US Pharm. 2009;34(10):HS-3-HS-13. 

New molecular entities (NMEs), as defined by the FDA, are new drug products containing as their active ingredient a chemical substance marketed for the first time in the United States. The following descriptions of NMEs approved in 2008-2009 (TABLE) detail the clinical and pharmacologic profile of each new drug and provide a summary of selected pharmacokinetic, adverse-reaction, drug-interaction, and dosing data. This review is intended to be objective rather than evaluative in content. The information for each NME was obtained primarily from sources published prior to FDA approval. Experience clearly demonstrates that many aspects of a new drug's therapeutic profile are not detected in premarketing studies and emerge after the drug is used in large numbers of patients. For example, "new" adverse reactions are detected for many NMEs within 2 to 3 years of becoming available. Some of these drugs may eventually acquire at least one black box warning for serious adverse reactions or even be withdrawn from the market for safety reasons not recognized at the time of approval. Hence, while this review offers a starting point for learning about new drugs, it is essential that practitioners be vigilant about changes in a drug's therapeutic profile as reported by their own patients and in the pharmaceutical literature.


Everolimus (Afinitor, Novartis)


Indication and Clinical Profile1,2: Everolimus has been approved for the treatment of advanced renal cell carcinoma (RCC) after failure of treatment with Sutent (sunitinib) or Nexavar (sorafenib). Sunitinib and sorafenib are commonly used as initial treatments for advanced RCC, but when these drugs fail, there are few alternatives. Prior to the approval of everolimus, no other therapy had been studied in a phase III trial in this population. RCC is the most common type of kidney cancer, with occurrence rates rising steadily owing in part to smoking and obesity. Approximately 54,000 new cases of RCC occurred in the U.S. in 2008, with more than 13,000 deaths.

The approval of everolimus for advanced RCC was based on data from the multicenter RECORD-1 ( REnal Cell cancer treatment with Oral RAD001 given Daily) trial involving 416 advanced-RCC patients whose cancer progressed despite prior treatment with sunitinib, sorafenib, or both sequentially. Prior therapy with bevacizumab, interferon alfa, and interleukin-2 was allowed. Progression-free survival (PFS) was assessed via a blinded, independent radiologic review. Everolimus-treated patients had a median PFS of 4.9 months versus 1.9 months with placebo. Additional data showed that, after 10 months of treatment with everolimus, approximately 25% of patients had no tumor growth.


Pharmacology and Pharmacokinetics1,2: Everolimus is a kinase inhibitor that acts by blocking mTOR (mammalian target of rapamycin), a protein in the cancer cell that controls tumor cell division, cell metabolism, and blood-vessel growth. Preclinical and clinical data have established the importance of mTOR in the development and progression of several types of tumors.

In patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours postadministration, and AUC is dose-proportional over the range of 5 mg to 70 mg. The drug's half-life is about 30 hours, with 80% eliminated in the feces as metabolites. While everolimus is the main circulating component, six metabolites have been detected, all of which appear to be significantly (100-fold) less active than the parent drug. Everolimus is a substrate of CYP3A4 and P-glycoprotein (Pgp) (see Drug Interactions). Based on the drug's clearance profile, dose reduction is recommended in moderate hepatic impairment, and everolimus should not be used in patients with severe hepatic impairment. 

Adverse Reactions, Precautions, and Warnings1,2: The most common adverse events (≥30%) associated with everolimus in clinical trials were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. Common laboratory abnormalities (≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. Renal function, blood glucose, lipids, and hematologic parameters should be evaluated prior to starting everolimus and periodically thereafter. Rarely, deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed in patients receiving everolimus.

Everolimus is contraindicated in patients with hypersensitivity to the drug, to other rapamycin derivatives, or to any of the excipients. Potentially serious adverse reactions include noninfectious pneumonitis and infections for which patients should be monitored and treated as needed. Some infections have been severe or fatal. Noninfectious pneumonitis may require temporary dose reduction and/or interruption or discontinuation. Patients with systemic invasive fungal infections should not receive everolimus. Live vaccinations and close contact with individuals who have received live vaccines should be avoided during treatment. Everolimus may cause fetal harm in pregnant women (pregnancy category D). 

Drug Interactions1,2: Everolimus is a substrate of CYP3A4; it also is a substrate and moderate inhibitor of the efflux pump Pgp. Thus, drugs that function as both CYP3A4 and Pgp inhibitors (ketoconazole, erythromycin, verapamil) can significantly increase the Cmax and AUC of everolimus if used concurrently. Strong or moderate inhibitors of CYP3A4 and Pgp inhibitors should not be used in patients receiving everolimus. Conversely, drugs that induce CYP3A4 (rifampin) can significantly decrease the Cmax and AUC of everolimus if used concurrently, necessitating dose adjustment. 

Dosage and Administration1,2: Everolimus is supplied as 5-mg and 10-mg tablets. The tablet should be swallowed whole with a glass of water. The recommended dose in advanced RCC is 10 mg once daily taken the same time every day, with or without food. Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs. In the case of severe and/or intolerable adverse reactions, temporary dose reduction to 5 mg daily or interruption of therapy may be necessary. A dose reduction to 5 mg daily is recommended for patients with moderate hepatic impairment. Patients requiring both everolimus and a strong CYP3A4 inducer may need the everolimus dose increased incrementally to 20 mg daily. 


Plerixafor Injection (Mozobil, Genzyme)


Indication and Clinical Profile3,4: Plerixafor, in combination with granulocyte colony-stimulating factor (G-CSF), has been approved to mobilize hematopoietic stem cells (HSCs) for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). This drug has been granted orphan drug designation.

The efficacy of this agent was assessed in two controlled studies in which patients were treated with either plerixafor 0.24 mg/kg or placebo each evening before apheresis. Patients also received G-CSF 10 mcg/kg every morning for 4 days before the first dose of plerixafor or placebo and every morning before apheresis. Study 1 included patients with NHL; Study 2 involved those with MM. In Study 1, 59% of plerixafor-treated patients collected ≥5 x 106 CD34+ cells/kg (target levels) from peripheral blood in ≤4 apheresis sessions versus 20% of placebo-treated patients. In Study 2, 72% of plerixafor-treated patients collected ≥6 x 106 CD34+ cells/kg from peripheral blood in ≤2 apheresis sessions versus 34% of placebo-treated patients. The median number of days to reach the target cell count was 1 for the plerixafor group and 4 for the placebo group.

Pharmacology and Pharmacokinetics3,4: Plerixafor is a novel CXCR4 chemokine receptor antagonist that blocks binding of its ligand, stromal cell-derived factor-1 alpha. This action results in a rapid increase in the number of stem cells in circulation in the blood in patients with NHL and MM. Circulating stem cells can be collected for use in an autologous stem cell transplant.

Peak plasma concentrations of plerixafor occur approximately 30 to 60 minutes after a subcutaneous (SC) dose, and the drug exhibits linear kinetics over the therapeutic dosage range. The volume of distribution (Vd) is 0.3 L/kg, demonstrating that plerixafor is largely confined to the extravascular-fluid space. Plerixafor is not metabolized by and does not interact with cytochrome enzymes. The drug is eliminated primarily in the urine (70%) as the parent drug, with a terminal plasma half-life of 3 to 5 hours; dose reduction therefore is advised in patients with moderate-to-severe renal impairment (creatinine clearance [CrCl] ≤50 mL/minute [min]). 

Adverse Reactions, Drug Interactions, and Warnings3,4: The most common adverse events (≥10%) associated with plerixafor in conjunction with G-CSF in clinical trials were diarrhea, nausea, fatigue, injection-site reactions, headache, arthralgia, dizziness, and vomiting. Plerixafor may cause mobilization of leukemic cells, which may result in contamination of the apheresis product; for this reason, it is not approved for use in patients with leukemia. Administration of plerixafor and G-CSF increases levels of circulating leukocytes and HSCs; WBC count should therefore be monitored during therapy. Patients treated with plerixafor also have experienced thrombocytopenia. Treatment with plerixafor and G-CSF may lead to a release of tumor cells from the marrow. Patients treated with plerixafor and G-CSF should be evaluated for splenic integrity if they report upper left abdominal pain or shoulder pain. Women should avoid becoming pregnant during treatment with plerixafor; the agent may cause fetal harm, as suggested by animal studies (pregnancy category D).

Plerixafor does not appear to be a substrate, inhibitor, or inducer of human CYP450 isozymes. Thus, this agent is not likely to cause interactions with other drugs known to interact with CYP450 isozymes. 

Dosage and Administration3,4: Plerixafor is supplied as a single-use vial containing 1.2 mL of a 20-mg/mL solution for SC injection. Treatment should be initiated after the patient has received G-CSF once daily for 4 days. G-CSF 10 mcg/kg should be administered in the morning each day before apheresis; the patient should then receive plerixafor 0.24 mg/kg approximately 11 hours before initiation of apheresis for up to 4 consecutive days. The maximum recommended dose of plerixafor is 40 mg/day. Patients with moderate or severe renal impairment (CrCl ≤50 mL/min) should receive 0.16 mg/kg once daily, not to exceed 27 mg/day. 


Recombinant Antithrombin (ATryn, Ovation Pharmaceuticals)


Indication and Clinical Profile5,6: ATryn has been approved for the prevention of perioperative and peripartum thromboembolic events in patients with hereditary antithrombin deficiency (HAD). It is not indicated for treatment of thromboembolic events in HAD patients. ATryn is the first transgenically produced therapeutic protein and the first recombinant antithrombin (AT) approved in the U.S.

Patients with HAD are at increased risk for venous thromboembolic events including pulmonary embolism and deep venous thrombosis, which can be life-threatening, particularly in high-risk situations. AT is a natural anticoagulant that plays an important part in controlling the formation of blood clots. Purified recombinant AT has the same amino acid sequence as AT derived from human plasma. The prevalence of HAD in the general population is approximately 1 in 2,000 to 1 in 5,000. Half of these patients may experience thrombosis before 25 years of age, and up to 85% may suffer a thromboembolic event by age 50.

FDA approval of ATryn was based on results of two clinical trials. These single-arm, open-label studies were conducted in 31 ATryn-treated HAD patients and 35 HAD patients treated with human plasma-derived AT. The endpoint was noninferiority in the reduction in incidence of occurrence of venous thromboembolic events between the two treatment arms. ATryn was administered as a continuous infusion for at least 3 days, starting 1 day prior to surgery or delivery. Plasma AT was administered for at least 2 days as single bolus infusions. Efficacy was assessed during AT treatment and up to 7 days after stopping AT. Among patients receiving ATryn, 1 patient (3.2%) experienced a confirmed thromboembolic event, versus no patients receiving plasma AT (95% lower confidence bound [CB] of difference -0.167). As the 95% lower CB of difference was greater than the prespecified lower CB of -0.20, ATryn was determined to be noninferior to plasma AT.

Pharmacology and Pharmacokinetics5,6: ATryn is a recombinant AT produced by recombinant DNA technology. The DNA for human AT, along with a mammary gland-specific DNA sequence, is inserted into a single-celled goat embryo. This embryo is implanted into a surrogate doe. The resulting transgenic offspring produce high levels of AT in their milk, which is collected and purified to form the final drug product. The amino acid sequence of this recombinant AT is identical to that of human plasma-derived AT. AT plays a central role in the regulation of hemostasis and is the principal inhibitor of thrombin and factor Xa5, the serine proteases that play pivotal roles in blood coagulation. AT neutralizes the activity of thrombin and Factor Xa by forming a complex that is rapidly removed from the circulation.

Pharmacokinetic analysis of HAD patients in a high-risk situation revealed that clearance and Vd in pregnant patients were 1.38 L/h and 14.3 L, respectively, which are higher than in nonpregnant patients (0.67 L/h and 7.7 L, respectively). Therefore, distinct dosing formulas for surgical and pregnant patients should be used. Compared with plasma-derived AT, ATryn has a shorter half-life and more rapid clearance (approximately 9 and 7 times, respectively). Pharmacokinetics may be influenced by concomitant heparin administration, as well as by surgical procedures, delivery, or bleeding. AT activity should be monitored to properly treat such patients. 

Adverse Reactions and Drug Interactions5,6: The most common adverse events (≥5%) associated with ATryn in clinical trials were hemorrhage (intra-abdominal, hemarthrosis, and postprocedural) and infusion-site reactions. Patients treated with ATryn may experience allergic-type hypersensitivity reactions and therefore should be closely monitored for symptoms of a hypersensitivity reaction throughout the infusion. If a reaction occurs during administration, treatment must be discontinued immediately and emergency treatment administered. ATryn is contraindicated in patients with known hypersensitivity to goat and goat's-milk proteins.

The anticoagulant effect of heparin and low-molecular-weight heparin (LMWH) is enhanced by AT. The half-life of AT may be altered by concomitant treatment with these anticoagulants owing to altered AT turnover. Thus, concurrent administration of AT with heparin, LMWH, or other anticoagulants that use AT to exert their anticoagulant effect must be monitored clinically and biologically. To avoid excessive anticoagulation, regular coagulation tests (activated partial thromboplastin time and, where appropriate, anti-factor Xa activity) should be performed at close intervals, particularly in the hours immediately after initiation or withdrawal of ATryn treatment. Additionally, patients must be monitored for bleeding or thrombosis in such situations.

ATryn is a pregnancy category C drug. Studies in pregnant women have not shown that ATryn increases the risk of fetal abnormalities if administered during the third trimester. ATryn is used to treat peripartum women with HAD. 

Dosage and Administration5,6: ATryn is supplied as a powder for reconstitution designed for IV administration. The dosage of ATryn should be individualized based on the patient's pretreatment functional AT-activity level (expressed in percentage of normal) and body weight (expressed in kg) and using therapeutic drug monitoring. The goal of treatment is to restore and maintain functional AT-activity levels between 80% and 120% of normal (0.8-1.2 IU/mL). Treatment should be initiated prior to delivery or approximately 24 hours prior to surgery. A loading dose ([(100 - baseline AT activity level)/1.3] x body weight [kg]) should be administered as a 15-minute infusion, immediately followed by continuous infusion of the maintenance dose ([(100 - baseline AT activity level)/5.4] x body weight [kg]). AT activity should be checked once or twice daily, beginning 2 hours after therapy initiation, and dosing adjustments should be made as follows: If AT level is <80% of normal, the dose should be increased by 30%, and AT level should be rechecked 2 hours later; if AT level is >120% of normal, the dose should be decreased by 30%, and AT level should be rechecked 2 hours later. 


Romiplostim (Nplate, Amgen) and Eltrombopag (Promacta, GlaxoSmithKline)


Indication and Clinical Profile7-10: Romiplostim, a recombinant fusion protein for SC injection, and eltrombopag, a nonpeptide taken orally, have been approved for the treatment of chronic immune thrombocytopenic purpura (ITP) refractory to corticosteroids, immunoglobulins, and/or splenectomy. In two 6-month trials of romiplostim, 63 splenectomized and 62 nonsplenectomized adults with chronic ITP who had insufficient response to standard therapy and platelet counts ≤30 x 109/L were randomized to receive active drug or placebo in a 2:1 ratio. The starting dose of romiplostim was 1 mcg/kg/wk, which could be increased or decreased by 1 mcg/kg at intervals of 1 to 2 weeks. After 1 week of treatment, 25% of patients reached a platelet count ≥50 x 109/L, and 50% did so by 2 to 3 weeks. Platelet counts ≥50 x 109/L were reported for 6 of the last 8 weeks of the study (primary endpoint) in 61% (25/41) of nonsplenectomized and 38% (16/42) of splenectomized patients receiving romiplostim, and in 1 of 42 patients receiving placebo. In an open-label continuation study, patients took the drug for a median of 65 weeks (range 1-156 wk); 87% (124/142) achieved platelet counts ≥50 x 109/L, and 29 of 84 maintained that level for 52 weeks.

The efficacy of eltrombopag was examined in two controlled trials involving 231 adults with chronic ITP whose platelet counts were <30 x 109/L after at least one prior ITP therapy. The primary endpoint was a platelet count ≥50 x 109/L at the end of treatment. In these studies, response rates for eltrombopag 50 mg/day were 70% and 59% compared with 11% and 16% with placebo. Response rates were similar in patients with or without splenectomy. In an open-label study that followed 207 ITP patients receiving eltrombopag for up to 523 days, 79% of patients achieved a platelet count ≥50 x 109/L, and 18 of 75 maintained that level for 25 weeks or more. Furthermore, many patients who responded to either drug were able to reduce the dosage of or discontinue other ITP therapies such as corticosteroids.

Pharmacology and Pharmacokinetics7-10: ITP appears to result from antibody-mediated peripheral platelet destruction and impaired platelet production. Thrombopoietin (TPO) values are normal or low in most patients with ITP. Both romiplostim and eltrombopag bind to and activate the human TPO receptor agonists, initiating signaling cascades that induce proliferation and differentiation of megakaryocytes from bone marrow progenitor cells. Unlike romiplostim, eltrombopag does not compete for the same binding site as endogenous TPO.

SC doses of romiplostim (3-15 mcg/kg) provide peak serum concentrations at about 7 to 50 hours (median 14 hours), with a half-life ranging from 1 to 34 days (median 3.5 days). The elimination of serum romiplostim depends in part on the TPO receptor on platelets; thus, serum levels are inversely correlated with platelet counts. Metabolism and excretion do not appear to be involved in romiplostim clearance.

Oral eltrombopag is about 50% absorbed, producing peak plasma concentrations 2 to 6 hours after oral administration. Absorption of eltrombopag is greater in East Asian and African-American individuals than in Caucasian individuals. It is metabolized by cleavage, oxidation, and conjugation with glucuronic acid, glutathione, or cysteine. CYP1A2 and CYP2C8 appear to be responsible for the oxidative metabolism of eltrombopag, whereas uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A3 are responsible for glucuronidation. The predominant route of eltrombopag excretion is via the feces (59%), and 31% of the dose is found in the urine. 

Adverse Reactions7-10: In clinical trials, adverse events reported more often with romiplostim than with placebo included headache, dizziness, insomnia, myalgia, abdominal pain, dyspepsia, and paresthesia. The most common adverse effects associated with eltrombopag were nausea, vomiting, myalgia, paresthesia, menorrhagia, dyspepsia, and cataract. Liver-function test (LFT) abnormalities occurred in 10% of patients treated with eltrombopag and 8% of those receiving placebo; one eltrombopag patient had grade 4 LFT abnormalities and died. The prescribing information includes a boxed warning on the risk of hepatotoxicity and recommends measuring alanine aminotransferase, aspartate aminotransferase, and bilirubin before starting eltrombopag, every 2 weeks during dose adjustment, and monthly thereafter. Cataracts developed or worsened in 5% of patients treated with eltrombopag in the controlled trials and in 4% in the extension study.

Bone marrow reticulin deposition, which could lead to fibrosis, was reported in seven patients taking eltrombopag and in 10 patients taking romiplostim. In about 10% of patients, discontinuation of romiplostim or eltrombopag may be associated with an abrupt fall of platelet count to levels below baseline. Serious hemorrhagic events and thrombotic complications have been reported for both drugs. Stimulation of the TPO receptor by either drug could lead to development of hematologic malignancies. A Risk Evaluation and Mitigation Strategy (REMS) program requiring registration of all patients, physicians, and pharmacists is being instituted for both drugs, with mandatory reporting of clinical data to the FDA every 6 months. 

Drug Interactions7-10: Since eltrombopag is a substrate of CYP1A2 and CYP2C8, patients receiving other drugs that interact with these isozymes, especially inhibitors, should be monitored carefully. Also, since eltrombopag is both a substrate and an inhibitor of several UGT enzymes, caution should be exercised when it is administered with other drugs that are substrates or inhibitors of these isozymes. Eltrombopag inhibits the organic anion-transporting polypeptide (OATP) 1B1 and can increase systemic exposure of other drugs that are substrates of this transporter (e.g., benzylpenicillin, atorvastatin, fluvastatin, pravastatin, rosuvastatin, methotrexate, nateglinide, repaglinide, rifampin), perhaps requiring dose reduction of other OATP1B1 substrates. No formal drug-interaction studies of romiplostim have been performed. 

Dosage and Administration7-10: Romiplostim is supplied in single-use vials as a sterile, preservative-free, lyophilized powder that must be reconstituted per manufacturer's instructions. Therapy should be initiated at a dose of 1 mcg/kg/wk, to a maximum of 10 mcg/kg/wk. The dose should be adjusted as necessary in increments of 1 mcg/kg until a platelet count ≥50 x 109/L is achieved, to reduce the risk of bleeding. Platelet count and peripheral blood smears should be assessed weekly until a platelet count ≥50 x 109/L is maintained for ≥4 weeks without dose adjustment; CBCs should then be assessed monthly. If the platelet count is >200 x 109/L for 2 consecutive weeks, the romiplostim dose should be reduced by 1 mcg/kg; if the platelet count is >400 x 109/L, the drug should be withheld until the platelet count has decreased to <200 x 109/L, at which time dosing should be resumed at a dose reduced by 1 mcg/kg.

Eltrombopag is supplied as 25-mg and 50-mg film-coated tablets. It should be taken at least 1 hour before or 2 hours after a meal. Therapy should be initiated at a dose of 50 mg/day; in patients of East Asian ancestry or with moderate-to-severe hepatic impairment, initial doses of 25 mg/day are recommended. The dose should then be adjusted as necessary to maintain a platelet count ≥50 x 109/L to reduce bleeding risk. The maximum dose is 75 mg/day. If the platelet count is <50 x 109/L after ≥2 weeks of therapy, the dose should be increased by 25 mg/day. If the platelet count increases to ≥200 x 109/L but ≤400 x 109/L, the dose should be reduced by 25 mg/day. If the platelet count increases to >400 x 109/L, eltrombopag should be discontinued; once the platelet count reaches <150 x 109/L, therapy can be reinitiated at a dose reduced by 25 mg/day. If the platelet count reaches >400 x 109/L after 2 weeks of treatment with the lowest dose of eltrombopag, therapy should be permanently discontinued. A 4-hour interval should elapse between administration of eltrombopag and products containing polyvalent cations. 


Tetrabenazine (Xenazine, Lundbeck)


Indication and Clinical Profile11,12: Tetrabenazine, a drug first synthesized 50 years ago for the treatment of schizophrenia, has been approved by the FDA for the treatment of chorea associated with Huntington's disease (HD). The drug, which has been available in other countries for decades for the treatment of involuntary movement disorders, is the first and only FDA-approved treatment for any symptom of HD. Xenazine has been designated as an orphan drug.

HD is an autosomal-dominant disorder affecting an estimated 30,000 Americans. HD is caused by mutations in the IT-15 gene encoding the Huntington protein; this mutation results in production of an abnormal form of the protein huntingtin, which in turn produces cellular and anatomical changes in the brain. These changes result in a devastating neurodegenerative disease that causes progressive movement disorders, cognitive dysfunction, and behavioral changes. Although the disorder is not fatal, complications reduce life expectancy to about 20 years after symptom onset. Chorea, the most common and visible symptom, affects approximately 90% of HD patients and is characterized by excessive, involuntary, and repetitive movements that interfere with the patient's ability to perform activities of daily living, including self-care. Currently there is no treatment that slows the progression of HD, but treatment of disease-associated depression, anxiety, cognition, and chorea may improve quality of life. Such treatments include benzodiazepines, amantadine, and antipsychotics such as haloperidol, risperidone, ziprasidone, and quetiapine. Reserpine has been used to treat chorea, but it can cause depression and hypotension, and its prolonged half-life makes it difficult to use.

Tetrabenazine's efficacy was evaluated in a multicenter, controlled, 12-week trial involving 84 HD patients with at least moderate chorea. Tetrabenazine was initiated at a dose of 12.5 mg/day and was titrated at weekly intervals in 12.5-mg increments until control of chorea was achieved, side effects were intolerable, or a maximum dose of 100 mg/day was reached. The primary endpoint was change in total chorea score, which rates chorea on a scale of 0 (no chorea) to 4 for seven different parts of the body (total scale 0-28). Tetrabenazine treatment produced a 23.5% improvement in chorea severity score, and benefits were lost when the drug was stopped. A single dose of tetrabenazine improved chorea for a mean of about 5 hours, but some patients continued to benefit from the drug after 5 years of treatment.

Pharmacology and Pharmacokinetics11,12: Tetrabenazine is a reversible inhibitor of the vesicle monoamine transporter type 2 (VMAT-2). Thus, it inhibits the uptake of the monoaminergic neurotransmitters serotonin, norepinephrine, and--especially--dopamine into the granular vesicles of presynaptic neurons, thereby depleting these neurotransmitters.

Following oral administration, the extent of tetrabenazine absorption is at least 75%. Administration with food has no effect on mean plasma levels of the drug. Tetrabenazine undergoes rapid and extensive hepatic metabolism by carbonyl reductase to alpha-dihydrotetrabenazine (HTBZ) and beta-HTBZ, the major circulating metabolites with respective half-lives of 4 to 8 hours and 2 to 4 hours. Both alpha-HTBZ and beta-HTBZ are further metabolized by O-dealkylation, primarily by CYP2D6, with some contribution of CYP1A2 for alpha-HTBZ. These metabolites are primarily eliminated in the urine (75%). Patients taking strong CYP2D6 inhibitors experience significant (3-9 times) increases in exposure to alpha-HTBZ and beta-HTBZ. Although not specifically evaluated, it is anticipated that patients who do not express CYP2D6 (poor metabolizers) also will have increased exposure to alpha-HTBZ and beta-HTBZ compared with those who express CYP2D6 (extensive metabolizers). 

Adverse Reactions11,12: The most common adverse events associated with tetrabenazine are sedation/somnolence, fatigue, insomnia, depression, postural dizziness, akathisia, parkinsonism, and nausea. HD is characterized by changes in mood, cognition, chorea, rigidity, and functional capacity; tetrabenazine use may worsen these conditions. Patients with HD are at increased risk for depression and suicidal ideation/behavior; tetrabenazine increases these risks, prompting a boxed warning about depression and increased suicide risk. Tetrabenazine is being marketed under an FDA-approved REMS to decrease the risks of depression and suicidal ideation potentially associated with the drug. Patients treated with neuroleptics may develop a potentially irreversible syndrome of involuntary dyskinetic movements. Tetrabenazine has been associated with neuroleptic malignant syndrome rarely, and with a slight increase in the corrected QT interval. 

Drug Interactions11,12: Reserpine binds to VMAT-2 and depletes monoamines in the central nervous system; thus, it should not be used concurrently with tetrabenazine. When a patient is being switched from reserpine, at least 3 weeks should elapse before tetrabenazine is initiated. Drugs that strongly inhibit CYP2D6 (fluoxetine, paroxetine, quinidine) may decrease the metabolism of tetrabenazine, requiring dose reduction. Tetrabenazine should not be administered with monoamine oxidase inhibitors. 

Dosage and Administration11,12: Tetrabenazine, available only through a specialty pharmacy distribution network, is supplied as 12.5-mg and 25-mg tablets. Therapy should be initiated at a dose of 12.5 mg/day administered in the morning. After 1 week, the dose should be increased to 25 mg/day administered as 2 doses of 12.5 mg. The drug should then be titrated by 12.5 mg/wk until a well-tolerated dose that reduces chorea is reached. Doses ≥37.5 mg/day should be administered as 3 daily doses. The maximum recommended dose is 100 mg/day. In patients who are poor metabolizers of CYP2D6, the maximum recommended dose is 50 mg/day. In patients who are extensive and intermediate metabolizers of CYP2D6, the maximum recommended single dose is 37.5 mg. The drug should not be used in patients with impaired hepatic function. 


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