiracetam, lamotrigine, or carbamazepine is often used for the initial treatment of partial-onset seizures, with other agents added to the regimen as clinically indicated.
Cenobamate (Xcopri - SK Life Science) is indicated for the treatment of partial-onset seizures in adults. The exact mechanism by which it exerts its therapeutic effect has not been determined, but it has been demonstrated to reduce repetitive neuronal firing by inhibiting voltage-gated sodium currents. It is also a positive allosteric modulator of the gammabutyric acid ion channel.
Cenobamate was evaluated in two placebo-controlled studies in patients who had seizures that were not adequately controlled with 1 to 3 concomitant AEDs, had a mean duration of epilepsy of 24 years, and median baseline seizure frequency of 8.5 seizures per 28 days. Patients treated with cenobamate had a median reduction of 55% from baseline seizure frequency per 28 days in both studies, compared with a median percent reduction of 22% and 24%, respectively, in those receiving placebo.
As with other AEDs, CNS adverse events are often experienced with cenobamate and include somnolence (22%), dizziness (22%), fatigue (14%), headache (12%), nystagmus (7%), and diplopia (7%). Patients should be advised against engaging in activities requiring mental alertness, such as operating vehicles or machinery, until the response to the medication has been determined. Concomitant use with other CNS depressants or alcoholic beverages may have additive effects. The AEDs, including cenobamate, may increase the risk of suicidal thoughts or behavior, and patients should be monitored for the emergence or worsening of depression and/or any unusual changes in mood or behavior. Cenobamate has the potential to cause euphoria and physical dependence, and it is classified in Schedule V under the provisions of the Controlled Substances Act. When treatment is to be discontinued, it should be done gradually to reduce the risk of withdrawal syndrome and increased seizure frequency.
Patients treated with cenobamate may experience shortening of the QT interval and the new agent is contraindicated in patients with familial short QT syndrome because of the increased risk of ventricular dysrhythmias and sudden death. Concurrent use with other drugs that shorten the QT interval (for example, lamotrigine, rufinamide) should be closely monitored.
There have been several reports of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, with the use of cenobamate that included one death. This response may have been associated with rapid dosage titration. The recommended dosage and titration intervals should not be exceeded.
Based on the results of studies in animals, cenobamate may be associated with a risk of adverse developmental effects if it is used during pregnancy. Women who are being treated with the drug during pregnancy should be advised to enroll in the North American Antiepileptic Drug Pregnancy Registry (1-888-233-2334). Cenobamate may reduce the concentrations and activity of hormonal contraceptives, and women of child-bearing potential should use additional or alternative nonhormonal birth control while being treated with the new agent. The effectiveness and safety of cenobamate in pediatric patients have not been established.
Following oral administration, almost 90% of a dose of cenobamate is absorbed. It is extensively metabolized via glucuronidation and oxidation (CYP450) pathways, and most of the dose is eliminated as metabolites in the urine. In patients with mild to moderate hepatic impairment, a lower maximum dosage should be used, and its use in patients with severe hepatic impairment is not recommended. The plasma exposure of cenobamate may be increased in patients with mild, moderate, or severe renal impairment and a reduction in dosage should be considered. Its use is not recommended in patients with end-stage renal disease undergoing dialysis.
Cenobamate may interact with certain other AEDs with which it is used concurrently. It has been reported to decrease plasma concentrations of carbamazepine and lamotrigine, and it may be necessary to increase the dosage of the latter agents. Conversely, it may increase plasma concentrations and activity of phenytoin, phenobarbital, and the active metabolite of clobazam. It is recommended that the dosage of phenytoin be gradually decreased by up to 50% as cenobamate is being titrated, and a reduction in dosage of phenobarbital or clobazam should be considered. Cenobamate is not likely to significantly alter the pharmacokinetic characteristics of levetiracetam, valproate, or lacosamide.
The concurrent use of cenobamate may reduce plasma concentrations of CYP2D6 substrates such as bupropion, as well as CYP3A substrates (for example, midazolam), and an increase in dosage of the latter agents may be necessary. The new agent may increase plasma concentrations and activity of CYP2C19 substrates such as omeprazole.
Cenobamate is administered orally once a day and may be administered with or without food. The recommended initial dosage is 12.5 mg once a day during Weeks 1 and 2, and is titrated to 25 mg once a day for Weeks 3 and 4, 50 mg once a day in Weeks 5 and 6, 100 mg once a day in Weeks 7 and 8, 150 mg once a day in Weeks 9 and 10, and to the usual maintenance dosage of 200 mg once a day in Week 11 and thereafter. If needed based on clinical response and tolerability, the dosage may be increased above 200 mg by increments of 50 mg once a day every 2 weeks to the maximum recommended dosage of 400 mg once a day. In patients with mild to moderate hepatic impairment, the maximum recommended dosage is 200 mg once a day. When treatment is discontinued, the dosage should be gradually reduced over a period of several weeks, unless the occurrence of a serious adverse event warrants prompt withdrawal.
Cenobamate tablets are supplied in 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg potencies. The tablets should be swallowed whole and not crushed or chewed.
ANTIEMETIC
Amisulpride
A selective D2 and D3 receptor antagonist I.V. for postoperative nausea and vomiting
Postoperative nausea and vomiting (PONV) is a frequent complication of surgery and is particularly common following abdominal, breast, gynecological, eye, and ear operations, especially those lasting an hour or more. Approximately 65 million surgical procedures are conducted in the US each year that are eligible for antiemetic use to prevent PONV, and an estimated 16 million surgical patients each year experience PONV despite receiving prophylaxis. In addition to the type and duration of surgery, risk factors for PONV include a history of PONV or motion sickness, female gender, nonsmoker status, and postoperative use of opioids. A serotonin-3 (5-HT3) receptor antagonist (for example, ondansetron), often with a corticosteroid (for example, dexamethasone), is most often used for the prevention and treatment of PONV, with other options including the neurokinin 1 (NK1) receptor antagonists aprepitant, a phenothiazine (for example, prochlorperazine), the dopamine-2 (D2) receptor antagonist droperidol, and a transdermal formulation of the anticholinergic agent scopolamine.
D2 receptors are located in the chemoreceptor trigger zone (CTZ) and respond to the dopamine released from the nerve endings. Activation of CTZ relays stimuli to the vomiting center which is involved in emesis. D3 receptors also appear to have a role in emesis. Amisulpride (Barhemsys - Acacia Pharma) is a selective D2 and D3 receptor antagonist that is administered I.V. for the prevention and treatment of PONV. It is specifically indicated for use in adults for the prevention of PONV, either alone or in combination with an antiemetic of a different class, and for the treatment of PONV in patients who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis. It is the first antiemetic to be approved for the rescue treatment of PONV in patients who have failed prior prophylaxis.
The effectiveness of amisulpride for the prevention of PONV was evaluated in two placebo-controlled clinical trials in patients undergoing general anesthesia and elective surgery. In the first study patients received amisulpride as monotherapy, whereas in the second study patients received amisulpride in combination with one other I.V. administered antiemetic (ondansetron, dexamethasone, or betamethasone). The primary efficacy endpoint in both studies was a complete response, defined as the absence of any episode of emesis or use of rescue medication within the first 24 hours postoperatively. In the first study, 44% of the patients treated with amisulpride experienced a complete response, compared with 33% of those in the placebo group. In the second study, 58% of the patients treated with amisulpride plus another antiemetic experienced a complete response, compared with 47% of those receiving placebo plus another antiemetic.
Amisulpride was evaluated for the treatment of PONV in two placebo-controlled trials, the first of which enrolled patients who had not received prior PONV prophylaxis, with the second including patients who had received and failed PONV prophylaxis with an antiemetic of another class. In the first of these studies, 31% of the patients treated with amisulpride experienced a complete response, compared with 22% of those in the placebo group. In the second study, 42% of the patients treated with amisulpride experienced a complete response, compared with 29% of those receiving placebo.
The adverse events most often experienced with the 5 mg dose of amisulpride used for the prevention of PONV include chills (4%), hypokalemia (4%), procedural hypotension (3%), abdominal distension (2%), and increased blood prolactin concentrations (5%). With the use of a 10 mg dose for the treatment of PONV, the most commonly reported adverse event was infusion site pain (6%).
Amisulpride causes dose-dependent prolongation of the QT interval and its use should be avoided in patients with congenital long QT syndrome and in patients taking droperidol. Electrocardiogram monitoring is recommended in patients with preexisting dysrhythmias/cardiac conduction disorders, electrolyte abnormalities (hypokalemia, hypomagnesemia), heart failure, and in patients taking other medications (for example, ondansetron) or with other medical conditions known to prolong the QT interval.
The use of amisulpride should be avoided in patients who are being treated with the dopamine agonist levodopa because of the opposing pharmacologic actions of the two drugs.
There are insufficient data to assess the risk of using amisulpride in pregnant women but the results of studies in animals suggest that adverse developmental effects are not likely. The new agent is present in human milk in appreciable concentrations, and a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for 48 hours after amisulpride administration to minimize drug exposure to a breastfed infant. The effectiveness and safety of amisulpride in pediatric patients have not been established.
Approximately 75% of a dose of amisulpride is excreted in the urine, primarily as unchanged drug. Dosage adjustment is not necessary in patients with mild to moderate renal impairment, but the new drug has not been adequately studied in patients with severe renal impairment and use in these patients is not recommended.
The recommended dosage of amisulpride for the prevention of PONV is 5 mg as a single I.V. injection administered over 1 to 2 minutes at the time of induction of anesthesia. For the treatment of PONV, the recommended dosage is 10 mg as a single I.V. injection infused over 1 to 2 minutes in the event of nausea and/or vomiting after a surgical procedure.
Amisulpride injection is supplied in single-dose vials containing 5 mg/2 mL and 10 mg/4 mL. The drug is subject to photodegradation and should be protected from light. The medication should be administered within 12 hours of the removal of the vial from the protective carton.
ANTIPARKINSON AGENT
Opicapone
Adjunctive treatment to levodopa/carbidopa in patients with Parkinson disease experiencing "off" episodes
More than 1 million Americans have Parkinson disease, the second most common neurodegenerative disorder after Alzheimer disease. Parkinson disease is associated with a reduction in dopamine activity in the brain, and most of the medications used in treatment increase the concentration and activity of this neurotransmitter (that is, a dopaminergic or dopamine agonist action). The combination of levodopa and carbidopa is the most effective treatment for the motor symptoms of Parkinson disease, but its effectiveness diminishes with long-term use (for example, 3-5 years). As the extent and duration of the benefit of levodopa/carbidopa decreases, patients experience more and/or longer "off" episodes, representing periods during treatment in which there is an increase in Parkinson signs and symptoms such as tremor and difficulty walking.
Because levodopa is extensively metabolized in the periphery by dopa decarboxylase (DDC), carbidopa is used concurrently as a DDC inhibitor, with the result that more levodopa reaches and crosses the blood-brain barrier into the central nervous system, thereby increasing its effectiveness. When the decarboxylation pathway is inhibited by carbidopa, the primary pathway for the metabolism of levodopa in the peripheral tissues is via catechol-O-methyltransferase (COMT). In 1998, tolcapone was marketed as the first COMT inhibitor to be used with levodopa to reduce its peripheral metabolism. Although it increases the effectiveness of levodopa/carbidopa, its use has been very limited because of hepatotoxicity concerns, and the approval the following year of entacapone (for example, Comtan), a COMT inhibitor with less risk. Entacapone is used with a levodopa/carbidopa formulation, or in a combination product (for example, Stalevo) that contains all three agents.
Opicapone (Ongentys - Neurocrine) is a peripherally acting reversible inhibitor of COMT and indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson disease experiencing "off" episodes. The administration of opicapone once a day at bedtime, with levodopa/carbidopa administered every 3 or 4 hours, increased peak and overall levodopa exposure compared with after administration of levodopa/carbidopa alone. The new agent was evaluated in two placebo-controlled clinical trials in patients experiencing "off" episodes while being treated with levodopa/carbidopa, with or without other medications used for the treatment of Parkinson disease. The primary efficacy endpoint was the change in mean absolute OFF-time based on 24-hour patient diaries completed 3 days prior to each of the scheduled visits. Opicapone reduced OFF-time from a baseline of approximately 6.2 hours by about 2 hours in each study, compared with a reduction of about 1 hour in patients receiving placebo. A secondary efficacy endpoint was the change in ON-time without troublesome dyskinesia in patients with a baseline of approximately 9.5 hours. Patients treated with opicapone had increases in ON-time of 1.84 hours and 1.43 hours in the two studies, compared with increases of 0.75 hours and 0.8 hours, respectively, in those receiving placebo. In one of the studies, one group of patients received entacapone, and opicapone was determined to be noninferior to entacapone.
The most commonly reported adverse events attributed to the addition of opicapone to levodopa/carbidopa and other antiparkinson agents in the clinical studies include dyskinesia (20%), constipation (6%), hypotension/syncope (5%), weight loss (4%), and increased blood creatine kinase (5%). Diarrhea was reported in less than 2% of patients, whereas it is one of the most common adverse events with entacapone. Unlike entacapone, the new agent does not cause discoloration of the urine.
By potentiating the effects of levodopa, opicapone may cause dyskinesia or exacerbation of preexisting dyskinesia, and this was the most common reason for discontinuation of treatment. A reduction in the daily dosage of levodopa or another dopaminergic drug may mitigate this response. Patients should be advised about the risk of hypotension and syncope. If such events are experienced, discontinuation of opicapone or adjusting the dosage of other medications that lower pressure should be considered.
Other adverse experiences reported with the use of treatment regimens containing opicapone include hallucinations (3%), impulse control/compulsive disorders (for example, urges to gamble, spend money, binge eating; 1%), and sedation/somnolence. Patients should be cautioned regarding the potential for daytime sleepiness and the risks during activities (for example, driving) that require full alertness and attention. There have been infrequent reports of withdrawal-emergent hyperpyrexia and confusion due to rapid dosage reduction or withdrawal of other medications that increase central dopaminergic tone, but there were no reports of these events in the clinical trials with opicapone.
There are no data regarding the safety of using opicapone during pregnancy or lactation, but the results of animal studies suggest a risk of developmental effects if used during pregnancy and adverse events in breastfed infants.
The selective MAO-B inhibitors (selegiline, rasagiline [Azilect], safinamide [Xadago]) that are used in the treatment of Parkinson disease may be used concomitantly with opicapone. However, both opicapone and nonselective MAO inhibitors (for example, phenelzine, isocarboxazid, tranylcypromine) inhibit catecholamine metabolism, and their concurrent use is contraindicated because of the increased risk of dysrhythmias, increased heart rate, and excessive changes in BP. The new drug is also contraindicated in patients with pheochromocytoma, paraganglioma, and other catecholamine-secreting neoplasms. Cardiovascular risks also exist if opicapone is used concurrently with drugs that are metabolized by COMT (for example, isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine), regardless of the route of administration, and patients being treated concomitantly with these medications should be closely monitored.
The peak plasma concentration and bioavailability of opicapone are reduced by food, and it should be administered apart from food. It is extensively metabolized, primarily via the sulphation pathway, and approximately 70% of a dose is recovered in feces (mostly as metabolites), 20% in expired air, and 5% in urine. The plasma exposure of opicapone is increased in patients with hepatic impairment; it should be used in a reduced dosage in patients with moderate hepatic impairment, and its use should be avoided in patients with severe hepatic impairment. Dosage adjustment is not necessary in patients with mild or moderate renal impairment, but opicapone has not been studied in patients with severe renal impairment and its use should be avoided in these patients.
Opicapone has a longer duration of action than entacapone and is administered once a day, whereas entacapone is administered with each dose of levodopa/carbidopa or in the combination formulation that includes all three agents. The recommended dosage of opicapone is 50 mg orally once a day at bedtime. Patients should not eat food for 1 hour before and for at least 1 hour after administration of opicapone. In patients with moderate hepatic impairment, the dosage should be reduced to 25 mg once a day at bedtime apart from food.
Opicapone capsules are supplied in 25 mg and 50 mg potencies.
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