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The article briefly reviews selected new drug entities approved by the Food and Drug Administration in 2009.
Recombinant antithrombin (1), marketed as ATryn, is indicated for the prevention of perioperative and peripartum thromboembolic events in hereditary antithrombin-deficient patients. Patients with an antithrombin deficiency have an increased risk of developing venous thromboembolism. This risk is a result of a decreased ability to inhibit thrombin and factor Xa, which alters the body's blood coagulation balance.
The recommended dosage should be individualized based on indication, patient weight, and baseline antithrombin activity level (Table Table11). The loading dose should be administered over 15 minutes, immediately followed by continuous infusion of the maintenance dose. Antithrombin activity should be monitored once or twice daily to determine the need for dosage adjustment (Table Table22). Therapy should continue until anticoagulation has been established in the patient. Recombinant antithrombin is available in single-dose vials containing approximately 1750 international units each.
The concurrent use of anticoagulants (e.g., heparin, low-molecular-weight heparin) with antithrombin requires close monitoring. Regular coagulation testing performed at small, regular intervals is necessary to avoid excessive anticoagulation.
Effects most commonly associated with therapy are hemorrhage and infusion-site reactions.
Product must be refrigerated at a temperature of 2° to 8°C.
Atypical antipsychotic asenapine (2–4) is indicated for the acute treatment of schizophrenia and manic episodes associated with bipolar I disorder in adult patients. The exact mechanism of asenapine is unknown, but it is believed that the drug works as a D2 and 5-HT2A receptor antagonist. The efficacy of asenapine for the treatment of acute mania in patients with bipolar I disorder appears similar to that of olanzapine; asenapine revealed a similar rate of adverse events compared with placebo but fewer adverse events when compared with olanzapine.
The recommended starting dose of asenapine for the treatment of schizophrenia is 5 mg sublingually twice daily; doses may be increased to 10 mg daily as needed. In the treatment of acute mania, initiation of asenapine at 10 mg sublingually twice daily is recommended. The sublingual tablet should be placed under the tongue until it is completely dissolved, and the patient should avoid eating or drinking for 10 minutes after administration. Asenapine is available in 5- and 10-mg sublingual tablets.
The use of asenapine with other drugs has not been extensively studied. Use caution when administering asenapine with other central nervous system–active agents since the primary effects of asenapine involve the central nervous system. In vitro studies have demonstrated that asenapine is a weak inhibitor of cytochrome P450 (CYP)2D6. Coadministration of asenapine with CYP2D6 substrates and inhibitors should be done cautiously.
Asenapine has been associated with increased mortality in elderly patients with dementia-related psychosis and should not be used in this patient population.
In schizophrenia, the most common adverse reactions are akathisia, oral hypoesthesia, and somnolence. The most common adverse reactions noted in bipolar disorder are somnolence, dizziness, extrapyramidal symptoms, and weight gain. Asenapine has the potential to cause serious adverse events including dementia-related psychosis in elderly patients, neuroleptic malignant syndrome, QT interval prolongation, and suicidal ideologies.
Besifloxacin (5, 6) is an ophthalmic antimicrobial indicated for the treatment of bacterial conjunctivitis caused by susceptible isolates of Centers for Disease Control and Prevention coryneform group G, Corynebacterium pseudodiphtheriticum, Corynebacterium striatum, Haemophilus influenzae, Moraxella lacunata, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus hominis, Staphylococcus lugdunensis, Streptococcus mitis group, Streptococcus oralis, Streptococcus pneumoniae, and Streptococcus salivarius. It is a member of the fluoroquinolone class and functions as a bactericidal antimicrobial that inhibits DNA gyrase and topoisomerase IV. Treatment with besifloxacin has proven to significantly improve clinical symptoms and increase bacterial eradication in patients with bacterial conjunctivitis compared with placebo.
Prior to use, the bottle should be shaken once. The recommended dosage is 1 drop instilled in the affected eye 3 times daily for 7 days. Besifloxacin is available as a 0.6% ophthalmic suspension.
Treatment is well tolerated; conjunctival redness, blurred vision, eye pain, eye irritation, eye pruritus, and headache were the most commonly reported adverse reactions reported in clinical trials.
The medication should be protected from light. Contact lenses should not be worn during the 7-day treatment.
Human C1 esterase inhibitor (7, 8) is indicated for the treatment of acute abdominal or facial attacks of hereditary angioedema (HAE) in adult and adolescent patients. Affected patients are known to have decreased levels of functional C1 esterase inhibitor, which is important for the regulation of vascular permeability for the complement system. A study enrolling patients with type I or II HAE confirmed that C1 esterase inhibitor was more effective and more rapid than placebo in treating acute HAE abdominal and facial attacks.
A one-time dose of 20 units/kg administered intravenously is recommended. The room-temperature solution should be administered at a rate of 4 mL/minute. C1 esterase inhibitor is available in a 500-unit single-use vial.
Studies evaluating drug interactions with C1 esterase inhibitor have not been conducted.
Adverse reactions with C1 esterase inhibitor noted in clinical trials were fewer compared with placebo. Determination of causality is difficult since many events reported may also be a result of unsatisfactory treatment efficacy. The most common adverse reactions reported include subsequent HAE attack, headache, abdominal pain, nausea, muscle spasm, pain, diarrhea, and vomiting.
Reconstituted solution should remain at room temperature and be used within 8 hours.
Canakinumab (9, 10) is a human anti-interleukin-1β blocker indicated for the treatment of cryopyrin-associated periodic syndromes (i.e., familial cold autoinflammatory syndrome, Muckle-Wells syndrome) in adults and children at least 4 years of age. The interleukin-1β inhibition is selective with no effect on interleukin-1β or interleukin-1 receptor antagonist. A small, well-designed trial demonstrated the benefit of canakinumab over placebo in achievement and maintenance of remission of cryopyrin-associated periodic syndromes.
The recommended dose varies depending on patient age and body weight; patients >40 kg should receive 150 mg and patients weighing 15 to 40 kg should receive 2 mg per kg. Children weighing 15 to 40 kg who achieve an inadequate response with a 2 mg/kg dose may benefit from a dosage increase up to 3 mg/kg. The dose is administered via subcutaneous injection and should be repeated in 8-week intervals. Canakinumab is available in single-use 180-mg vials.
Formal drug interaction studies have not been performed. However, based on studies in other populations and similar entities, canakinumab should not be administered in combination with tumor necrosis factor (TNF) inhibitors due to a potential for increased risk of neutropenia and serious infection. The concomitant use of canakinumab and other medications that inhibit interleukin-1 is not recommended. Due to the potential for secondary transmission of infection, live vaccines should be avoided during canakinumab treatment. Also, it is important to monitor the effect on narrow therapeutic index medications metabolized by the CYP system since increased levels of cytokines can alter the formation of CYP enzymes.
Increased risk of serious infection, reactivation of latent tuberculosis, susceptibility to opportunistic infections, and development of malignancies are all warnings associated with canakinumab use. Nasopharyngitis, diarrhea, influenza, headache, and nausea are the most common adverse reactions associated with canakinumab use.
Unopened vials must be refrigerated (2°–8°C) and stored in the original packaging. Reconstituted vials at room temperature must be used within 60 minutes; if refrigerated, they remain stable for 4 hours.
Dronedarone (11–13), a new antiarrhythmic agent, is indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation or flutter who are in sinus rhythm or who will be cardioverted. Similar to amiodarone in its mechanism of action, dronedarone inhibits calcium, sodium, and potassium channels and is an alpha- and beta-adrenergic receptor antagonist. Clinical trial data have demonstrated that dronedarone significantly reduces the incidence of hospitalization due to cardiovascular events and deaths from cardiovascular causes compared with placebo; however, head-to-head trials with amiodarone are currently unavailable.
One 400-mg tablet is recommended to be given by mouth twice daily with meals. Dronedarone is available as 400-mg film-coated tablets.
Dronedarone is metabolized by the CYP3A system and is a moderate inhibitor of CYP3A and CYP2D6; therefore, it is possible that dronedarone can interact with drugs that are substrates of CYP3A and CYP2D6. Use caution when dronedarone is given along with digoxin, calcium-channel blockers, beta-blockers, grapefruit juice, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, tacrolimus, or sirolimus.
Dronedarone is contraindicated in patients with New York Heart Association Class IV heart failure or Class II or III heart failure with recent decompensation requiring hospitalization. In a placebo-controlled trial, patients on dronedarone with severe heart failure had a significant increase in mortality.
The most common adverse reactions associated with dronedarone include diarrhea, nausea, abdominal pain, vomiting, and dyspepsia. Dronedarone has the potential to cause or worsen heart failure and can also prolong the QT interval.
Ecallantide (14, 15), a selective, reversible kallikrein inhibitor, is indicated for the treatment of acute attacks of HAE in patients 16 years of age and older. HAE is a rare genetic disorder involving a mutation of C1 esterase inhibitor on chromosome 11. C1 esterase inhibitor is the primary suppressor of the kallikrein-kinin system; HAE attacks occur as a result of overactivation of the kallikrein-kinin cascade and production of bradykinin. Ecallantide works to inhibit this excessive production of kallikrein and subsequently bradykinin. In clinical trials, 72.5% of patients treated with ecallantide reported a significant improvement in symptoms within 4 hours of treatment.
The recommended dose of ecallantide is 30 mg subcutaneously to be given as three 10-mg injections. An additional 30-mg dose may be given to patients with persistent attacks.
No drug interaction studies have been performed. Ecallantide is available as a 10-mg/mL solution in single-use vials.
There is a risk of anaphylaxis with the administration of ecallantide. Patients should be monitored closely by a health care professional who can differentiate between HAE and anaphylaxis.
In clinical studies, the incidence of adverse reactions was similar between ecallantide and placebo. The most common side effects associated with ecallantide were headache, nausea, diarrhea, pyrexia, injection-site reaction, and nasopharyngitis.
Ecallantide should be refrigerated and protected from light.
Febuxostat (16, 17) is a xanthine oxidase inhibitor indicated for the chronic management of hyperuricemia in patients with gout. By inhibiting xanthine oxidase, febuxostat results in decreased serum uric acid levels and minimizes gout attacks. A clinical study demonstrated that the use of febuxostat led to a significantly higher percentage of patients who attained a serum uric acid level of <6 mg/dL compared with allopurinol and placebo.
The recommended starting dose of febuxostat is 40 mg daily. If a patient does not achieve a serum uric acid level of <6 mg/dL after 2 weeks, it is recommended that the dose be increased to 80 mg daily. Febuxostat may be given with or without food, and no adjustment is necessary in patients with mild to moderate renal or hepatic failure. Febuxostat is available as 40- and 80-mg tablets.
Studies have not been completed evaluating the use of febuxostat with drugs that are metabolized by xanthine oxidase (e.g., theophylline, mercaptopurine, azathioprine). The plasma concentrations of these drugs may be increased due to xanthine oxidase inhibition, and coadministration of these drugs with febuxostat is contraindicated.
The most common adverse reactions with febuxostat include liver function abnormalities, dizziness, nausea, rash, and arthralgia. Initiation of febuxostat may lead to gout flares, which may be managed prophylactically with nonsteroidal antiinflammatory drugs. Clinical trials also revealed a higher rate of cardiovascular events in patients treated with febuxostat compared with allopurinol.
Human fibrinogen concentrate (18) is indicated for the treatment of acute bleeding episodes in patients with congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia. Fibrinogen concentrate is manufactured from pooled human plasma and is the substrate of three enzymes: thrombin, factor XIIIa, and plasmin. These enzymes play a critical role in the coagulation cascade and assist in platelet plug formation.
Fibrinogen concentrate is given intravenously, and doses should be calculated for each patient based on the target plasma fibrinogen level. The dose should be calculated using the following formula: (Target level [mg/dL] – measured level [mg/dL])/(1.7 [mg/dL per mg/kg body weight]). If a patient's fibrinogen level is unknown, the recommended dose is 70 mg/kg body weight. A target fibrinogen level of 100 mg/dL should be maintained until hemostasis is achieved. Fibrinogen concentrate is available in single-use vials containing 900 to 1300 mg.
The most common adverse reactions noted in clinical studies were fever and headache. Serious adverse events that may occur with fibrinogen concentrate include anaphylactic reactions, thrombosis, myocardial infarction, and transmissible infectious agents.
Administration should occur under physician supervision at a rate not to exceed 5 mL per minute.
Golimumab (19–22) is a human monoclonal antibody that binds to TNF-alpha, inhibiting its activity. In combination with methotrexate, golimumab is indicated for the treatment of moderately to severely active rheumatoid arthritis and active psoriatic arthritis in adults. Additionally, golimumab is indicated as monotherapy for active psoriatic arthritis and active ankylosing spondylitis in adults. Its use as an adjunct to methotrexate in rheumatoid arthritis and psoriatic arthritis clinical trials resulted in greater response rates compared with use of methotrexate alone. Additionally, in ankylosing spondylitis studies, golimumab resulted in a significant improvement in signs and symptoms compared with placebo.
The recommended dose for all indications of golimumab is 50 mg subcutaneously once a month. Golimumab is available as a 50 mg/0.5 mL solution in prefilled syringes or SmartJect autoinjectors.
Due to the risk of serious infections, it is recommended that other TNF-blockers not be used in combination with golimumab. Additionally, live vaccines should not be given while a patient is receiving golimumab.
Serious infections including tuberculosis, sepsis, invasive fungal infections, and other opportunistic infections have occurred in patients receiving golimumab. Tuberculosis tests should be performed prior to initiating therapy as well as throughout treatment with golimumab.
Upper respiratory tract infection, nasopharyngitis, and increased hepatic enzymes were the most commonly reported adverse reactions in clinical trials. Other less common adverse reactions include serious infections, malignancies, injection-site reactions, and the formation of autoantibodies.
Iloperidone (23–26) is a new atypical antipsychotic indicated for the acute treatment of schizophrenia in adults. Iloperidone has demonstrated similar efficacy to haloperidol with an improved side effect profile. Adverse effect rates of each atypical antipsychotic are unique and should be considered to determine the most appropriate option for each patient.
The initial recommended dose should be 1 mg by mouth twice daily, titrated up in 2-mg increments each day to a target dose of 12 to 24 mg daily. Patient tolerance should be monitored and considered as doses increase. Concomitant administration of iloperidone with strong CYP2D6 or CYP3A4 inhibitors may require a 50% dose reduction of the antipsychotic. Iloperidone is available in 1-, 2-, 4-, 6-, 8-, 10-, and 12-mg tablets.
As noted by the dose modification above, iloperidone is a substrate for both CYP2D6 and CYP3A4; caution is required with concomitant administration of iloperidone and inhibitors of these enzymes. Concomitant administration of iloperidone with other medications that prolong the QT interval should be avoided.
The use of antipsychotic medications in elderly patients for the treatment of dementia-related psychosis can lead to an increased risk of death in this population.
Numerous warnings and precautions are associated with the use of iloperidone and other antipsychotics, including their association with QT interval prolongation; neuroleptic malignant syndrome; tardive dyskinesia; hyperglycemia and diabetes mellitus; weight gain; seizures; orthostatic hypotension and syncope; leukopenia, neutropenia, and agranulocytosis; hyperprolactinemia; body temperature dysregulation; dysphagia; priapism; and cognitive and motor impairment potential. Patients receiving iloperidone should also be monitored and managed based on their risk level for suicide. The most common adverse reactions associated with use include dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight gain.
Milnacipran (27–29) is a dual norepinephrine and serotonin reuptake inhibitor indicated for the treatment of fibromyalgia. Clinical trials comparing milnacipran with duloxetine are currently unavailable; however, placebo-controlled trials have demonstrated that milnacipran is associated with significant improvements in pain after 1 week as well as significant improvements in numerous secondary outcomes (i.e., global status, physical function, and fatigue).
Milnacipran doses >12.5 mg should be administered in two divided doses per day. On day 1, a single dose of 12.5 mg by mouth should be used and increased up to 100 mg daily over week 1 of treatment. The daily dose may be further increased to 200 mg daily based on patient response. Milnacipran daily doses should be halved in patients with severe renal dysfunction (creatinine clearance [CrCl], 5–29 mL/min). Use of the agent is not recommended in patients with end-stage renal disease (ESRD). Milnacipran is available as 12.5-, 25-, 50-, and 100-mg tablets.
No significant drug interactions have been described in clinical trials; however, there are potential interactions with lithium, epinephrine, norepinephrine, digoxin, clonidine, and monoamine oxidase inhibitors. Coadministration of milnacipran and lithium may result in serotonin syndrome. Since milnacipran inhibits the reuptake of norepinephrine, concomitant use of norepinephrine and epinephrine with milnacipran may result in hypertension. Hypotension and tachycardia may be seen in patients receiving digoxin and milnacipran. Concurrent use of milnacipran and clonidine may inhibit clonidine's antihypertensive effects. The use of monoamine oxidase inhibitors with milnacipran is contraindicated due to the possibility of neuroleptic malignant syndrome.
The most common adverse reactions associated with milnacipran include nausea, headache, constipation, insomnia, and dizziness.
Pitavastatin (30–32), a HMG-CoA reductase inhibitor, is indicated for patients with primary hyperlipidemia and mixed hyperlipidemia as an adjunct to diet to decrease total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, and triglycerides and to increase high-density lipoprotein cholesterol. Clinical trials comparing pitavastatin 2 mg daily to atorvastatin 10 mg daily have concluded that the treatments have similar efficacy in improvement of lipid profiles.
The dose range for pitavastatin is 1 to 4 mg by mouth daily without regard to timing or food intake. It is recommended to initiate therapy at 2 mg and titrate to a maximum dose of 4 mg daily as needed. In patients with moderate renal insufficiency (glomerular filtration rate [GFR], 30–60 mL/min) and ESRD receiving hemodialysis, the recommended starting dose is 1 mg daily with a maximum dose of 2 mg daily. Pitavastatin should not be used in patients with severe renal impairment (GFR <30 mL/min). In patients concurrently receiving erythromycin, the maximum dose is 1 mg daily; pitavastatin should be dosed at a maximum of 2 mg daily in patients concurrently receiving rifampin. Pitavastatin is available as 1-, 2-, and 4-mg tablets.
Pitavastatin is known to interact with cyclosporine, lopinavir/ritonavir, erythromycin, rifampin, fibrates, niacin, and warfarin. Cyclosporine, lopinavir/ritonavir, erythromycin, and rifampin can significantly increase pitavastatin exposure. Using fibrates or niacin along with pitavastatin can increase the risk of skeletal muscle pain. In healthy volunteers, the pharmacokinetics and pharmacodynamics of warfarin were not affected by pitavastatin; however, it is recommended that patients receiving warfarin should have their prothrombin time (PT) and international normalized ratio (INR) tested. Pitavastatin is minimally metabolized by the CYP450 system.
Serious adverse reactions may occur with pitavastatin use. Rhabdomyolysis leading to acute renal failure as well as liver enzyme abnormalities are the most common serious adverse events. Other common adverse reactions include myalgias, constipation, diarrhea, and back pain. In order to prevent serious adverse events, it is important to monitor creatine phosphokinase levels and liver function tests.
Prasugrel (33–36), a thienopyridine, is indicated for the reduction of thrombotic cardiovascular events in patients with acute coronary syndrome who are to be managed with percutaneous coronary intervention (PCI) (i.e., patients with unstable angina or non–ST-elevation myocardial infarction and patients with ST-elevation myocardial infarction when managed with either primary or delayed PCI). Prasugrel has shown reductions in risk for myocardial infarction, urgent revascularization, stent thrombosis, and ischemic events when compared with clopidogrel. However, an increased risk of bleeding, including fatal bleeding, has been observed with prasugrel compared with clopidogrel; the overall mortality rate appears similar between treatments.
Prasugrel should be initiated as a 60-mg oral loading dose and continued as 10 mg by mouth once daily. Patients on prasugrel should also be taking aspirin (75–325 mg) daily. Low-weight patients (<60 kg) demonstrate increased exposure to prasugrel's active metabolite; selecting a lower maintenance dose of 5 mg should be considered in this population. Prasugrel is available in 5- and 10-mg tablets.
Concomitant administration of prasugrel with other medications that increase bleeding risk (e.g., heparin, aspirin, warfarin, nonsteroidal antiinflammatory drugs) could result in additive effects.
Prasugrel is associated with an increased risk of bleeding and should not be used in patients with active pathological bleeding or a history of transient ischemic attack or stroke or in patients likely to undergo coronary artery bypass surgery within the next 7 days. Use caution in patients with risk factors for bleeding (e.g., advanced age, low body weight).
Bleeding reports for prasugrel were epistaxis (6.2%), gastrointestinal hemorrhage (1.5%), hemoptysis (0.6%), subcutaneous hematoma (0.5%), postprocedural hemorrhage (0.5%), and retroperitoneal hemorrhage (0.3%). The most common nonhemorrhagic adverse events reported with prasugrel are anemia, allergic reactions, abnormal hepatic function, severe thrombocytopenia, and angioedema.
Saxagliptin (37–39), the second dipeptidyl peptidase-4 inhibitor available on the market, is indicated as adjunctive therapy to be given in combination with lifestyle modifications for improvement of glycemic control in patients with type 2 diabetes. Inhibition of dipeptidyl peptidase-4 inhibitor leads to the inactivation of incretin hormones and glucagon-like peptide-1. Glucagon-like peptide-1 plays a role in regulating glucose homeostasis, delaying gastric emptying, and inhibiting glucagon secretion. Saxagliptin has been studied as monotherapy and in combination with metformin, glyburide, and thiazolidinedione therapy. In placebo-controlled trials, saxagliptin revealed significant improvements in hemoglobin A1c, fasting plasma glucose, and 2-hour postprandial glucose levels. The greatest reductions in hemoglobin A1c levels have been seen with the 5-mg dose of saxagliptin.
The recommended dose of saxagliptin is 2.5 or 5 mg by mouth once daily with or without food. In patients with moderate to severe renal impairment (CrCl <50 mL/min) or with ESRD requiring hemodialysis, the recommended dose is 2.5 mg once daily. Saxagliptin is available as 2.5- and 5-mg tablets.
The metabolism of saxagliptin is mediated by the CYP3A4/5 system, and the dose of saxagliptin should be a maximum of 2.5 mg daily when coadministered with strong CYP3A4/5 inhibitors (e.g., ketoconazole, atazanavir, clarithromycin).
The most commonly reported adverse reactions were upper respiratory tract infection, peripheral edema, and headache. The incidence of hypoglycemia was similar between placebo and saxagliptin.
Telavancin (40, 41), a lipoglycopeptide antibiotic, is indicated for the treatment of adult patients with complicated skin and skin structure infections caused by susceptible gram-positive bacteria. Telavancin exerts a concentration-dependent bactericidal activity and works by inhibiting bacterial cell wall synthesis as well as disrupting the bacterial membrane. A phase III trial found telavancin to be as effective as vancomycin for the treatment of complicated skin and skin structure infections, including methicillin-resistant Staphylococcus aureus infections.
The recommended dose of telavancin is 10 mg/kg given as a 60-minute intravenous infusion every 24 hours for 7 to 14 days. For patients with mild renal insufficiency (CrCl, 30–50 mL/min), the telavancin dose should be decreased to 7.5 mg/kg every 24 hours. For patients with severe renal insufficiency (CrCl, 10–29 mL/min), telavancin should be administered as a 10 mg/kg dose every 48 hours. Telavancin is available in 250- and 750-mg single-use vials.
No formal drug interaction studies have been performed. In vitro studies have evaluated the inhibitory activity of telavancin against CYP450 enzymes and found that telavancin inhibits CYP3A4/5; the clinical importance of this is not known. Telavancin is known to interfere with factor Xa and PT/INR testing but does not interact with anticoagulation medications.
Telavancin should be avoided in pregnancy unless the potential benefit to the patient outweighs the potential risk to the fetus. If a pregnant patient receives telavancin, physicians are encouraged to enroll the patient in the pregnancy registry.
The most common adverse reactions occurring in patients treated with telavancin include taste disturbance, nausea, vomiting, and foamy urine. Serious adverse events have occurred with telavancin including nephrotoxicity, QT prolongation, infusion-related reactions, and Clostridium difficile–associated diarrhea. Clinical studies revealed that a higher proportion of patients treated with telavancin experienced renal dysfunction compared with patients treated with vancomycin.
Tolvaptan (42–44) is a selective vasopressin V2-receptor antagonist indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia, including patients with heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone. Clinical trials evaluating tolvaptan in patients with hyponatremia found that serum sodium concentrations increased more in the tolvaptan group compared with placebo at day 4 and 30 of therapy. The EVEREST trial enrolled patients with heart failure and found that tolvaptan did not affect all-cause mortality, cardiovascular death, or the incidence of hospitalization due to heart failure; however, tolvaptan was noted to improve dyspnea, edema, serum sodium levels, and body weight. Tolvaptan offers an oral alternative to conivaptan; efficacy comparisons are not available.
It is recommended that tolvaptan be initiated and reinitiated in the hospital setting. The recommended starting dose is 15 mg by mouth once daily, which may be titrated up in 24-hour intervals to a maximum dose of 60 mg once daily as appropriate per patient response. Serum sodium levels and volume status should be monitored. Tolvaptan is available as 15- and 30-mg tablets.
Tolvaptan is metabolized by CYP3A, so when given along with CYP3A inducers or inhibitors, patient response should be monitored and the dose adjusted if necessary. Coadministration with strong CYP3A inhibitors has revealed a significant increase in tolvaptan concentrations. Likewise, coadministration with strong CYP3A inducers reduces tolvaptan plasma concentrations considerably.
Tolvaptan should only be initiated and reinitiated in hospitalized patients where serum sodium levels can be closely monitored. Rapid correction of hyponatremia can lead to significant adverse effects including osmotic demyelination leading to dysarthria, dysphagia, lethargy, seizures, and possibly death.
The most common side effects encountered with tolvaptan include dry mouth, constipation, thirst, asthenia, hyperglycemia, and polyuria.
Ustekinumab (45, 46), a human interleukin-12 and -23 antagonist, is indicated for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. As a human monoclonal antibody, ustekinumab disrupts interleukin- and cytokine-mediated signaling involved in inflammatory and immune responses. A clinical trial comparing ustekinumab with etanercept for psoriasis demonstrated a 75% improvement in the psoriasis area-and-severity index in 65.1% of patients receiving 45 mg of ustekinumab compared with 49% of those who received high-dose etanercept; adverse effects were similar between agents.
Ustekinumab is given by subcutaneous injection based on patient body weight. For patients weighing 100 kg, the recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks. For patients weighing >100 kg, the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks. Ustekinumab is available in 45- and 90-mg single-use vials.
Drug interaction studies have not been performed with ustekinumab. It is recommended that patients not receive live vaccines while on ustekinumab.
The most common adverse effects include nasopharyngitis, upper respiratory tract infection, headache, and fatigue. Infections, malignancies, and reversible posterior leukoencephalopathy syndrome are serious adverse events that have occurred in clinical trials. Patients should be tested for tuberculosis prior to initiating ustekinumab.
Vigabatrin (47–50) is an antiepileptic drug indicated for refractory complex partial seizures in adults. It is recommended for use as adjunctive therapy in patients who have failed to respond to other agents. Vigabatrin is an irreversible inhibitor of gamma-aminobutyric acid transaminase, which results in increased levels of gamma-aminobutyric acid in the central nervous system. Placebo-controlled trials in the United States have found that vigabatrin 3 g/day given as adjunctive therapy is significantly more effective than placebo in reducing seizure frequency.
Initial dosing for vigabatrin is 500 mg by mouth twice daily. Daily dosing may be increased in 500-mg increments weekly based on patient response. The recommended maintenance dose is 3 g/day (1.5 g twice daily). Dose adjustment is needed in patients with renal impairment based on CrCl. For CrCl 51 to 80 mL/min, decrease the dose by 25%; for CrCl 31 to 50 mL/min, decrease the dose by 50%; and for CrCl 11 to 30 mL/min, decrease the dose by 75%. Vigabatrin doses should be tapered upon treatment discontinuation. Vigabatrin is available as 500-mg tablets.
When vigabatrin is given concurrently with phenytoin, in vitro studies have shown that vigabatrin results in decreased phenytoin levels. Phenytoin adjustments are not required but may be necessary if clinically indicated. Coadministration with other antiepileptic drugs does not appear to affect plasma concentrations of vigabatrin.
Vigabatrin causes progressive and permanent visual field constriction in a large proportion of patients. The risk of vision loss increases with the total dose and duration of use. Vision tests are required at baseline and every 3 to 6 months for patients on vigabatrin, but this testing may not prevent vision damage.
The most commonly observed adverse reactions include headache, somnolence, fatigue, convulsion, nystagmus, weight gain, tremor, abnormal coordination, and upper respiratory tract infection. Serious adverse events have been associated with vigabatrin use including vision loss, birth defects, deafness, and angioedema.
Because of the risk of permanent vision loss, vigabatrin is available only under a special restricted distribution program called the SHARE program. Prescribers and pharmacies must be registered with the program to distribute vigabatrin. Patients must also enroll in and agree with the conditions of the SHARE program.
Table Table33 provides information regarding new chemotherapeutic agents and their approved indications.