CONTRAINDICATIONS

CUVPOSA is contraindicated in:

• Patients with medical conditions that preclude anticholinergic therapy (e.g., glaucoma, paralytic

ileus, unstable cardiovascular status in acute hemorrhage, severe ulcerative colitis, toxic megacolon

complicating ulcerative colitis, myasthenia gravis).

• Patients taking solid oral dosage forms of potassium chloride. The passage of potassium chloride

tablets through the gastrointestinal (GI) tract may be arrested or delayed with coadministration of

CUVPOSA.

WARNINGS AND PRECAUTIONS

Constipation or Intestinal Pseudo-obstruction

Constipation is a common dose-limiting adverse reaction which sometimes leads to glycopyrrolate

discontinuation [see Adverse Reactions (6.1)]. Assess patients for constipation, particularly within 4-5 days of

initial dosing or after a dose increase. Intestinal pseudo-obstruction has been reported and may present as

abdominal distention, pain, nausea or vomiting.

Incomplete Mechanical Intestinal Obstruction

Diarrhea may be an early symptom of incomplete mechanical intestinal obstruction, especially in patients with

ileostomy or colostomy. If incomplete mechanical intestinal obstruction is suspected, discontinue treatment

with CUVPOSA and evaluate for intestinal obstruction.

High Ambient Temperatures

In the presence of high ambient temperature, heat prostration (fever and heat stroke due to decreased

sweating) can occur with use of anticholinergic drugs such as CUVPOSA. Advise parents/caregivers to avoid

exposure of the patient to hot or very warm environmental temperatures.

Operating Machinery or an Automobile

CUVPOSA may produce drowsiness or blurred vision. As appropriate for a given age, warn the patient not

to engage in activities requiring mental alertness such as operating a motor vehicle or other machinery, or

performing hazardous work while taking CUVPOSA.

Anticholinergic Drug Effects

Use CUVPOSA with caution in patients with conditions that are exacerbated by anticholinergic drug effects

including:

• Autonomic neuropathy

• Renal disease

• Ulcerative colitis – Large doses may suppress intestinal motility to the point of producing a paralytic

ileus and for this reason may precipitate or aggravate “toxic megacolon,” a serious complication of

the disease.

• Hyperthyroidism

• Coronary heart disease, congestive heart failure, cardiac tachyarrhythmias, tachycardia, and

hypertension

• Hiatal hernia associated with reflux esophagitis, since anticholinergic drugs may aggravate this

condition

ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

• Constipation or intestinal pseudo-obstruction [see Warnings and Precautions (5.1)]

• Incomplete mechanical intestinal obstruction [see Warnings and Precautions (5.2)]

The most common adverse reactions reported with CUVPOSA are dry mouth, vomiting, constipation, flushing,

and nasal congestion.

Clinical Trials 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 trials of another drug and may not

reflect the rates observed in practice.

The data described below reflect exposure to CUVPOSA in 151 subjects, including 20 subjects who

participated in a 8-week placebo-controlled study (Study 1) and 137 subjects who participated in a 24-week

open-label study (six subjects who received CUVPOSA in the placebo-controlled study and 131 new subjects).

Table 2 presents adverse reactions reported by ≥ 15% of CUVPOSA-treated subjects from the placebo-

controlled clinical trial.

CUVPOSA

(N=20) n (%)

Placebo

(N=18) n (%)

Dry Mouth 8 (40%) 2 (11%)

Vomiting 8 (40%) 2 (11%)

Constipation 7 (35%) 4 (22%)

Flushing 6 (30%) 3 (17%)

Nasal Congestion 6 (30%) 2 (11%)

Headache 3 (15%) 1 (6%)

Sinusitis 3 (15%) 1 (6%)

Upper Respiratory Tract Infection 3 (15%) 0

Urinary Retention 3 (15%) 0

Table 2: Adverse Reactions Occurring in ≥ 15% of CUVPOSA-Treated

Subjects and at a Greater Frequency than Placebo in Study 1

The following adverse reactions occurred at a rate of <2% of patients receiving CUVPOSA in the open-label

study.

Gastrointestinal: Abdominal distention, abdominal pain, stomach discomfort, chapped lips, flatulence,

retching, dry tongue

General Disorders: Irritability, pain

Infections: Pneumonia, sinusitis, tracheostomy infection, upper respiratory tract infection, urinary tract

infection

Investigations: Heart rate increased

4 NEWS N O V E M B E R / D E C E M B E R 2 0 1 1 • C L I N I C A L N E U R O L O G Y N E W S

Pages 4a—4b�

Tremor Guideline Reconsiders Some TherapiesB Y J E N N I E S M I T H

FROM NEUROLOGY

Anew evidence-based guideline is-sued by the American Academyof Neurology for the treatment of

essential tremor reinforces the use ofpropranolol and primidone as the go-toagents for the disease.

However, these first-line agents – usedas monotherapy or combination therapy

since the 1980s – do not work in between30% and 50% of people with essentialtremor (ET). Moreover, a 2010 study of223 ET patients in a clinical database re-vealed that more than half of patientstaking primidone and/or propranololhad discontinued them, suggesting thatthe need for alternatives is great (Parkin-sonism Relat. Disord. 2010;16:604-7).Primidone and propranolol are known tocause side effects at higher doses.

Essential tremor is a common, pro-gressive neurological disease, formerlycalled “benign essential tremor,” thatcauses a rhythmic trembling of thehands, head, voice, legs, or trunk, andis sometimes mistaken for Parkinson’sdisease.

In its new ET guideline, published on-line Oct. 19 as an update of its 2005guideline for ET, the AAN continues torecommend topiramate, alprazolam,

atenolol, gabapentin, and sotalol as sec-ond-line treatments, based on clinical ev-idence that they are probably effective.The AAN’s new recommendations arebased on reviews of 589 articles (252 ofthese complete reviews) of randomizedcontrolled trials, observational studies,cohort studies, and case series publishedbetween 2004 and 2010 (Neurology 2011Oct. 19 [Epub ahead of print]).

The AAN’s team of reviewers, led byDr. Theresa A. Zesiewicz of the Univer-sity of South Florida in Tampa, foundthat they could not recommend leve-tiracetam and 3,4-diaminopyridine assecond-line agents, based on quality (lev-el B) clinical evidence that they do not re-duce limb tremor. The evidence on flu-narizine suggests that it is probably

ineffective in reducing limb tremor. Andthe reviewers could not recommend pre-gabalin, zonisamide, and clozapine,based on insufficient evidence to supportor refute their use in ET.

“There were some agents we hadsome hopes for that didn’t pan out, andlevetiracetam was one of them,” Dr. Ze-siewicz said in an interview, adding thatpatients not responding to primidone orpropranolol, or in whom these are con-traindicated, might benefit from any ofthe currently recommended second-lineagents with level B evidence supportingthem. Of these, she said, topiramate issupported by the largest cohort studies,but “any of the level B, or level C agents”can be tried. Surgical interventions in ETpatients, though seen to have greatertreatment effect than medications, areseldom tried before a second-line agentdoesn’t work and a tremor becomes de-bilitating. “The reason we don’t go to[surgery] right away is because whenthe side effects do occur – which is rela-tively rare – they can be serious,” Dr. Ze-siewicz said.

The guideline’s advice on surgical in-terventions for ET remain unchangedfrom 2005, with deep brain stimulation(DBS) still recommended. DBS, by whicha device is implanted in the brain totransmit electrical impulses, “has reallybecome the surgery of choice,” Dr. Ze-siewicz said.

There is still too little evidence for theAAN to recommend gamma knife thal-amotomy, which uses targeted radio-therapy, and concern remains about rarebut serious side effects with the proce-dure. Nonetheless, “the story about gam-ma knife has yet to be completely writ-ten,” Dr. Zesiewicz said.

Another surgical intervention cur-rently being explored, which uses MR-

The reviewers could notrecommend levetiracetam and3,4-diaminopyridine as second-line agents, and evidencesuggests that flunarazine is noteffective in reducing limb tremor.

Continued on following page

N O V E M B E R / D E C E M B E R 2 0 1 1 • W W W. C L I N I C A L N E U R O L O G Y N E W S . C O M NEWS 5

Our creativity as a species stemsin part from our ability to useknowledge passed from older

generations and to receive guidancefrom leaders in how to use it in newways. The shared mission of neurolo-gists within their owngroups, departments, and in-stitutions, and within thespecialty, is no exception.But our ability to work to-gether and accept the direc-tion of leaders is relativelynew in Homo sapiens’ rough-ly 200,000-year-old exis-tence. In that time, it took195,000 years to invent awheel, 199,500 years to cre-ate a printing press, and199,900 years to develop anautomobile. Given that time frame,how can we account for this unprece-dented leap in creativity if there was notenough time for natural selection’s in-cremental physiological, structural, andgenetic “improvements?”

Alfred Russell Wallace was a contem-porary of Charles Darwin, and both pro-posed a theory of natural selection as thebasis for the evolution of species. How-ever, Wallace felt that the human mindwas an exception to this theory. He posit-ed a more spiritual explanation. Many re-garded this scientific “softness” with de-rision, but his observation that naturalselection was a poor explanation forman’s unprecedented creative leap mayhave been more scientifically astute thanDarwin’s failure to question it. Manyanthropologists currently agree withWallace that incremental improvementsalone fail to explain this behavioral leap.They instead explain it by human cul-tural evolution, which, in a nutshell, isthe sharing of information within andacross generations. The emergence oflanguage probably made this sharingpossible.

Homo sapiens’ success in developing acumulative culture is based on cooper-ation with both kin and nonkin, and ex-ceptional reliance on cultural transmis-sion within and across generations. Thisis rare or absent in other apes whose co-

operative behaviors are much moreclosely kin focused. Kinship is an im-portant organizing principle in primatesocial groups. In macaques, for example,as the genetic relatedness of membersdecreases within a group, the social in-

stability of the group in-creases, resulting in morefighting and wounding (PLoSOne 2011;6:e16365).

In contrast, primitive hu-man hunter gatherer societiesare 25% genetically unrelat-ed, 50% distantly related, andonly 25% closely related. Thisnonrelatedness fosters inter-group interactions that maylead to the spread of cooper-ative institutions. When peo-ple reside together they have

frequent opportunities to observe inno-vations and imitate successful traits. Thechange in ancestral human residentialstructure, compared with our evolu-tionary ancestors, may have thereforeled to greater exposure to more ideas ofvalue and may explain why humans andno other animals developed the costlysocial learningmechanisms thathave resulted incultural evolu-tion (Science2011;331:1286-9). This increas-ingly complexsocial behavior iscorrelated withbrain size, espe-cially in the frontal neocortex.

The wheel and the space shuttle areboth products of creativity, but amongtheir many obvious differences is one wecan call the “creative unit.” The wheel’screative unit could have been a singleperson with all the tools needed to gen-erate the first prototype, whereas thespace shuttle clearly required manyteams of people working together. Co-ordinating a team requires leadership.Effective leaders maintain high mutualcooperation among their group’s mem-bers by ensuring that the penalty fornoncooperation is fair and outweighed

by any possible reward for noncoopera-tion. Leaders must enforce social norms,rules, or laws. If mutual cooperationwith a social norm is perceived by themembership to drop, then individualdefection rates will rise and the previ-ously defined social norm will breakdown (Trends Cogn. Sci.2004;8:185-90). Saying some-thing is so will work only aslong as it usually is so, and itis the leader’s role to main-tain that consistency. Onecaveat is that leaders shouldalso be perceived as toler-ant. Few people have per-fect track records of cooper-ation, and occasional minormissteps must be accommo-dated. In a study that lookedat the reaction of leadershipto such noncooperative be-havior, it was shown that co-operative behavior in a social groupingis enhanced by perceived mercy of thosein charge (Nature 2003;422:137-40). Con-sistency, fairness, and temperance inholding members accountable all matter

in a leader’s abil-ity to foster co-operation.

Effective lead-ers create a cul-ture of identityand mission,and foster beliefin the group’scompetitive su-periority so that

the group believes it can win. The cul-ture must distinguish the group’s cre-ative unit from others (“Myth and Mean-ing” [New York: Schocken Books, 1979,p. 20]). Within such a unit, teamworkwill flourish and space shuttles will fly.Cooperation is enhanced by perceivedsimilarity among a group’s members.While this can apply to physical ap-pearances, similarity is more defined ina business setting, research lab, or neu-rology department by a sense of sharedmission. Just as the role of every mem-ber of NASA, from astronomer to jani-tor, is to put us into space, the mission

of a health care organization, from thedoctors to the secretaries, is to heal pa-tients.

Jonathan Haidt in his book, “TheHappiness Hypothesis” (New York: Ba-sic Books, 2006), makes the compellingargument, drawing from the school of

positive psychology, thatvirtue enhances happiness.Virtue, in this case, is definedbroadly as excellence and in-volves morality. A leaderwho can cast the actions ofthe group as serving a noblecause can increase thegroup’s level of happiness,and in this virtue-inspiredhappy state the group willbe further motivated to worktoward the virtuous goal.The shared sense of a virtu-ous mission creates a sharedidentity, and the competitive,

proud sense that they will excel inachieving that mission.

We in the medical world have littleproblem believing that we have a virtu-ous mission. Let us continue to work asa team within our groups, institutions,specialty, and in the broader role wehave in society to use our talents cre-atively and cooperatively so as to con-tinue advancing our mission for neuro-logic health. ■

DR. CASELLI is the medical editor ofCLINICAL NEUROLOGY NEWS and isprofessor of neurology at the Mayo Clinicin Scottsdale, Ariz.

EVOKED POTENTIALS

Group Creativity Requires Knowledge, Leadership

R I C H A R D J.C A S E L L I , M . D.

The complexity and size of the‘creative unit’ has become everlarger over time, using moreknowledge and leadership, fromthe invention of the wheel to thedevelopment of the space shuttle.

This is the last

installment of

Dr. Caselli’s

10-part series on

creativity. Watch

for next year’s

series on

disorders of

creativity.

LETTERS Letters in response to articles in CLINICAL NEUROLOGY NEWS and itssupplements should include your nameand address, affiliation, and conflicts ofinterest in regard to the topic discussed.Letters may be edited for space andclarity.

Mail: Letters, CLINICAL NEUROLOGY NEWS, 5635 Fishers Lane, Suite 6000,Rockville, MD 20852

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E-mail: clinicalneurologynews@elsevier.com

guided focused ultrasound, was notmentioned in the current guidance, butDr. Zesiewicz called it “extremely inter-esting,” and hopes that the procedure, pi-oneered by Dr. W. Jeffrey Elias of theUniversity of Virginia, Charlottesville,will hold up in long-term safety studiesand randomized controlled trials. “Gam-ma ray looked good too,” she noted –until some rare but severe delayed ad-verse effects were seen.

Dr. Zesiewicz and her colleagues not-ed that more and larger randomizedcontrolled trials, with standardized out-come measures, were needed for ETtreatments.

“We lost a lot of ground in researchbecause of the [former] name ‘benign es-sential tremor,’ ” Dr. Zesiewicz said.“Once that ‘benign’ was dropped it be-came a more serious priority. Hopefullywe’ll be able to gain ground now that weknow that this is a serious condition, itis a disease, and it’s certainly not benign.”

However, the pathology of ET, nowthought to be a heterogeneous set of de-generative changes in the brain, has be-come much better understood in recentyears, thanks to researchers’ post-mortem studies of the brains of ET pa-tients at Columbia University in NewYork.

The Columbia brain bank’s research isbeing led by Dr. Elan Louis, one of the

new ET guideline’s coauthors. Dr. Louisand colleagues have made “tremendousheadway,” Dr. Zesiewicz said, in eluci-dating the causes of ET.

Dr. Zesiewicz said she hopes newagents will be designed to target ETspecifically. The currently recommend-ed agents range from antiepileptics tomedications used to treat schizophrenia– and only one, propranolol, is approvedby the U.S. Food and Drug Administra-tion to treat ET. (Even primidone is notFDA-approved, despite its widespread,long-term use.)

“What’s important to understand isthat ET may be a heterogeneous condi-tion,” Dr. Zesiewicz said. “When wepick that apart and truly understand the

mechanisms by which ET occurs, wemay be able to develop research andmedications specific to the problem.”

Dr. Zesiewicz disclosed having re-ceived speakers’ fees other forms of sup-port from Teva, Boehringer Ingelheim,Allergan, and Novartis, along with re-search support from Pfizer, and is an in-ventor on a provisional patent on the useof nicotinic modulators in treating atax-ia and imbalance held by the Universityof South Florida. Several of Dr. Ze-siewicz’s coauthors on the ET guidelineacknowledged support from these andother companies, including Glaxo-SmithKline, Phytopharm, Janssen, Al-lergan, Novartis, Ipsen, Merz, Lundbeck,and Bayer. ■

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