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Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a trend toward reduced risk with antidepressant use in patients aged 65 and older [see WARNINGS AND PRECAUTIONS].
In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see WARNINGS AND PRECAUTIONS].
BRINTELLIX has not been evaluated for use in pediatric patients [see Use in Specific Populations].
BRINTELLIX is an immediate-release tablet for oral administration that contains the beta (β) polymorph of vortioxetine hydrobromide (HBr), an antidepressant. Vortioxetine HBr is known chemically as 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine, hydrobromide. The empirical formula is C18H22N2S, HBr with a molecular weight of 379.36 g/mol. The structural formula is:
Vortioxetine HBr is a white to very slightly beige powder that is slightly soluble in water.
Each BRINTELLIX tablet contains 6.355 mg, 12.71 mg, 19.065 mg, or 25.42 mg of vortioxetine HBr equivalent to 5 mg, 10 mg, 15 mg, or 20 mg of vortioxetine, respectively. The inactive ingredients in BRINTELLIX tablets include mannitol, microcrystalline cellulose, hydroxypropyl cellulose, sodium starch glycolate, magnesium stearate and film coating which consists of hypromellose, titanium dioxide, polyethylene glycol 400, iron oxide red (5 mg, 15 mg, and 20 mg) and iron oxide yellow (10 mg and 15 mg).
Major Depressive Disorder
BRINTELLIX is indicated for the treatment of major depressive disorder (MDD). The efficacy of BRINTELLIX was established in six 6 to 8 week studies (including one study in the elderly) and one maintenance study in adults [see Clinical Studies].
General Instruction For Use
The recommended starting dose is 10 mg administered orally once daily without regard to meals. Dosage should then be increased to 20 mg/day, as tolerated, because higher doses demonstrated better treatment effects in trials conducted in the United States. The efficacy and safety of doses above 20 mg/day have not been evaluated in controlled clinical trials. A dose decrease down to 5 mg/day may be considered for patients who do not tolerate higher doses [see Clinical Studies].
Maintenance/Continuation/Extended Treatment
It is generally agreed that acute episodes of major depression should be followed by several months or longer of sustained pharmacologic therapy. A maintenance study of BRINTELLIX demonstrated that BRINTELLIX decreased the risk of recurrence of depressive episodes compared to placebo.
Discontinuing Treatment
Although BRINTELLIX can be abruptly discontinued, in placebo-controlled trials patients experienced transient adverse reactions such as headache and muscle tension following abrupt discontinuation of BRINTELLIX 15 mg/day or 20 mg/day. To avoid these adverse reactions, it is recommended that the dose be decreased to 10 mg/day for one week before full discontinuation of BRINTELLIX 15 mg/day or 20 mg/day [see ADVERSE REACTIONS].
Switching A Patient To Or From A Monoamine Oxidase Inhibitor (MAOI) Intended To Treat Psychiatric Disorders
At least 14 days should elapse between discontinuation of a MAOI intended to treat psychiatric disorders and initiation of therapy with BRINTELLIX to avoid the risk of Serotonin Syndrome [see WARNINGS AND PRECAUTIONS]. Conversely, at least 21 days should be allowed after stopping BRINTELLIX before starting an MAOI intended to treat psychiatric disorders [see CONTRAINDICATIONS].
Use Of BRINTELLIX With Other MAOIs Such As Linezolid Or Methylene Blue
Do not start BRINTELLIX in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see CONTRAINDICATIONS].
In some cases, a patient already receiving BRINTELLIX therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, BRINTELLIX should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 21 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with BRINTELLIX may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see WARNINGS AND PRECAUTIONS].
The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with BRINTELLIX is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see WARNINGS AND PRECAUTIONS].
Use Of BRINTELLIX In Known CYP2D6 Poor Metabolizers Or In Patients Taking Strong CYP2D6 Inhibitors
The maximum recommended dose of BRINTELLIX is 10 mg/day in known CYP2D6 poor metabolizers. Reduce the dose of BRINTELLIX by one-half when patients are receiving a CYP2D6 strong inhibitor (e.g., bupropion, fluoxetine, paroxetine, or quinidine) concomitantly. The dose should be increased to the original level when the CYP2D6 inhibitor is discontinued [see DRUG INTERACTIONS].
Use Of BRINTELLIX In Patients Taking Strong CYP Inducers
Consider increasing the dose of BRINTELLIX when a strong CYP inducer (e.g., rifampin, carbamazepine, or phenytoin) is coadministered for greater than 14 days. The maximum recommended dose should not exceed three times the original dose. The dose of BRINTELLIX should be reduced to the original level within 14 days, when the inducer is discontinued [see DRUG INTERACTIONS].
Dosage Forms And Strengths
BRINTELLIX is available as immediate-release, film-coated tablets in the following strengths:
- 5 mg: pink, almond shaped biconvex film coated tablet, debossed with "5" on one side and "TL" on the other side
- 10 mg: yellow, almond shaped biconvex film coated tablet, debossed with "10" on one side and "TL" on the other side
- 15 mg: orange, almond shaped biconvex film coated tablet, debossed with "15" on one side and "TL" on the other side
- 20 mg: red, almond shaped biconvex film coated tablet, debossed with "20" on one side and "TL" on the other side
Storage And Handling
BRINTELLIX tablets are available as follows:
|5 mg
|10 mg
|15 mg
|20 mg
|"5" on one side of tablet
|"10" on one side of tablet
|"15" on one side of tablet
|"20" on one side of tablet
|"TL" on other side of tablet
|"TL" on other side of tablet
|"TL" on other side of tablet
|"TL" on other side of tablet
|Presentations and NDC Codes
|Bottles of 30
|Bottles of 90
|Bottles of 500
Store at 77°F (25°C); excursions permitted to 59°F to 86°F (15°C to 30°C) [see USP Controlled Room Temperature].
Distributed and marketed by: Takeda Pharmaceuticals America, Inc., Deerfield, IL 60015 Marketed by: Lundbeck, Deerfield, IL 60015. Revised: July 2014
The following adverse reactions are discussed in greater detail in other sections of the label.
- Hypersensitivity [see CONTRAINDICATIONS]
- Clinical Worsening and Suicide Risk [see WARNINGS AND PRECAUTIONS]
- Serotonin Syndrome [see WARNINGS AND PRECAUTIONS]
- Abnormal Bleeding [see WARNINGS AND PRECAUTIONS]
- Activation of Mania/Hypomania [see WARNINGS AND PRECAUTIONS]
- Hyponatremia [see WARNINGS AND PRECAUTIONS]
Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
Patient Exposure
BRINTELLIX was evaluated for safety in 4746 patients (18 years to 88 years of age) diagnosed with MDD who participated in pre-marketing clinical studies; 2616 of those patients were exposed to BRINTELLIX in 6 to 8 week, placebo-controlled studies at doses ranging from 5 mg to 20 mg once daily and 204 patients were exposed to BRINTELLIX in a 24 week to 64 week placebo-controlled maintenance study at doses of 5 mg to 10 mg once daily. Patients from the 6 to 8 week studies continued into 12-month open-label studies. A total of 2586 patients were exposed to at least one dose of BRINTELLIX in open-label studies, 1727 were exposed to BRINTELLIX for six months and 885 were exposed for at least one year.
Adverse Reactions Reported as Reasons for Discontinuation of Treatment
In pooled 6 to 8 week placebo-controlled studies the incidence of patients who received BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day and 20 mg/day and discontinued treatment because of an adverse reaction was 5%, 6%, 8% and 8%, respectively, compared to 4% of placebo-treated patients. Nausea was the most common adverse reaction reported as a reason for discontinuation.
Common Adverse Reactions in Placebo-Controlled MDD Studies
The most commonly observed adverse reactions in MDD patients treated with BRINTELLIX in 6 to 8 week placebo-controlled studies (incidence ≥ 5% and at least twice the rate of placebo) were nausea, constipation and vomiting.
Table 2 shows the incidence of common adverse reactions that occurred in ≥ 2% of MDD patients treated with any BRINTELLIX dose and at least 2% more frequently than in placebo-treated patients in the 6 to 8 week placebo-controlled studies.
Table 2: Common Adverse Reactions Occurring in ≥ 2%
of Patients Treated with any BRINTELLIX Dose and at Least 2% Greater than the
Incidence in Placebo-treated Patients
|System Organ Class Preferred Term
|BRINTELLIX 5 mg/day
|BRINTELLIX 10 mg/day
|BRINTELLIX 15 mg/day
|BRINTELLIX 20 mg/day
|Gastrointestinal disorders
|Dry mouth
|Nervous system disorders
|Psychiatric disorders
|Abnormal dreams
|< 1
|< 1
|Skin and subcutaneous tissue disorders
|*includes pruritus generalized
Nausea was the most common adverse reaction and its frequency was dose-related (Table 2). It was usually considered mild or moderate in intensity and the median duration was 2 weeks. Nausea was more common in females than males. Nausea most commonly occurred in the first week of BRINTELLIX treatment with 15 to 20% of patients experiencing nausea after 1 to 2 days of treatment. Approximately 10% of patients taking BRINTELLIX 10 mg/day to 20 mg/day had nausea at the end of the 6 to 8 week placebo-controlled studies.
Sexual Dysfunction
Difficulties in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders, but they may also be consequences of pharmacologic treatment.
In the MDD 6 to 8 week controlled trials of BRINTELLIX, voluntarily reported adverse reactions related to sexual dysfunction were captured as individual event terms. These event terms have been aggregated and the overall incidence was as follows. In male patients the overall incidence was 3%, 4%, 4%, 5% in BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to 2% in placebo. In female patients, the overall incidence was < 1%, 1%, < 1%, 2% in BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to < 1% in placebo.
Because voluntarily reported adverse sexual reactions are known to be underreported, in part because patients and physicians may be reluctant to discuss them, the Arizona Sexual Experiences Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in seven placebo-controlled trials. The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction.
The presence or absence of sexual dysfunction among patients entering clinical studies was based on their ASEX scores. For patients without sexual dysfunction at baseline (approximately 1/3 of the population across all treatment groups in each study), Table 3 shows the incidence of patients that developed treatment-emergent sexual dysfunction when treated with BRINTELLIX or placebo in any fixed dose group. Physicians should routinely inquire about possible sexual side effects.
Table 3: ASEX Incidence of Treatment Emergent Sexual
|BRINTELLIX 5 mg/day
|BRINTELLIX 10 mg/day
|BRINTELLIX 15 mg/day
|BRINTELLIX 20 mg/day
|*Incidence based on number of subjects with sexual
dysfunction during the study / number of subjects without sexual dysfunction at
baseline. Sexual dysfunction was defined as a subject scoring any of the
following on the ASEX scale at two consecutive visits during the study: 1)
total score ≥ 19; 2) any single item ≥ 5; 3) three or more items each
with a score ≥ 4
†Sample size for each dose group is the number of patients (females:males) without sexual dysfunction at baseline
Adverse Reactions Following Abrupt Discontinuation of BRINTELLIX Treatment
Discontinuation symptoms have been prospectively evaluated in patients taking BRINTELLIX 10 mg/day, 15 mg/day, and 20 mg/day using the Discontinuation-Emergent Signs and Symptoms (DESS) scale in clinical trials. Some patients experienced discontinuation symptoms such as headache, muscle tension, mood swings, sudden outbursts of anger, dizziness, and runny nose in the first week of abrupt discontinuation of BRINTELLIX 15 mg/day and 20 mg/day.
Laboratory Tests
BRINTELLIX has not been associated with any clinically important changes in laboratory test parameters in serum chemistry (except sodium), hematology and urinalysis as measured in the 6 to 8 week placebo-controlled studies. Hyponatremia has been reported with the treatment of BRINTELLIX [see WARNINGS AND PRECAUTIONS]. In the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to BRINTELLIX during the initial 12-week, open-label phase, there were no clinically important changes in lab test parameters between BRINTELLIX and placebo-treated patients.
BRINTELLIX had no significant effect on body weight as measured by the mean change from baseline in the 6 to 8 week placebo-controlled studies. In the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to BRINTELLIX during the initial 12-week, open-label phase, there was no significant effect on body weight between BRINTELLIX and placebo-treated patients.
Vital Signs
BRINTELLIX has not been associated with any clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies.
Other Adverse Reactions Observed in Clinical Studies
The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.
Ear and labyrinth disorders — vertigo
Gastrointestinal disorders — dyspepsia
Nervous system disorders — dysgeusia
Vascular disorders — flushing
CNS Active Agents
Monoamine Oxidase Inhibitors
Adverse reactions, some of which are serious or fatal, can develop in patients who use MAOIs or who have recently been discontinued from an MAOI and started on a serotonergic antidepressant(s) or who have recently had SSRI or SNRI therapy discontinued prior to initiation of an MAOI [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
Serotonergic Drugs
Based on the mechanism of action of BRINTELLIX and the potential for serotonin toxicity, serotonin syndrome may occur when BRINTELLIX is coadministered with other drugs that may affect the serotonergic neurotransmitter systems (e.g., SSRIs, SNRIs, triptans, buspirone, tramadol, and tryptophan products etc.). Closely monitor symptoms of serotonin syndrome if BRINTELLIX is co-administered with other serotonergic drugs. Treatment with BRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if serotonin syndrome occurs [see WARNINGS AND PRECAUTIONS].
Other CNS Active Agents
No clinically relevant effect was observed on steady state lithium exposure following coadministration with multiple daily doses of BRINTELLIX. Multiple doses of BRINTELLIX did not affect the pharmacokinetics or pharmacodynamics (composite cognitive score) of diazepam. A clinical study has shown that BRINTELLIX (single dose of 20 or 40 mg) did not increase the impairment of mental and motor skills caused by alcohol (single dose of 0.6 g/kg). Details on the potential pharmacokinetic interactions between BRINTELLIX and bupropion can be found in Section 7.3.
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin.
Following coadministration of stable doses of warfarin (1 to 10 mg/day) with multiple daily doses of BRINTELLIX, no significant effects were observed in INR, prothrombin values or total warfarin (protein bound plus free drug) pharmacokinetics for both R- and S-warfarin [see Potential for BRINTELLIX to Affect Other Drugs]. Coadministration of aspirin 150 mg/day with multiple daily doses of BRINTELLIX had no significant inhibitory effect on platelet aggregation or pharmacokinetics of aspirin and salicylic acid [see Potential for BRINTELLIX to Affect Other Drugs]. Patients receiving other drugs that interfere with hemostasis should be carefully monitored when BRINTELLIX is initiated or discontinued [see WARNINGS AND PRECAUTIONS].
Potential For Other Drugs To Affect BRINTELLIX
Reduce BRINTELLIX dose by half when a strong CYP2D6 inhibitor (e.g., bupropion, fluoxetine, paroxetine, quinidine) is coadministered. Consider increasing the BRINTELLIX dose when a strong CYP inducer (e.g., rifampicin, carbamazepine, phenytoin) is coadministered. The maximum dose is not recommended to exceed three times the original dose [see DOSAGE AND ADMINISTRATION] (Figure 1).
Figure 1: Impact of Other Drugs on Vortioxetine PK
Potential For BRINTELLIX To Affect Other Drugs
No dose adjustment for the comedications is needed when BRINTELLIX is coadministered with a substrate of CYP1A2 (e.g., duloxetine), CYP2A6, CYP2B6 (e.g., bupropion), CYP2C8 (e.g., repaglinide), CYP2C9 (e.g., S-warfarin), CYP2C19 (e.g., diazepam), CYP2D6 (e.g., venlafaxine), CYP3A4/5 (e.g., budesonide), and P-gp (e.g., digoxin). In addition, no dose adjustment for lithium, aspirin, and warfarin is necessary.
Vortioxetine and its metabolites are unlikely to inhibit the following CYP enzymes and transporter based on in vitro data: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and P-gp. As such, no clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected.
In addition, vortioxetine did not induce CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 in an in vitro study in cultured human hepatocytes. Chronic administration of BRINTELLIX is unlikely to induce the metabolism of drugs metabolized by these CYP isoforms. Furthermore, in a series of clinical drug interaction studies, coadministration of BRINTELLIX with substrates for CYP2B6 (e.g., bupropion), CYP2C9 (e.g., warfarin), and CYP2C19 (e.g., diazepam), had no clinical meaningful effect on the pharmacokinetics of these substrates (Figure 2).
Because vortioxetine is highly bound to plasma protein, coadministration of BRINTELLIX with another drug that is highly protein bound may increase free concentrations of the other drug. However, in a clinical study with coadministration of BRINTELLIX (10 mg/day) and warfarin (1 mg/day to 10 mg/day), a highly protein-bound drug, no significant change in INR was observed [see Drugs that Interfere with Hemostasis].
Figure 2: Impact of Vortioxetine on PK of Other Drugs
Drug Abuse And Dependence
BRINTELLIX is not a controlled substance.
Included as part of the PRECAUTIONS section.
Clinical Worsening And Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a trend toward reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive-compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of nine antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of two months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
Table 1: Drug-Placebo Difference in Number of Cases of
Suicidality per 1000 Patients Treated
|Age Range
|Increases Compared to Placebo
|< 18
|14 additional cases
|5 additional cases
|Decreases Compared to Placebo
|1 fewer case
|≥ 65
|6 fewer cases
No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.
Screening Patients for Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that BRINTELLIX is not approved for use in treating bipolar depression.
Serotonin Syndrome
The development of a potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants including BRINTELLIX, when used alone but more often when used concomitantly with other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
The concomitant use of BRINTELLIX with MAOIs intended to treat psychiatric disorders is contraindicated. BRINTELLIX should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking BRINTELLIX. BRINTELLIX should be discontinued before initiating treatment with the MAOI [see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION].
If concomitant use of BRINTELLIX with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with BRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Abnormal Bleeding
The use of drugs that interfere with serotonin reuptake inhibition, including BRINTELLIX, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.
Patients should be cautioned about the increased risk of bleeding when BRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation or bleeding [see DRUG INTERACTIONS].
Activation Of Mania/Hypomania
Symptoms of mania/hypomania were reported in < 0.1% of patients treated with BRINTELLIX in pre-marketing clinical studies. Activation of mania/hypomania has been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. As with all antidepressants, use BRINTELLIX cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania.
Angle Closure Glaucoma
Angle Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs, including BRINTELLIX, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
Hyponatremia has occurred as a result of treatment with serotonergic drugs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). One case with serum sodium lower than 110 mmol/L was reported in a subject treated with BRINTELLIX in a pre-marketing clinical study. Elderly patients may be at greater risk of developing hyponatremia with a serotonergic antidepressant. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk. Discontinuation of BRINTELLIX in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. More severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide) Advise patients and their caregivers about the benefits and risks associated with treatment with BRINTELLIX and counsel them in its appropriate use. Advise patients and their caregivers to read the Medication Guide and assist them in understanding its contents. The complete text of the Medication Guide is reprinted at the end of this document.
Suicide Risk
Advise patients and caregivers to look for the emergence of suicidal ideation and behavior, especially early during treatment and when the dose is adjusted up or down [see BOXED WARNING and WARNINGS AND PRECAUTIONS].
Discontinuation of Treatment
Patients who are on BRINTELLIX 15 mg/day or 20 mg/day may experience headache, muscle tension, mood swings, sudden outburst of anger, dizziness and runny nose if they abruptly stop their medicine. Advise patients not stopping BRINTELLIX without talking to their healthcare provider [see ADVERSE REACTIONS].
Concomitant Medication
Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications because of a potential for interactions. Instruct patients not to take BRINTELLIX with an MAOI or within 14 days of stopping an MAOI and to allow 21 days after stopping BRINTELLIX before starting an MAOI [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS].
Serotonin Syndrome
Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of BRINTELLIX and triptans, tricyclic antidepressants, fentanyl, Lithium, tramadol, tryptophan supplements, and St. John's Wort supplements [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Abnormal Bleeding
Caution patients about the increased risk of abnormal bleeding when BRINTELLIX is given with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [see WARNINGS AND PRECAUTIONS].
Activation of Mania/Hypomania
Advise patients and their caregivers to look for signs of activation of mania/hypomania [see WARNINGS AND PRECAUTIONS].
Angle Closure Glaucoma
Patients should be advised that taking BRINTELLIX can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see WARNINGS AND PRECAUTIONS].
Advise patients that if they are treated with diuretics, or are otherwise volume depleted, or are elderly, they may be at greater risk of developing hyponatremia while taking BRINTELLIX [see WARNINGS AND PRECAUTIONS].
Advise patients that nausea is the most common adverse reaction, and is dose related. Nausea commonly occurs within the first week of treatment, then decreases in frequency but can persist in some patients.
A clinical study has shown that BRINTELLIX (single dose of 20 or 40 mg/day) did not increase the impairment of mental and motor skills caused by alcohol.
Allergic Reactions
Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing.
Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy with BRINTELLIX [see Use In Specific Populations].
Nursing Mothers
Advise patients to notify their healthcare provider if they are breast-feeding an infant and would like to continue or start BRINTELLIX [see Use In Specific Populations].
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity studies were conducted in which CD-1 mice and Wistar rats were given oral doses of vortioxetine up to 50 and 100 mg/kg/day for male and female mice, respectively, and 40 and 80 mg/kg/day for male and female rats, respectively, for 2 years. The doses in the two species were approximately 12, 24, 20, and 39 times, respectively, the maximum recommended human dose (MRHD) of 20 mg on a mg/m² basis.
In rats, the incidence of benign polypoid adenomas of the rectum was statistically significantly increased in females at doses 39 times the MRHD, but not at 15 times the MRHD. These were considered related to inflammation and hyperplasia and possibly caused by an interaction with a vehicle component of the formulation used for the study. The finding did not occur in male rats at 20 times the MRHD.
In mice, vortioxetine was not carcinogenic in males or females at doses up to 12 and 24 times, respectively, the MRHD.
Vortioxetine was not genotoxic in the in vitro bacterial reverse mutation assay (Ames test), an in vitro chromosome aberration assay in cultured human lymphocytes, and an in vivo rat bone marrow micronucleus assay.
Impairment of Fertility
Treatment of rats with vortioxetine at doses up to 120 mg/kg/day had no effect on male or female fertility, which is 58 times the maximum recommended human dose (MRHD) of 20 mg on a mg/m² basis.
Use In Specific Populations
Pregnancy Category C
Risk Summary
There are no adequate and well-controlled studies of BRINTELLIX in pregnant women. Vortioxetine caused developmental delays when administered during pregnancy to rats and rabbits at doses 15 and 10 times the maximum recommended human dose (MRHD) of 20 mg, respectively. Developmental delays were also seen after birth in rats at doses 20 times the MRHD of vortioxetine given during pregnancy and through lactation. There were no teratogenic effects in rats or rabbits at doses up to 77 and 58 times, the MRHD of vortioxetine, respectively, given during organogenesis. The incidence of malformations in human pregnancies has not been established for BRINTELLIX. All human pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. BRINTELLIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Clinical Considerations
Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of these classes of drugs or possibly, a drug discontinuation syndrome. It should be noted that in some cases, the clinical picture is consistent with serotonin syndrome [see WARNINGS AND PRECAUTIONS]. When treating a pregnant woman with BRINTELLIX during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
Neonates exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in one to two per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use in pregnancy and PPHN. Other studies do not show a significant statistical association.
A prospective longitudinal study was conducted of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. When treating a pregnant woman with BRINTELLIX, the physician should carefully consider both the potential risks of taking a serotonergic antidepressant, along with the established benefits of treating depression with an antidepressant.
Animal Data
In pregnant rats and rabbits, no teratogenic effects were seen when vortioxetine was given during the period of organogenesis at oral doses up to 160 and 60 mg/kg/day, respectively. These doses are 77 and 58 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 20 mg on a mg/m² basis. Developmental delay, seen as decreased fetal body weight and delayed ossification, occurred in rats and rabbits at doses equal to and greater than 30 and 10 mg/kg (15 and 10 times the MRHD, respectively) in the presence of maternal toxicity (decreased food consumption and decreased body weight gain). When vortioxetine was administered to pregnant rats at oral doses up to 120 mg/kg (58 times the MRHD) throughout pregnancy and lactation, the number of live-born pups was decreased and early postnatal pup mortality was increased at 40 and 120 mg/kg. Additionally, pup weights were decreased at birth to weaning at 120 mg/kg and development (specifically eye opening) was slightly delayed at 40 and 120 mg/kg. These effects were not seen at 10 mg/kg (5 times the MRHD).
Nursing Mothers
It is not known whether vortioxetine is present in human milk. Vortioxetine is present in the milk of lactating rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from BRINTELLIX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Clinical studies on the use of BRINTELLIX in pediatric patients have not been conducted; therefore, the safety and effectiveness of BRINTELLIX in the pediatric population have not been established.
Geriatric Use
No dose adjustment is recommended on the basis of age (Figure 3). Results from a single-dose pharmacokinetic study in elderly ( > 65 years old) vs. young (24 to 45 years old) subjects demonstrated that the pharmacokinetics were generally similar between the two age groups.
Of the 2616 subjects in clinical studies of BRINTELLIX, 11% (286) were 65 and over, which included subjects from a placebo-controlled study specifically in elderly patients [see Clinical Studies]. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.
Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see WARNINGS AND PRECAUTIONS].
Use In Other Patient Populations
No dose adjustment of BRINTELLIX on the basis of race, gender, ethnicity, or renal function (from mild renal impairment to end-stage renal disease) is necessary. In addition, the same dose can be administered in patients with mild to moderate hepatic impairment (Figure 3). BRINTELLIX has not been studied in patients with severe hepatic impairment. Therefore, BRINTELLIX is not recommended in patients with severe hepatic impairment.
Figure 3: Impact of Intrinsic Factors on Vortioxetine
Human Experience
There is limited clinical trial experience regarding human overdosage with BRINTELLIX. In pre-marketing clinical studies, cases of overdose were limited to patients who accidentally or intentionally consumed up to a maximum dose of 40 mg of BRINTELLIX. The maximum single dose tested was 75 mg in men. Ingestion of BRINTELLIX in the dose range of 40 to 75 mg was associated with increased rates of nausea, dizziness, diarrhea, abdominal discomfort, generalized pruritus, somnolence, and flushing.
Management Of Overdose
No specific antidotes for BRINTELLIX are known. In managing over dosage, consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center at 1800-222-1222 for latest recommendations.
- Hypersensitivity to vortioxetine or any components of the formulation. Angioedema has been reported in patients treated with BRINTELLIX.
- The use of MAOIs intended to treat psychiatric disorders with BRINTELLIX or within 21 days of stopping treatment with BRINTELLIX is contraindicated because of an increased risk of serotonin syndrome. The use of BRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
Starting BRINTELLIX in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
Mechanism Of Action
The mechanism of the antidepressant effect of vortioxetine is not fully understood, but is thought to be related to its enhancement of serotonergic activity in the CNS through inhibition of the reuptake of serotonin (5-HT). It also has several other activities including 5-HT3 receptor antagonism and 5-HT1A receptor agonism. The contribution of these activities to vortioxetine's antidepressant effect has not been established.
Vortioxetine binds with high affinity to the human serotonin transporter (Ki=1.6 nM), but not to the norepinephrine (Ki=113 nM) or dopamine (Ki > 1000 nM) transporters. Vortioxetine potently and selectively inhibits reuptake of serotonin (IC50=5.4 nM). Vortioxetine binds to 5-HT3 (Ki=3.7 nM), 5-HT1A (Ki=15 nM), 5-HT7 (Ki=19 nM), 5-HT1D (Ki=54 nM), and 5-HT1B (Ki=33 nM), receptors and is a 5-HT3, 5-HT1D, and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, and 5-HT1A receptor agonist.
In humans, the mean 5-HT transporter occupancy, based on the results from 2 clinical PET studies using 5-HTT ligands ([11C]-MADAM or [11C]-DASB), was approximately 50% at 5 mg/day, 65% at 10 mg/day and approximately 80% at 20 mg/day in the regions of interest.
Effect on Cardiac Repolarization
The effect of vortioxetine 10 mg and 40 mg administered once daily on QTc interval was evaluated in a randomized, double-blind, placebo-, and active-controlled (moxifloxacin 400 mg), four-treatment-arm parallel study in 340 male subjects. In the study the upper bound of the one-sided 95% confidence interval for the QTc was below 10 ms, the threshold for regulatory concern. The oral dose of 40 mg is sufficient to assess the effect of metabolic inhibition.
Effect on Driving Performance
In a clinical study in healthy subjects, BRINTELLIX did not impair driving performance, or have adverse psychomotor or cognitive effects following single and multiple doses of 10 mg/day. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that BRINTELLIX therapy does not affect their ability to engage in such activities.
Vortioxetine pharmacological activity is due to the parent drug. The pharmacokinetics of vortioxetine (2.5 mg to 60 mg) are linear and dose-proportional when vortioxetine is administered once daily. The mean terminal half-life is approximately 66 hours, and steady-state plasma concentrations are typically achieved within two weeks of dosing.
The maximal plasma vortioxetine concentration (Cmax) after dosing is reached within 7 to 11 hours postdose (Tmax). Steady-state mean Cmax values were 9, 18, and 33 ng/mL following doses of 5, 10, and 20 mg/day. Absolute bioavailability is 75%. No effect of food on the pharmacokinetics was observed.
The apparent volume of distribution of vortioxetine is approximately 2600 L, indicating extensive extravascular distribution. The plasma protein binding of vortioxetine in humans is 98%, independent of plasma concentrations. No apparent difference in the plasma protein binding between healthy subjects and subjects with hepatic (mild, moderate) or renal (mild, moderate, severe, ESRD) impairment is observed.
Metabolism and Elimination
Vortioxetine is extensively metabolized primarily through oxidation via cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 and subsequent glucuronic acid conjugation. CYP2D6 is the primary enzyme catalyzing the metabolism of vortioxetine to its major, pharmacologically inactive, carboxylic acid metabolite, and poor metabolizers of CYP2D6 have approximately twice the vortioxetine plasma concentration of extensive metabolizers.
Following a single oral dose of [14C]-labeled vortioxetine, approximately 59% and 26% of the administered radioactivity was recovered in the urine and feces, respectively as metabolites. Negligible amounts of unchanged vortioxetine were excreted in the urine up to 48 hours. The presence of hepatic (mild or moderate) or renal impairment (mild, moderate, severe and ESRD) did not affect the apparent clearance of vortioxetine.
Clinical Studies
The efficacy of BRINTELLIX in treatment for MDD was established in six 6 to 8 week randomized, double-blind, placebo-controlled, fixed-dose studies (including one study in the elderly) and one maintenance study in adult inpatients and outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD.
Adults (aged 18 years to 75 years)
The efficacy of BRINTELLIX in patients aged 18 years to 75 years was demonstrated in five 6 to 8 week, placebo-controlled studies (Studies 1 to 5 in Table 4). In these studies, patients were randomized to BRINTELLIX 5 mg, 10 mg, 15 mg or 20 mg or placebo once daily. For patients who were randomized to BRINTELLIX 15 mg/day or 20 mg/day, the final doses were titrated up from 10 mg/day after the first week.
The primary efficacy measures were the Hamilton Depression Scale (HAMD-24) total score in Study 2 and the Montgomery-Asberg Depression Rating Scale (MADRS) total score in all other studies. In each of these studies, at least one dose group of BRINTELLIX was superior to placebo in improvement of depressive symptoms as measured by mean change from baseline to endpoint visit on the primary efficacy measurement (see Table 4). Subgroup analysis by age, gender or race did not suggest any clear evidence of differential responsiveness. Two studies of the 5 mg dose in the U.S. (not represented in Table 4) failed to show effectiveness.
Elderly Study (aged 64 years to 88 years)
The efficacy of BRINTELLIX for the treatment of MDD was also demonstrated in a randomized, double-blind, placebo-controlled, fixed-dose study of BRINTELLIX in elderly patients (aged 64 years to 88 years) with MDD (Study 6 in Table 4). Patients meeting the diagnostic criteria for recurrent MDD with at least one previous major depressive episode before the age of 60 years and without comorbid cognitive impairment (Mini Mental State Examination score < 24) received BRINTELLIX 5 mg or placebo.
Table 4: Primary Efficacy Results of 6 Week to 8 Week
Clinical Trials
|Study No. [Primary Measure]
|Treatment Group
|Number of Patients
|Mean Baseline Score (SD)
|LS Mean Change from Baseline (SE)
|Placebo-subtracted Difference1 (95% CI)
|Study 1 [MADRS] Non-US Study
|BRINTELLIX (5 mg/day)‡
|34.1 (2.6)
|-20.4 (1.0)
|-5.9 (-8.6, -3.2)
|BRINTELLIX (10 mg/day)‡
|34.0 (2.8)
|-20.2 (1.0)
|-5.7 (-8.5, -2.9)
|33.9 (2.7)
|-14.5 (1.0)
|Study 2 [HAMD-24] Non-US Study
|BRINTELLIX (5 mg/day)
|32.2 (5.0)
|-15.4 (0.7)
|-4.1 (-6.2, -2.1)
|BRINTELLIX (10 mg/day)‡
|33.1 (4.8)
|-16.2 (0.8)
|-4.9 (-7.0, -2.9)
|32.7 (4.4)
|-11.3 (0.7)
|Study 3 [MADRS] Non-US Study
|BRINTELLIX (15 mg/day) ‡
|31.8 (3.4)
|-17.2 (0.8)
|-5.5 (-7.7, -3.4)
|BRINTELLIX (20 mg/day) ‡
|31.2 (3.4)
|-18.8 (0.8)
|-7.1 (-9.2, -5.0)
|31.5 (3.6)
|-11.7 (0.8)
|Study 4 [MADRS] US Study
|BRINTELLIX (15 mg/day)
|31.9 (4.1)
|-14.3 (0.9)
|-1.5 (-3.9, 0.9)
|BRINTELLIX (20 mg/day) ‡
|32.0 (4.4)
|-15.6 (0.9)
|-2.8 (-5.1, -0.4)
|31.5 (4.2)
|-12.8 (0.8)
|Study 5 [MADRS] US Study
|BRINTELLIX (10 mg/day)
|32.2 (4.5)
|-13.0 (0.8)
|-2.2 (-4.5, 0.1)
|BRINTELLIX (20 mg/day) ‡
|32.5 (4.3)
|-14.4 (0.9)
|-3.6 (-5.9, -1.4)
|32.0 (4.0)
|-10.8 (0.8)
|Study 6 (elderly) [HAMD-24] US and Non-US
|BRINTELLIX (5 mg/day) ‡
|29.2 (5.0)
|-13.7 (0.7)
|-3.3 (-5.3, -1.3)
|29.4 (5.1)
|-10.3 (0.8)
|SD: standard deviation; SE: standard error; LS Mean:
least-squares mean; CI: unadjusted confidence interval.
†Difference (drug minus placebo) in least-squares mean change from baseline.
†Doses that are statistically significantly superior to placebo after adjusting for multiplicity.
Time Course of Treatment Response
In the 6 to 8 week placebo-controlled studies, an effect of BRINTELLIX based on the primary efficacy measure was generally observed starting at Week 2 and increased in subsequent weeks with the full antidepressant effect of BRINTELLIX generally not seen until Study Week 4 or later. Figure 4 depicts time course of response in U.S. based on the primary efficacy measure (MADRS) in Study 5.
Figure 4: Change from
Baseline in MADRS Total Score by Study Visit (Week) in Study 5
Figure 5: Difference from
Placebo in Mean Change from Baseline in MADRS Total Score at Week 6 or Week 8
†Results (point estimate and unadjusted 95% confidence interval) are from mixed model for repeated measures (MMRM) analysis. In Studies 1 and 6, the primary analysis was not based on MMRM and in Studies 2 and 6 the primary efficacy measure was not based on MADRS.
Maintenance Study
In a non-US maintenance study (Study 7 in Figure 6), 639 patients meeting DSM-IV-TR criteria for MDD received flexible doses of BRINTELLIX (5 mg or 10 mg) once daily during an initial 12 week open-label treatment phase; the dose of BRINTELLIX was fixed during Weeks 8 to 12. Three hundred ninety six (396) patients who were in remission (MADRS total score ≤ 10 at both Weeks 10 and 12) after open-label treatment were randomly assigned to continuation of a fixed dose of BRINTELLIX at the final dose they responded to (about 75% of patients were on 10 mg/day) during the open-label phase or to placebo for 24 to 64 weeks. Approximately 61% of randomized patients satisfied remission criterion (MADRS total score ≤ 10) for at least 4 weeks (since Week 8), and 15% for at least 8 weeks (since Week 4). Patients on BRINTELLIX experienced a statistically significantly longer time to have recurrence of depressive episodes than did patients on placebo. Recurrence of depressive episode was defined as a MADRS total score ≥ 22 or lack of efficacy as judged by the investigator.
Figure 6: Kaplan-Meier Estimates of Proportion of
Patients with Recurrence (Study 7)
(vortioxetine) Tablets
Read this Medication Guide before you start taking BRINTELLIX and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about BRINTELLIX?
BRINTELLIX and other antidepressant medicines may cause serious side effects.
- Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment.
- Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.
- How can I watch for and try to prevent suicidal
thoughts and actions?
- Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
- Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
- Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms.
Call your healthcare provider right away if you have any of the following symptoms, especially if they are new, worse, or worry you:
- attempts to commit suicide
- trouble sleeping
- an extreme increase in activity or
- acting on dangerous impulses talking (mania)
- acting aggressive, being angry or violent
- other unusual changes in behavior or mood
- thoughts about suicide or dying
- new or worse depression
- panic attacks
- new or worse anxiety
- new or worse irritability
- feeling agitated, restless, angry or irritable
What is BRINTELLIX?
BRINTELLIX is a prescription medicine used to treat a certain type of depression called Major Depressive Disorder (MDD).
It is important to talk with your healthcare provider about the risks of treating depression and also the risk of not treating it. You should discuss all treatment choices with your healthcare provider.
- Talk to your healthcare provider if you do not think that your condition is getting better with BRINTELLIX treatment.
Who should not take BRINTELLIX?
Do not take BRINTELLIX if you:
- are allergic to vortioxetine, or any of the ingredients in BRINTELLIX. See the end of this Medication Guide for a complete list of ingredients in BRINTELLIX.
- take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
- Do not take an MAOI within 21 days of stopping BRINTELLIX.
- Do not start BRINTELLIX if you stopped taking an MAOI in the last 14 days.
What should I tell my healthcare provider before taking BRINTELLIX?
Tell your healthcare provider if you:
- have liver problems
- have or had seizures or convulsions
- have mania or bipolar disorder (manic depression)
- have low salt (sodium) levels in your blood
- have or had bleeding problems
- drink alcohol
- have any other medical conditions
- are pregnant or plan to become pregnant. It is not known if BRINTELLIX will harm your unborn baby.
- are breastfeeding or plan to breastfeed. It is not known if BRINTELLIX passes into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take BRINTELLIX.
Tell your healthcare provider about all the medicines that you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. BRINTELLIX and some medicines may interact with each other, may not work as well, or may cause serious side effects when taken together.
Especially tell your healthcare provider if you take:
- medicines used to treat migraine headache (e.g. triptans)
- medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), buspirone, or antipsychotics
- MAOIs (including linezolid, an antibiotic)
- Tramadol or fentanyl
- over-the-counter supplements such as tryptophan or St. John's Wort
- nonsteroidal anti-inflammatory drugs (NSAIDs)
- aspirin
- warfarin (Coumadin, Jantoven)
- diuretics
- rifampicin
- carbamazepine
- phenytoin
- quinidine
Ask your healthcare provider if you are not sure if you are taking any of these medicines.
Before you take BRINTELLIX with any of these medicines, talk to your healthcare provider about serotonin syndrome. See "What are the possible side effects of BRINTELLIX?"
Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get new medicine.
How should I take BRINTELLIX?
- Take BRINTELLIX exactly as your healthcare provider tells you to take it.
- Take BRINTELLIX at about the same time each day.
- Your healthcare provider may need to change the dose of BRINTELLIX until it is the right dose for you.
- Do not start or stop taking BRINTELLIX without talking to
your healthcare provider first. Suddenly stopping BRINTELLIX when you take
higher doses may cause you to have side effects, including:
- headache
- sudden outburst of anger
- stiff muscles
- dizziness or feeling lightheaded
- mood swings
- runny nose
- BRINTELLIX may be taken with or without food.
- If you take too much BRINTELLIX, call the Poison Control Center at 1-800-222-1222 or go to the nearest hospital emergency room right away.
What should I avoid while taking BRINTELLIX?
- Do not drive, operate heavy machinery, or do other dangerous activities until you know how BRINTELLIX affects you.
- Avoid drinking alcohol while taking BRINTELLIX.
What are the possible side effects of BRINTELLIX?
BRINTELLIX may cause serious side effects, including:
See "What is the most important information I should know about BRINTELLIX?"
- serotonin syndrome. A potentially life-threatening
problem called serotonin syndrome can happen when medicines such as BRINTELLIX
are taken with certain other medicines. Symptoms of serotonin syndrome may
- agitation, hallucinations, coma or other changes in mental status
- problems controlling your movements or muscle twitching
- fast heartbeat
- high or low blood pressure
- sweating or fever
- nausea or vomiting
- diarrhea
- muscle stiffness or tightness
- abnormal bleeding or bruising. BRINTELLIX may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin®, Jantoven®), a non-steroidal anti-inflammatory drug (NSAID), or aspirin.
- hypomania (manic episodes). Symptoms of manic
episodes include:
- greatly increased energy
- excessive happiness or irritability
- severe problems sleeping
- talking more or faster than usual
- racing thoughts
- reckless behavior
- unusually grand ideas
- visual problems
- eye pain
- changes in vision
- swelling or redness in or around the eye
Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.
- low levels of salt (sodium) in your blood. Symptoms of this may include: headache, difficulty concentrating, memory changes, confusion, weakness and unsteadiness on your feet. Symptoms of severe or sudden cases of low salt levels in your blood may include: hallucinations (seeing or hearing things that are not real), fainting, seizures and coma. If not treated, severe low sodium levels can cause death.
Common side effects in people who take BRINTELLIX include:
- nausea
- constipation
- vomiting
Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of BRINTELLIX. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store BRINTELLIX?
Store BRINTELLIX at room temperature between 59°F to 86°F (15°C to 30°C).
Keep BRINTELLIX and all medicines out of the reach of children.
General information about the safe and effective use of BRINTELLIX.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BRINTELLIX for a condition for which it was not prescribed. Do not give BRINTELLIX to other people, even if they have the same condition. It may harm them.
This Medication Guide summarizes the most important information about BRINTELLIX. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about BRINTELLIX that is written for healthcare professionals.
For more information, go to www.BRINTELLIX.com or call 1-877-TAKEDA-7 (1-877-8253327).
What are the ingredients in BRINTELLIX?
Active ingredient: vortioxetine hydrobromide
Inactive ingredients: mannitol, microcrystalline cellulose, hydroxypropyl cellulose, sodium starch glycolate, magnesium stearate and film coating consisting of hypromellose, titanium dioxide, polyethylene glycol 400, iron oxide red (5 mg, 15 mg, and 20 mg) and iron oxide yellow (10 mg and 15 mg)
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You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


text:
Watching a Dodge Caliber slam Gejea Ejeta through a storefront window is pretty disturbing. Even more disturbing: the way the passenger—now identified as Tylese Pitts—pops open the car door and strolls away from the scene, cigarette in hand.
Pitts' excuse? "I was in shock," she said to an ABC reporter. "I had to go." Sure lady, tell that to the now-debilitated Ejeta. [ABC Local]

subset: commoncrawl


text:
Since hearing John Fenton expound this reading, I have often taught it myself. Usually people are somewhat shocked at first, but as time goes on the reading becomes more appealing and, ultimately, quite persuasive. If the cry is sarcastic, it makes sense in its narrative context. Take another look:
Mark 15.37: ὁ δὲ Ἰησοῦς ἀφεὶς φωνὴν μεγάλην ἐξέπνευσεν. 38. Καὶ τὸ καταπέτασμα τοῦ ναοῦ ἐσχίσθη εἰς δύο ἀπ' ἄνωθεν ἕως κάτω. 39 Ἰδὼν δὲ ὁ κεντυρίων ὁ παρεστηκὼς ἐξ ἐναντίας αὐτοῦ ὅτι οὕτως ἐξέπνευσεν εἶπεν, Ἀληθῶς οὗτος ὁ ἄνθρωπος υἱὸς θεοῦ ἦν.There is nothing that the centurion has seen that suggests that we should read the text as implying his admiration for Jesus. He makes his comment when he saw how Jesus died (ὅτι οὕτως ἐξέπνευσεν εἶπεν), that is, in despair (15.34), apparently unable to call down Elijah to deliver him (15.35-6). The reader, on the other hand, is given some privileged information, that the veil of the temple was torn in two, from top to bottom. This is classic dramatic irony: the reader knows what the actors in the drama do not know, and the actors do not realize the truth of the words that they are speaking in mockery.
Mark 15.37: And Jesus gave a loud cry and breathed his last. 38. And the veil of the temple was torn in two, from top to bottom. And when the centurion, who was standing facing him, saw how he died, he said, "Truly this was a son of god".
To read the text in this way coheres with the rest of Mark's Passion Narrative, which is commonly regarded as rich in irony. Jesus is repeatedly mocked as a king (15.9, 12, 18, 26, 32) with purple cloak, crown of thorns and mock homage (15.17-20), but the reader knows that he really is a king. He is mocked as a prophet (14.65) while his very prophecies are being enacted all around him (the mockery itself, fulfilling his Passion predictions, and Peter's denial, fulfilling Jesus' Last Supper prophecies). Given this context, it is difficult to think that the centurion's remark can be intended as a "confession" of faith in Jesus. Reading the remark as the crowning element in the dramatic irony of Mark's Passion Narrative makes good narrative sense.
Now, the first time I heard the suggestion that we read the centurion's cry as ironic was from my tutor John Fenton. A friend tells me that he thinks Fenton got this interpretation from Austin Farrer. This is plausible because Fenton was an admirer of Farrer, but I don't remember that from what Fenton himself said -- and he was inclined to attribute ideas that were not original. I have cast around the literature too to see if anyone else has read the text in this way, and I am surprised to be struggling to find examples of this interpretation. I had thought that perhaps Donald Juel mentioned it, but again I can't find it. Fenton himself mentions it in written work once, as far as I am aware, as follows, with some helpful additional context connecting the saying to the Elijah on Horeb narrative:
Elijah had, it was believed, set up an experiment to prove that the Lord was God, not Baal (1 Kings 18). Someone now tries to repeat the experiment on Jesus: he is given the drink, and they say, Let us see if Elijah will come to take him down from the cross. If Elijah comes, Jesus is who he says he is; if Elijah does not come, he is not. Jesus dies, without the intervention of Elijah, thus proving to those who think in this way that he was not the Messiah, the king of Israel. (It is possible that the centurion's words should be taken in this sense: He really was God's son! Of course not! There is a parallel in the Greek between what the people said on Mount Horeb after Elijah's miracle: Truly the Lord is God; and what is said here, Truly this man was the Son of God. There is also the possibility that 'this man' should be translated 'this fellow', disparagingly, as in Acts 6.13.), John Fenton, Finding the Way Through Mark (London: Mowbray, 1995), 111.If anyone has any more from the literature on this theme, I would be interested to hear it.


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OCEAN CITY – Though the need for more doctors in this country is evident, fixing the healthcare system as a whole might be more complicated than just merely more hands on deck.
Last week's article touched on the challenges facing local healthcare workers and addressed some of the problems they are facing such as physician shortages, Maryland being amongst the worst in the country for doctor reimbursement and the struggles to recruit and retain physicians to this area.
Dr. Thomas Lawrence, Chief Medical Officer at Peninsula Regional Medical Center in Salisbury, addressed some of the ways to deal with not only the doctor shortages both locally and nationally, but also how to perhaps remedy a "sickness" in the healthcare system itself.
"From a manpower perspective, there's a real challenge for the delivery of healthcare in this country," he said. "We've all been to parties where someone said that it took them three months to actually get in to see a doctor. That might seem like a bargain in a few years if we don't find a way to fix this."
Lawrence said that though the number of physicians at PRMC (which is approximately 300) "is meeting the demands of patients pretty comfortably", he said that the need for doctors in the area's five counties is about 35 per year and around 100 within the next five years.
"There's no place in the country that isn't trying to recruit doctors in just about every specialty possible. There's hospitals in California that are trying to recruit about 700 doctors, so in comparison, we don't need that many based on our size, but finding a 100 doctors to practice in this area within the next five years is quite a challenge," he said.
Simply hiring more doctors might seem like an easy task, but there are less of those to go around, reports say. Fewer students are enrolling in medical schools, and the time it takes to train a doctor to the point where they are ready to practice medicine on their own, is not exactly a quick turnaround.
"Most students are leaving medical school with $150,000-$4250,000 in debt. Then if you factor in the fact that it takes four years of med school, plus another three years of residency, it takes about seven years to train someone to practice medicine, Lawrence said. "Yet, it's the post-graduate programs that need to be funded better and increase their numbers as if we don't fix that and train doctors in specialties, we are just rearranging chairs on the deck."
Lawrence said that the days of small private practice doctor's offices are "pretty much a thing of the past", and cited that the costs so greatly outweighing the profits that it leads doctors to more urbanized areas and certainly to states that have a higher reimbursement rate than Maryland.
"Expenses are way too high and the profits are way too low. At the end of the day, if we don't fix the reimbursement policy, we face a recruitment challenge that is almost impossible unless there's a fundamental change," he said. "For too long, it's been the doctors vs. the insurance companies, and the insurance companies are not suffering any losses."
A recent study by the New England Journal of Medicine stated that the proverbial battle between healthcare workers and insurance companies is incredibly lopsided, as insurance companies pick and choose whom to care by "cherrypicking" the young and healthy, and have the ability to deny care to anyone that isn't. The study also reiterated a pretty well known fact that Americans spend more per person on healthcare premiums than any other country on the planet by a long shot.
Lawrence agreed with the January report by the Maryland Hospital Association (MHA) projecting a "perfect storm" for the medical industry as doctors are harder to come by, more people are uninsured and lack a primary care physician and the country's population is getting older and sicker as the "baby boomer" generation reaches retirement age in 2011.
Roger Blackwell, Ph.D, and professor of marketing at Ohio State University, likened the American health care system to the retail industry, pointing out the success of companies that offer similar products at a lesser price.
"Hospitals and physicians are retailers facing the same problem as retailers that sell everything from computers to clothes," he said. "The same solutions that allowed Wal-Mart and Target to triumph over traditional department stores will lead to the triumph of innovative new forms of healthcare institutions. General hospitals that fail to understand this will feel the pain of polarity, and suffer the inevitable fate, like Montgomery Ward and K-Mart did."
Lawrence said that some quick fix remedies for the doctor shortage could be to ease the visa requirements allowing foreign doctors to practice medicine in this country as well as granting some loan forgiveness for doctors as they leave medical school.
"We've been living with a failed health care policy for some time, and we face the same challenges in rural and urban areas and that's to provide the best healthcare we can for those who need it," said Lawrence.
Though the industry looks grim, the occupation itself looks bright according to Lawrence.
"From a career standpoint, the healthcare profession has never looked brighter," he said.


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Sunday, June 12, 2011
1983 - Uncanny X-Men at the State Fair of Texas
Writers: Jim Salicrup/David Kraft
Artists: Kerry Gammil, Alan Kupperberg, and Chic Stone
This one-shot issue was included as a free supplement to the Dallas Times Herald newspaper. It featured a rather sad and uninspired plot with Magneto and the X-Men racing to find a new mutant. Thankfully, Eques, this new mutant has not appeared since.
The cover art was done by John Romita although I could barely tell it was his work.
11 comments:
Should I be embarrassed that I actually own this?ReplyDelete
Oddly enough, it used to be a high-priced, rare issue (not the reason I have it, as I used to be quite the X-collector).
- Stephen GurrJune 13, 2011 at 12:15 AM
"I like the way Storm made Big Tex kick Magneto in the pants!"ReplyDelete
I don't know, this is not too much to base my decision on...ReplyDelete
Was the story bad or simply a very basic one?
Eques has a nice design, so, not knowing his full story, I think he could be a nice character if some writer developed him.
At first I thought the mutant would be "Big Tex", and that would indeed have made me grateful for no more appearances from him, LOL.
You don't think the cover looks like Romita's work? It's Romita, Sr., remember - there are definitely distinctive curves and lines that could only be his.ReplyDelete
Hey PJ, it's Romita Sr. certainly, just isn't put together very well as I'm used to. Eques is actually a great rendering, as is Storm, but Colossus and Wolverine seem awkward to my eye.ReplyDelete
Hey Cesar, the story was very basic and limited and with such a setting and scope, there's not much that could be done to breathe any life into it! :)
- AnonymousJune 17, 2011 at 5:40 PM
Yeah, i always thought this was a rarity, but I found it a couple years ago in a $1 bin.ReplyDelete
think it might be more valuable since Big Tex just burned down?ReplyDelete
Hey Judah, thanks for the comment. Yikes, didn't know it burned down. Sad.ReplyDelete
I have this. Haven't read it.ReplyDelete
I had this, too! Not only did Big Tex burn, but the Dallas Times Herald was bought by their competitor and shut down in 1991 (I was working there). A piece of strange history relevant to my life...ReplyDeleteReplies
Thanks for stopping by!Delete


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Gblocks is a program written in ANSI C language that eliminates poorly
aligned positions and divergent regions of an alignment of DNA or
protein sequences. These positions may not be homologous or may have
been saturated by multiple substitutions and it is convenient to
eliminate them prior to phylogenetic analysis.
The use of a program such as Gblocks reduces the necessity of manually
editing multiple alignments, makes the automation of phylogenetic
analysis of large data sets feasible and, finally, facilitates the
reproduction of the alignments and subsequent phylogenetic analysis by
other researchers. Gblocks is very fast in processing alignments and
it is therefore highly suitable for large-scale phylogenetic analyses.
This just repackages the binaries provided from upstream.
Maintained by: Petar Petrov
Keywords: gblocks,alignments,phylogeny,biology,bioinformatics,science
ChangeLog: Gblocks
Download SlackBuild:
Gblocks.tar.gz.asc (FAQ)
(the SlackBuild does not include the source)
|Individual Files:
| Gblocks.SlackBuild
| Gblocks.info
| References
| slack-desc
© 2006-2023 SlackBuilds.org Project. All rights reserved.
Slackware® is a registered trademark of Patrick Volkerding
Linux® is a registered trademark of Linus Torvalds


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Wednesday, March 30, 2011
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Two of the amazing and extraordinary dishes from Sam & Harry's AMAZING sushi bar (inside the Newport Beach Marriott). I can promise you these dishes tasted even more amazing than they looked!
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Mining Jobs No Experience
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Discount Airfares To Australia: How To Get Low-cost Tickets
Australia has always been a popular destination for tourists from all over the globe. But in recent years, the tourism industry has risen tremendously. A lot of the credit for this goes to the Summer Olympics that were held in Sydney in 2000. Since then, tourism revenues in Australia reach an impressive $10 billion each year. So what makes Australia such a popular tourist destination? Most of the tourists head to Australia to experience the world-famous Great Barrier Reef in Queensland, see the wildlife in the Kakadu National Park, and take a peek at the architectural splendor of the Sydney Opera House. Outdoor enthusiasts also enjoy the surfing at the famous beaches of Brisbane, Sydney and Cairns.
Many people wrongly assume that a visit to Australia is only meant for the more affluent traveler, as transportation expenses can be quite high. While this is generally true, there are also discount airfares to Australia that make it possible for practically anyone to visit this beautiful country – you just have to know where and how to look. There are actually many places where you can avail of discount airfares to Australia. The most common is the Internet. In this age of technology, you can get almost anything you need just by a few clicks of the mouse.
This includes discount airfares to Australia as well. Tens of thousands of websites offer discount airfares to Australia. You have to be very discriminating in choosing which website you want to buy your tickets from. Many websites actually have scheming companies behind them who are using false advertising to lure customers into their traps. Most of the time, they are not displaying the real deal on their web pages. In order to avoid being victimized by these companies, it is highly important to read all the fine print on the websites before submitting your credit card information to them to buy your discount airfares to Australia. Another option is to go directly to the airline companies. They also offer discount airfares to Australia and other places in the world, but the savings you will get might be lower than if you purchased your tickets from a discount website. Of course, if you want to stay away from all the hassles of preparing your trip, you can just pay a travel agent to do all the hard work for you. With most travel agencies, you can be assured that they will be able to find you great deals on discount airfares to Australia.
All you have to do is unwind, relax, and dream of the fun time you will have down under. Another thing you may try when looking for discount airfares is typing in various keywords, like wholesale, cheap, discount, special airfares. These different words may net you travel sites on the internet that you have never seen before that offer even better deals than those advertising on television. There are many ways to find discount airfares. The key is to know where to look as well as taking the time to research a few things. Time is precious so when we can find a site that we are happy with it is important to remember that for the next trip.
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Programming Languages and Software Engineering
Programming Languages and Software Engineering
Programming languages are our means of expressing computations. Thus, programming languages are a powerful locus of research toward building high-quality software, i.e., software that is flexible, secure, reliable, available, efficient, reusable, and more. We can design new languages, or we can build tools that analyze programs in existing languages, toward maximizing quality.
The Lab for Programming Languages and the University of Maryland (PLUM) is engaged in exciting research that aims to improve software quality through new languages and software tools. Our work involves formalism and proof (e.g., to show that a particular analysis establishes a certain property of the programs it considers) as well as implementation and evaluation (e.g., to show that our ideas work on real software at reasonable cost). Current interests focus on cloud computing, mobile computing, high-availability systems, static analysis, functional programming, debugging, and privacy-preseving computation.


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RNA cataloging may take a big leap forward. A new study from the University of North Carolina describes a cost-effective technique that will help scientists understand the structures, and ultimately the functions, of the RNA molecules.
In a paper published in the journal Nature Methods, a team from the University of North Carolina at Chapel Hill demonstrates a simple, cost-effective technique for three-dimensional RNA structure prediction that will help scientists understand the structures, and ultimately the functions, of the RNA molecules that dictate almost every aspect of human cell behavior. When cell behavior goes wrong, diseases – including cancer and metabolic disorders – can be the result.
Over the past five decades, scientists have described more than 80,000 protein structures, most of which are now publicly available and provide important information to medical researchers searching for targets for drug therapy. However, a similar effort to catalog RNA structures has mapped only a few hundred RNA molecules. As a result, the potential of RNA molecules has just barely been developed as targets for new therapeutics.
"To effectively target these molecules, researchers often need a three-dimensional picture of what they look like," says Nikolay Dokholyan, PhD, professor in the department of biochemistry and biophysics, and the project's co-leader.
"With Dr. Kevin Weeks' lab, we have developed a way to create a three-dimensional map of complex RNAs that are not amenable to study through other methods. It builds on information from a routine laboratory experiment, used in the past to evaluate RNA models from a qualitative standpoint. Our team has created a sophisticated quantitative model that uses this simple information to predict structures for large, complex RNA molecules, which have previously been beyond the reach of modeling techniques," he adds.
Dokholyan, who is a member of UNC Lineberger Comprehensive Cancer Center and director of the UNC Center for Computational and Systems Biology, hopes that the method will help researchers who are trying to target RNAs molecules to change cellular metabolism in a way that ultimately reduces the effects of cellular diseases like cancer. He notes, "Rational, cost-effective screening for small molecules requires a good understanding of the targeted structure. We hope that this method will open doors to new findings applicable to a wide range of human diseases."
Reference: "Three-dimensional RNA structure refinement by hydroxyl radical probing" by Feng Ding, Christopher A Lavender, Kevin M Weeks and Nikolay V Dokholyan, 15 April 2012, Nature Methods.
DOI: 10.1038/nmeth.1976
Other members of the research team include Feng Ding, PhD, Research Assistant Professor of biochemistry and biophysics, Christopher Lavendar, a graduate student of in the department chemistry, and study co-leader Kevin Weeks, PhD, Kenan Distinguished Professor of Chemistry and UNC Lineberger member.
The research was funded by the National Institutes of Health and the University of North Carolina Research Council.


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There is no single "best" program for teaching reading. However, scientific investigators agree about the need for instruction to address certain key abilities involved in learning to read. The importance of different reading-related abilities tends to shift somewhat with grade level and stage of development in reading; the abilities needed to be a successful middle- or high-school reader are not exactly the same as those required for success in first grade. Many authorities also agree that certain qualities can help to make reading instruction more effective with most youngsters, although students with learning disabilities in reading may have some special instructional needs.
Effective primary grade instruction
At the primary level, kindergarten through grade three, general education instruction should address five key reading-related abilities: phonemic awareness (awareness of individual sounds in spoken words); phonics knowledge (knowledge of sounds for letters and common letter patterns, and the ability to apply that knowledge to read unfamiliar words); fluency (ease and speed of reading); vocabulary (knowledge of meanings of individual words); and comprehension (understanding what has been read or heard). Instruction in the latter two areas includes development of oral abilities as well as actual reading, as when teachers read age-appropriate stories aloud to children and discuss stories orally.
Reading instruction also should be explicit and systematic. "Explicit" means that important skills and types of knowledge are taught directly by the teacher; children are not expected to infer key skills and knowledge only from exposure or incidental learning opportunities. "Systematic" means that there is a planned and logical sequence of instruction; for example, children are not expected to read long, complex words until they first can read simpler words. Moreover, reading instruction should attempt to motivate and engage both normally-achieving and struggling readers. For instance, children need access to books on a variety of topics and from a variety of reading levels, as well as opportunities to choose books that interest them and to share books with each other.
Effective general education reading instruction can prevent or improve reading problems in many youngsters. However, some children, including some of those with learning disabilities, may need much more intensive instruction and more opportunities for practice than do normally-achieving readers to learn to read well. Providing this kind of intensive help as early as possible is essential, because reading difficulties often become much harder to remediate over time.
Beyond the primary grades
For normally-achieving readers beyond grade three, reading instruction focuses increasingly on vocabulary and on a range of comprehension skills necessary for successful reading at upper grade levels. Comprehension instruction should include the use of comprehension strategies (e.g., summarizing what one has read or heard, or using sentence context as an aid to determining the meanings of words); using knowledge about text structure to aid comprehension (e.g., in an expository text such as a science book, headings and subheadings often contain important information that should be attended to); and developing appreciation of literary devices and themes. Vocabulary instruction should include both explicit methods, such as direct teaching of important words, and more indirect methods, such as encouraging wide reading by children to increase their exposure to new words.
Phonemic awareness is well developed in normally-achieving readers by the end of grade one and basic phonics knowledge by the end of grade three, so these areas are not usually included in regular-classroom instruction beyond the primary grades. However, for youngsters with learning disabilities in reading, difficulties with phonemic awareness and phonics knowledge often persist well beyond grade three. If a child with LD has deficits in these areas, skilled and intensive remediation is essential to his or her reading progress. In addition, poor reading fluency is extremely common among older youngsters with LD, even those whose difficulties with phonemic awareness and phonics have been successfully remediated. Poor fluency is especially problematic in the upper grades because it impairs comprehension, reduces motivation to read, and makes it difficult for children to keep up with the reading demands of their classes. Thus, instruction that specifically targets fluency is very important. Finally, the use of oral comprehension activities may continue to be valuable for older youngsters with reading disabilities, because their oral comprehension often far exceeds their reading comprehension. Oral activities may be a vehicle for students with LD to develop higher-level comprehension skills and to display abilities that would not be revealed in their reading and writing. However, oral activities should not substitute for intensive remediation of specific reading weaknesses; otherwise, students with LD will not develop the skills they need to be capable, independent readers.
Examples of sources
Peer-reviewed journal articles:
- Bus, A. G., & van IJzendoorn, M. H. (1999). Phonological awareness and early reading: A meta-analysis of experimental training studies. Journal of Educational Psychology, 91, 403-414.
- Gersten, R., Fuchs, L. S., Williams, J. P., & Baker, S. (2001). Teaching reading-comprehension strategies to students with learning disabilities: A review of research. Review of Educational Research, 71, 279-320.
- Lovett, M. W., Lacerenza, L., Borden, S., Frijters, J., Steinbach, K., & DePalma, M. (2000). Components of effective remediation for developmental reading disabilities: Combining phonological and strategy-based instruction to improve outcomes. Journal of Educational Psychology, 92, 263-283.
- Meyer, M. S., & Felton, R. H. (1999). Repeated reading to enhance fluency: Old approaches and new directions. Annals of Dyslexia, 49, 283-306.
- Rankin-Erickson, J. L., & Pressley, M. (2000). A survey of instructional practices of special education teachers nominated as effective teachers of literacy. Learning Disabilities Research & Practice, 15, 206-225.
- Torgesen, J. K., Alexander, A., Wagner, R. K., Rashotte, C., Voeller, K., & Conway, T. (2001). Intensive remedial instruction for children with severe reading disabilities: Immediate and long-term outcomes from two instructional approaches. Journal of Learning Disabilities, 34, 33-58.
- Wolf, M., Miller, L., & Donnelly, K. (2000). Retrieval, automaticity, vocabulary, engagement with language, orthography (RAVE-O): A comprehensive fluency-based reading intervention program. Journal of Learning Disabilities, 33, 375-386.
Other helpful sources:
- Biemiller, A. (1999). Language and reading success. Cambridge, MA: Brookline Books.
- Ehri, L. C. (2004). Teaching phonemic awareness and phonics: An explanation of the National Reading Panel meta-analyses. In P. McCardle & V. Chhabra (Eds.), The voice of evidence in reading research. Baltimore, MD: Brookes Publishing Co.
- National Reading Panel. (2000). Teaching children to read: An evidence-based assessment of the scientific research literature on reading and its implications for reading instruction. Washington, DC: National Institutes of Health.
- National Research Council. (1998). Preventing reading difficulties in young children. Washington, DC: National Academy Press.
- Peterson, C. L., Caverly, D. C., Nicholson, S. A., ONeil, S., & Cusenbary, S. (2000). Building reading proficiency at the secondary level: A guide to resources. Austin, TX: Southwest Educational Development Laboratory.


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The big news is that Quality Letterpress is adding a new press to the floor soon! We'll be adding a Vandercook AB 219 New Style press in a few weeks . (I just need to get the time for a road trip to pick it up : ) This press will handle a sheet size… Continue reading More Letterpress love coming soon!
Tag: Invites
Classes are back in session
Hey everybody, the good news is that my wonderful doctor is happy and has turned me loose to get back to work, slowly but surely, but work non the less! That means classes are back in session. The new class schedule is up on the learn page but here's the lowdown for November: Wednesday the… Continue reading Classes are back in session
A video from Boyte Creative.
This is a short video done by my friend Shaun at Boyte Creative. Shaun did a wonderful job of capturing the 'vibe' here at the shop. Check out the entire post here. http://blog.boytecreative.com/ Thanks Shaun, it is always a pleasure working with you!
A quick update
Hi All, well it's that time again! I'll be going in for arm surgery this coming Tuesday and although we won't know how well it goes until I wake up, I'm confident in my doctor and we're all hoping for the best. Even though I may be out for a while things are moving ahead… Continue reading A quick update
Back to Business!
Hey Everyone, Yes, it's Sunday and I'm in the shop again, no rest for the wicked! The move went well, no one hurt and no machines broken, to say that moving 30,000lbs of equipment was tough is an understatement! So many helped and my clients were very understanding, I feel fortunate to work with such… Continue reading Back to Business!
Another year passes….
Well, it's that time of year again, out with the old, in with the new! It's also my time to reflect back on things. It's been a good year here at the shop (all things considered). I've had lots of fun with my friends and made some new ones along the way, and it's been a… Continue reading Another year passes….
One Lucky Five Year Old..!
I first met little Fiona shortly after her birth when her daddy, my good friend Marc Hedges at encompus, brought her into the shop to design and print her birth announcement. So when he needed an invite for her 5th birthday, all I could say was…yes! We used all handset/wood type and ornaments. The smaller type… Continue reading One Lucky Five Year Old..!
2010 LA Printer's Fair… Good Times!
We just finished up with the 2nd Annual Printers Fair at the International Printing Museum and I must say we had a great time! We met a lot of great people and even though it was a hot day, we came away with a bunch of new friends as well as a lot of new… Continue reading 2010 LA Printer's Fair… Good Times!
活字印刷 (katsu jin satsu) is "letterpress printing" in Japanese….
I got a really nice email from a good friend of mine today, Brandon Lavigne. He's studying Japanese Kanji over in Japan these days. Brandon, along with Brett at Anders Creative, was responsible for the great look of the Quality Letterpress website. When we first met, all I had was a basic splash page with… Continue reading 活字印刷 (katsu jin satsu) is "letterpress printing" in Japanese….
Everyday is an adventure…
Recently we had a cool visitor to our shop. Santiago Merino, a noted artist from Mexico City, came into town to see how the presses operate and take what he learned back to Mexico to start his own letterpress business. We had a great time discussing art, graphic design and the letterpress process. We talked… Continue reading Everyday is an adventure…