To the narcissist - and more so, to the psychopath - the future is a hazy concept. This misperception of time - a cognitive deficit - is due to a confluence of several narcissistic traits. The narcissist inhabits an eternal present.

I. Instability and Liability

The life of the narcissist is inherently unstable. This makes it difficult to perceive time as a linear flow of causes and their effects. The narcissist's time is cyclical, arbitrary, and magical.

A narcissist is a person who derives his Ego (and ego functions) from the reactions of his human environment to a projected, invented image called the False Self. Since no absolute control over such feedback of Narcissistic Supply is possible - it is bound to be volatile - the narcissist's view of himself and of his surroundings is correspondingly and equally volatile. As "public opinion" fluctuates, so do his self-confidence, self-esteem, generally, so does his self. Even his convictions are subject to a never-ending voting process by others.

The narcissistic personality is subject to instabilities in each and every one of its dimensions. It is the ultimate hybrid: rigidly amorphous, devoutly flexible, reliant for its sustenance on the opinion of people, whom the narcissist undervalues. A large part of this instability is subsumed under the Emotional Involvement Prevention Measures (EIPM) that I describe in the Essay. Instability is so ubiquitous, so all-pervasive, and so prevalent and dominant - that it might well be described as the ONLY stable feature of the narcissist's personality.

The narcissist does everything with one goal in mind: to attract Narcissistic Supply (attention).

An example of this kind of behaviour:

The narcissist may study a given subject diligently and in great depth in order to impress people later with this newly acquired erudition. But, having served its purpose, the narcissist lets the knowledge thus acquired evaporate. The narcissist maintains a sort of a "short-term" cell or warehouse where he stores whatever may come handy in the pursuit of Narcissistic Supply. But he is almost never really interested in what he does, studies, and experiences. From the outside, this might be perceived as instability. But think about it this way: the narcissist is constantly preparing for life's "exams" and feels that he is on a permanent trial. To forget material studied only in preparation for an examination or for a court appearance is normal. Short memory storage is a perfectly common behaviour. What sets the narcissist apart from others is the fact that for him this is a CONSTANT state of affairs and that it affects ALL his functions, not only those directly related to learning, or to emotions, or to experience, or to any single dimension of his life. Thus, the narcissist learns, remembers and forgets not in line with his real interests or hobbies, he loves and hates not the real subjects of his emotions but one dimensional, utilitarian, cartoons constructed by him. He judges, praises and condemns - all from the narrowest possible point of view: that of the potential amount of Narcissistic Supply. He asks not what he can do with the world and in it - but what can the world do for him as far as Narcissistic Supply goes. He falls in and out of love with people, workplaces, residences, vocations, hobbies, interests - because they seem to be able to provide more or less Narcissistic Supply and only because of that.

Still, narcissists belong to two broad categories: the "compensatory stability" and the "enhancing instability" types.

a. Compensatory Stability ("Classic") Narcissists

These narcissists isolate one or more (but never most) aspects of their lives and "make these aspect/s stable". They do not really invest themselves in it. The stability is maintained by artificial means: money, celebrity, power, fear. A typical example is a narcissist who changes numerous workplaces, a few careers, a myriad of hobbies, value systems or faiths. At the same time, he maintains (preserves) a relationship with a single woman (and even remains faithful to her). She is his "island of stability". To fulfil this role, she just needs to be there physically.

The narcissist is dependent upon "his" woman to maintain the stability lacking in all other areas of his life (to compensate for his instability). Yet, emotional closeness is bound to threaten the narcissist. Thus, he is likely to distance himself from her and to remain detached and indifferent to most of her needs. Despite this cruel emotional treatment, the narcissist considers her to be a point of exit, a form of sustenance, a fountain of empowerment. This mismatch between what he wishes to receive and what he is able to give, the narcissist prefers to deny, repress and bury deep in his unconscious. This is why he is always shocked and devastated to learn of his wife's estrangement, infidelity, or divorce intentions. Possessed of no emotional depth, being completely one track minded - he cannot fathom the needs of others. In other words, he cannot empathise.

Another - even more common - case is the "career narcissist". This narcissist marries, divorces and remarries with dizzying speed. Everything in his life is in constant flux: friends, emotions, judgements, values, beliefs, place of residence, affiliations, hobbies. Everything, that is, except his work. His career is the island of compensating stability in his volatile existence. This kind of narcissist doggedly pursues it with unmitigated ambition and devotion. He perseveres in one workplace or one job, patiently, persistently and blindly climbing up the ladder or treading the career path. In his pursuit of job fulfilment and achievements, the narcissist is ruthless and unscrupulous - and, very often, most successful.

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b. Enhancing Instability ("Borderline") Narcissist

The other kind of narcissist enhances instability in one aspect or dimension of his life - by introducing instability in others. Thus, if such a narcissist resigns (or, more likely, is made redundant) - he also relocates to another city or country. If he divorces, he is also likely to resign his job. This added instability gives these narcissists the feeling that all the dimensions of their life are changing simultaneously, that they are being "unshackled", that a transformation is in progress. This, of course, is an illusion. Those who know the narcissist, no longer trust his frequent "conversions", "decisions", "crises", "transformations", "developments" and "periods". They see through his pretensions and declarations into the core of his instability. They know that he is not to be relied upon. They know that with narcissists, temporariness is the only permanence.

Narcissists hate routine. When a narcissist finds himself doing the same things over and over again, he gets depressed. He oversleeps, over-eats, over-drinks and, in general, engages in addictive, impulsive, reckless, and compulsive behaviours. This is his way of re-introducing risk and excitement into what he (emotionally) perceives to be a barren life.

The problem is that even the most exciting and varied existence becomes routine after a while. Living in the same country or apartment, meeting the same people, doing essentially the same things (even with changing content) - all "qualify" as stultifying rote.

The narcissist feels entitled to more. He feels it is his right - due to his intellectual superiority - to lead a thrilling, rewarding, kaleidoscopic life. He feels entitled to force life itself, or, at least, people around him, to yield to his wishes and needs, supreme among them the need for stimulating variety.

This rejection of habit is part of a larger pattern of aggressive entitlement. The narcissist feels that the very existence of a sublime intellect (such as himself) warrants concessions and allowances by others. Standing in line is a waste of time better spent pursuing knowledge, inventing and creating. The narcissist should avail himself of the best medical treatment proffered by the most prominent medical authorities - lest the asset that he is lost to Mankind. He should not be bothered with trivial pursuits - these lowly functions are best assigned to the less gifted. The devil is in paying precious attention to detail.

Entitlement is sometimes justified in a Picasso or an Einstein. But few narcissists are either. Their achievements are grotesquely incommensurate with their overwhelming sense of entitlement and with their grandiose self-image.

Of course, the feeling of superiority often serves to mask a cancerous complex of inferiority. Moreover, the narcissist infects others with his projected grandiosity and their feedback constitutes the edifice upon which he constructs his self-esteem. He regulates his sense of self-worth by rigidly insisting that he is above the madding crowd while deriving his Narcissistic Supply from this very source.

But there is a second angle to this abhorrence of the predictable. Narcissists employ a host of Emotional Involvement Prevention Measures (EIPM). Despising routine and avoiding it is one of these mechanisms. Their function is to prevent the narcissist from getting emotionally involved and, subsequently, hurt. Their application results in an "approach-avoidance repetition complex". The narcissist, fearing and loathing intimacy, stability and security - yet craving them - approaches and then avoids significant others or important tasks in a rapid succession of apparently inconsistent and disconnected behaviours.

II. Recurrent Losses

Narcissists are accustomed to loss. Their obnoxious personality and intolerable behaviours makes them lose friends and spouses, mates and colleagues, jobs and family. Their peripatetic nature, their constant mobility and instability causes them to lose everything else: their place of residence, their property, their businesses, their country, and their language.

There is always a locus of loss in the narcissist's life. He may be faithful to his wife and a model family man - but then he is likely to change jobs frequently and renege on his financial and social obligations. Or, he may be a brilliant achiever - scientist, doctor, CEO, actor, pastor, politician, journalist - with a steady, long-term and successful career - but a lousy homemaker, thrice divorced, unfaithful, unstable, always on the lookout for better Narcissistic Supply.

The narcissist is aware of his propensity to lose everything that could have been of value, meaning, and significance in his life. If he is inclined to magical thinking and alloplastic defences, he blames life, or fate, or country, or his boss, or his nearest and dearest for his uninterrupted string of losses. Otherwise, he attributes it to people's inability to cope with his outstanding talents, towering intellect, or rare abilities. His losses, he convinces himself, are the outcomes of pettiness, pusillanimity, envy, malice, and ignorance. It would have turned out the same way even had he behaved differently, he consoles himself.

In time, the narcissist develops defence mechanisms against the inevitable pain and hurt he incurs with every loss and defeat. He ensconces himself in an ever thicker skin, an impenetrable shell, a make belief environment in which his sense of in-bred superiority and entitlement is preserved. He appears indifferent to the most harrowing and agonising experiences, not human in his unperturbed composure, emotionally detached and cold, inaccessible, and invulnerable. Deep inside, he, indeed, feels nothing.

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The narcissist cruises through his life as a tourist would through an exotic island. He observes events and people, his own experiences and loved ones - as a spectator would a movie that at times is mildly exciting and at others mildly boring. He is never fully there, entirely present, irreversibly committed. He is constantly with one hand on his emotional escape hatch, ready to bail out, to absent himself, to re-invent his life in another place, with other people. The narcissist is a coward, terrified of his True Self and protective of the deceit that is his new existence. He feels no pain. He feels no love. He feels no life.

III. Immunity and Magical Thinking

The narcissist's magical thinking and his alloplastic defences (his tendency to blame others for his failures, defeats, and misfortune) make him feel immune to the consequences of his actions. The narcissist does not feel the need to plan ahead. He believes that things will "sort themselves out" under the aegis of some cosmic plan which revolves around him and his role in history.

In many respects, narcissists are children. Like children, they engage in magical thinking. They feel omnipotent. They feel that there is nothing they couldn't do or achieve had they only really wanted to. They feel omniscient - they rarely admit that there is anything that they do not know. They believe that all knowledge resides within them. They are haughtily convinced that introspection is a more important and more efficient (not to mention easier to accomplish) method of obtaining knowledge than the systematic study of outside sources of information in accordance with strict (read: tedious) curricula. To some extent, they believe that they are omnipresent because they are either famous or about to become famous. Deeply immersed in their delusions of grandeur, they firmly believe that their acts have - or will have - a great influence on mankind, on their firm, on their country, on others. Having learned to manipulate their human environment to a masterly extent - they believe that they will always "get away with it".

Narcissistic immunity is the (erroneous) feeling, harboured by the narcissist, that he is immune to the consequences of his actions. That he will never be effected by the results of his own decisions, opinions, beliefs, deeds and misdeeds, acts, inaction and by his membership of certain groups of people. That he is above reproach and punishment (though not above adulation). That, magically, he is protected and will miraculously be saved at the last moment.

What are the sources of this unrealistic appraisal of situations and chains of events?

The first and foremost source is, of course, the False Self. It is constructed as a childish response to abuse and trauma. It is possessed of everything that the child wishes he had in order to retaliate: power, wisdom, magic - all of them unlimited and instantaneously available. The False Self, this Superman, is indifferent to abuse and punishment inflicted upon it. This way, the True Self is shielded from the harsh realities experienced by the child. This artificial, maladaptive separation between a vulnerable (but not punishable) True Self and a punishable (but invulnerable) False Self is an effective mechanism. It isolates the child from the unjust, capricious, emotionally dangerous world that he occupies. But, at the same time, it fosters a false sense of "nothing can happen to me, because I am not there, I cannot be punished because I am immune".

The second source is the sense of entitlement possessed by every narcissist. In his grandiose delusions, the narcissist is a rare specimen, a gift to humanity, a precious, fragile, object. Moreover, the narcissist is convinced both that this uniqueness is immediately discernible - and that it gives him special rights. The narcissist feels that he is protected under some cosmological law pertaining to "endangered species". He is convinced that his future contribution to humanity should (and does) exempt him from the mundane: daily chores, boring jobs, recurrent tasks, personal exertion, orderly investment of resources and efforts and so on. The narcissist is entitled to "special treatment": high living standards, constant and immediate catering to his needs, the avoidance of any encounter with the mundane and the routine, an all-engulfing absolution of his sins, fast track privileges (to higher education, in his encounters with the bureaucracy). Punishment is for ordinary people (where no great loss to humanity is involved). Narcissists are entitled to a different treatment and they are above it all.

The third source has to do with their ability to manipulate their (human) environment. Narcissists develop their manipulative skills to the level of an art form because that is the only way they could have survived their poisoned and dangerous childhood. Yet, they use this "gift" long after its usefulness is over. Narcissists are possessed of inordinate abilities to charm, to convince, to seduce and to persuade. They are gifted orators. In many cases, they ARE intellectually endowed. They put all this to the bad use of obtaining Narcissistic Supply. Many of them are con-men, politicians, or artists. Many of them do belong to the social and economic privileged classes. They mostly do get exempted many times by virtue of their standing in society, their charisma, or their ability to find the willing scapegoats. Having "got away with it" so many times - they develop a theory of personal immunity, which rests on some kind of societal and even cosmic "order of things". Some people are just above punishment, the "special ones", the "endowed or gifted ones". This is the "narcissistic hierarchy".

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But there is a fourth, simpler, explanation:

The narcissist just does not know what he is doing. Divorced from his True Self, unable to empathise (to understand what it is like to be someone else), unwilling to empathise (to constrain his actions in accordance with the feelings and needs of others) - he is in a constant dreamlike state. His life to him is a movie, autonomously unfolding, guided by a sublime (even divine) director. He is a mere spectator, mildly interested, greatly entertained at times. He does not feel that his actions are his. He, therefore, emotionally, cannot understand why he should be punished and when he is, he feels grossly wronged.

To be a narcissist is to be convinced of a great, inevitable personal destiny. The narcissist is preoccupied with ideal love, the construction of brilliant, revolutionary scientific theories, the composition or authoring or painting of the greatest work of art ever, the founding of a new school of thought, the attainment of fabulous wealth, the reshaping of the fate of a nation, becoming immortalised and so on. The narcissist never sets realistic goals to himself. He is forever floating amidst fantasies of uniqueness, record breaking, or breathtaking achievements. His speech reflects this grandiosity and is interlaced with such expressions. So convinced is the narcissist that he is destined to great things - that he refuses to accept setbacks, failures and punishments. He regards them as temporary, as someone else's errors, as part of the future mythology of his rise to power/brilliance/wealth/ideal love, etc. A punishment is a diversion of scarce energy and resources from the all-important task of fulfilling his mission in life. This over-riding goal is a divine certainty: a higher order has pre-ordained the narcissist to achieve something lasting, of substance, of import in this world, in this life. How could mere mortals interfere with the cosmic, the divine, scheme of things? Therefore, punishment is impossible and will not happen - is the narcissist's conclusion.

The narcissist is pathologically envious of people - and projects his feelings unto them. He is always over-suspicious, on guard, ready to fend off an imminent attack. A punishment to the narcissist is a major surprise and a nuisance but it also proves to him and validates what he suspected all the time: that he is being persecuted. Strong forces are poised against him. People are envious of his achievements, angry at him, out to get him. He constitutes a threat to the accepted order. When required to account for his (mis)deeds, the narcissist is always disdainful and bitter. He feels like Gulliver, a giant, chained to the ground by teeming dwarves while his soul soars to a future, in which people will recognise his greatness and applaud it.

IV. Depersonalisation and Derealisation

Time is a quality of the physical world - or, at least, of the way we perceive it. Many narcissists do not feel a part of reality. They feel "unreal", fake facsimiles of "tangible", normal, people. This dents their perception of time and causality. That the narcissist possesses a prominent False Self as well as a suppressed and dilapidated True Self is common knowledge. Yet, how intertwined and inseparable are these two? Do they interact? How do they influence each other? And what behaviours can be attributed squarely to one or the other of these protagonists? Moreover, does the False Self assume traits and attributes of the True Self in order to deceive?

Two years ago, I suggested a methodological framework. I compared the narcissist to a person suffering from the e Dissociative Identity Disorder (DID) - formerly known as the Multiple Personality Disorder (MPD).

Here is what I wrote:

"A debate is starting to stir: is the False Self an alter? In other words: Is the True Self of a narcissist the equivalent of a host personality in a DID (Dissociative Identity Disorder) - and the False Self one of the fragmented personalities, also known as 'alters'?

My personal opinion is that the False Self is a mental construct, not a self in the full sense. It is the locus of the fantasies of grandiosity, the feelings of entitlements, omnipotence, magical thinking, omniscience and magical immunity of the narcissist. It lacks so many elements that it can hardly be called a 'self'.

Moreover, it has no 'cut-off' date. DID alters have a date of inception, being reactions to trauma or abuse. The False Self is a process, not an entity, it is a reactive pattern and a reactive formation. All taken into account, the choice of words was poor. The False Self is not a Self, nor is it False. It is very real, more real to the narcissist than his True Self. A better choice would have been 'abuse reactive self' or something like this.

This is the core of my work. I say that narcissists have vanished and have been replaced by a False Self (bad term, but not my fault, write to Kernberg). There is NO True Self in there. It's gone. The narcissist is a hall of mirrors - but the hall itself is an optical illusion created by the mirrors... This is a little like the paintings of Escher.

MPD (DID) is more common than believed. The emotions are the ones to get segregated. The notion of 'unique separate multiple whole personalities' is primitive and untrue. DID is a continuum. The inner language breaks down into a polyglottal chaos. Emotions cannot communicate with each other for fear of the pain (and its fatal results). So, they are kept apart by various mechanisms (a host or birth personality, a facilitator, a moderator and so on).

And here we come to the crux of the matter: All PDs - except NPD - suffer from a modicum of DID, or incorporate it. Only the narcissists don't. This is because the narcissistic solution is to emotionally disappear so thoroughly that not one personality/emotion is left. Hence, the tremendous, insatiable need of the narcissist for external approval. He exists ONLY as a reflection. Since he is forbidden from loving his True Self - he chooses to have no self at all. It is not dissociation - it is a vanishing act.

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This is why I regard pathological narcissism as THE source of all PDs. The total, 'pure' solution is NPD: self-extinguishing, self-abolishing, totally fake. Then come variations on the self-hate and perpetuated self-abuse themes: HPD (NPD with sex or the body as the Source of Narcissistic Supply), BPD (emotional lability, movement between poles of life wish and death wish) and so on.

Why are narcissists not prone to suicide? Simple: they died a long time ago. They are the true zombies of the world. Read vampire and zombie legends and you will see how narcissistic these creatures are."

Many researchers and scholars and therapists tried to grapple with the void at the core of the narcissist. The common view is that the remnants of the True Self are so ossified, shredded, cowed into submission and repressed - that, for all practical purposes, they are functionless and useless. In treating the narcissist, the therapist often tries to invent a healthy self, rather than build upon the distorted wreckage strewn across the narcissist's psyche.

But what of the rare glimpses of True Self that the unfortunates who interact with narcissists keep reporting?

If the pathological narcissistic element is but one of many other disorders - the True Self may well have survived. Gradations and shades of narcissism occupy the narcissistic spectrum. Narcissistic traits (overlay) are often co-diagnosed with other disorders (co-morbidity). Some people have a narcissistic personality - but NOT NPD! These distinctions are important.

A person may well appear to be a narcissist - but is not, in the strict, psychiatric, sense of the word.

In a full-fledged narcissist, the False Self IMITATES the True Self.

To do so artfully, it deploys two mechanisms:

Re-Interpretation

It causes the narcissist to re-interpret certain emotions and reactions in a flattering, True Self-compatible, light. A narcissist may, for instance, interpret FEAR - as compassion. If I hurt someone I fear (e.g., an authority figure) - I may feel bad afterwards and interpret my discomfort as EMPATHY and COMPASSION. To be afraid is humiliating - to be compassionate is commendable and earns me social acceptance and understanding.

Emulation

The narcissist is possessed of an uncanny ability to psychologically penetrate others. Often, this gift is abused and put at the service of the narcissist's control freakery and sadism. The narcissist uses it liberally to annihilate the natural defences of his victims by faking unprecedented, almost inhuman, empathy.

This capacity is coupled with the narcissist's ability to frighteningly imitate emotions and their attendant behaviours. The narcissist possesses "resonance tables". He keeps records of every action and reaction, every utterance and consequence, every datum provided by others regarding their state of mind and emotional make-up. From these, he then constructs a set of formulas which often result in impeccably and eerily accurate renditions of emotional behaviour. This is enormously deceiving.

The narcissist experiences his own life as a prolonged, incomprehensible, unpredictable, frequently terrifying and deeply saddening nightmare. This is a result of the functional dichotomy - fostered by the narcissist himself - between his False Self and his True Self. The latter - the fossilised ashes of the original, immature, personality - is the one that does the experiencing.

The False Self is nothing but a concoction, a figment of the narcissist's disorder, a reflection in the narcissist's hall of mirrors. It is incapable of feeling, or experiencing. Yet, it is fully the master of the psychodynamic processes, which rage within the narcissist's psyche. The inner battle is so fierce that the True Self experiences it as a diffuse, though imminent and eminently ominous, threat. Anxiety ensues and the narcissist finds himself constantly ready for the next blow. He does things and he knows not why or wherefrom. He says things, acts and behaves in ways, which, he knows, endanger him and put him in line for punishment. Otherwise he hurts people around him, or breaks the law, or violates accepted morality. He knows that he is in the wrong and feels ill at ease on the rare moments that he does feel. He wants to stop but knows not how. Gradually, he feels estranged from himself, possessed by some kind of demon, a puppet on invisible, mental strings. He resents this feeling, he wants to rebel, he is repelled by this part in him with which he is not acquainted. In his efforts to exorcise this devil from his soul, he dissociates.

An eerie sensation sets in and pervades the psyche of the narcissist. At times of crisis, of danger, of depression, of narcissistic failure - he feels that he is watching himself from the outside. This is not a physical description of an ethereal voyage. The narcissist does not really "exit" his body. It is just that he assumes, involuntarily, the position of a spectator, a polite observer mildly interested in the whereabouts of one, Mr. Narcissist. It is akin to watching a movie, the illusion is not complete, nor is it precise. This detachment continues for as long as the unwanted behaviour persists, for as long as the crisis goes on, for as long as the narcissist cannot face who he is, what he is doing and the consequences of his deeds. Since this is the case most of the time, the narcissist gets used to seeing himself in the role of the hero of a motion picture or of a novel. It also sits well with his grandiosity and fantasies. Sometimes, he talks about himself in the third person singular. Sometimes he calls his "other", narcissistic, self by a different name. He describes his life, its events, ups and downs, pains, elation and disappointments in the most remote voice, "professional" and coldly analytical, as though describing (though with a modicum of involvement) the life of some exotic insect (yes, Kafka).

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The metaphor of "life as a movie", gaining control by "writing a scenario" or by "inventing a narrative" is, therefore, not a modern invention. Cavemen narcissists have, probably, done the same. But this is only the external, superficial, facet. The problem is that the narcissist FEELS this way. He really experiences his life as belonging to someone else, his body as dead weight (or as an instrument in the service of some entity), his deeds as a-moral and not immoral (he cannot be judged for something that he hasn't done, can he?). As time passes, the narcissist accumulates a mountain of mishaps, conflicts unresolved, pains well hidden, abrupt separations and bitter disappointments. He is subjected to a constant barrage of social criticism and condemnation. He is ashamed and fearful. He knows that something is wrong but there is no correlation between his cognition and his emotions. He prefers to run away and hide, as he did when he was an infant. Only this time he hides behind another self, the false one. People reflect to him this mask of his creation, until even he believes its very existence and acknowledges its dominance, until he forgets the truth and knows no better. The narcissist is only dimly aware of the decisive battle, which rages inside him. He feels threatened, very sad, suicidal - but there seems to be no outside cause of all this and it makes it even more mysteriously ominous.

This dissonance, these negative feelings, these nagging anxieties, transform the "motion picture" solution into a permanent one. It becomes a feature of the narcissist's life. Whenever confronted by an emotional threat or by an existential one - he retreats into this haven, this mode of coping. He relegates responsibility, submissively assuming the passive role of "the one acted upon". He who is not responsible cannot be punished - runs the subtext of this capitulation. The narcissist is thus classically conditioned to annihilate himself - both in order to avoid (emotional) pain and to bask in the light of his grandiose dreams. This he does with fanatic zeal and with efficacy. Prospectively, he assigns his very life (decisions to be made, judgements to be passed, agreements to be reached) to the False Self. Retroactively, he interprets his past life in a manner consistent with the current needs of the False Self. It is no wonder that there is no connection between what the narcissist did feel in a given period in his life, or in relation to a specific event or happening - and the way he sees or remembers these later on in his life. He describes certain occurrences or periods in his life as "tedious, painful, sad, burdening" - even though he felt entirely differently at the time. The same retroactive colouring occurs with regards to people. The narcissist completely distorts the way he regarded certain people and felt towards them. His inclination is directly and fully derived from the requirements of his False Self during the process of recasting and re-writing.

In sum, the narcissist does not occupy his own soul, nor does he inhabit his own body. He is the servant of an apparition, of a reflection, of an Ego function. To please and appease his Master, the narcissist sacrifices to it his very life. From that moment onwards, the narcissist lives vicariously, through the good offices of the False Self. He feels detached, alienated and estranged from his (False) Self. He constantly harbours the sensation that he is watching a movie with a plot of which he has but little control. It is with certain interest - even bemusement, fascination - that he does the watching. Still, watching it is and only that. The narcissist also engages in permanent Orwellian alterations to the emotional content, which accompanied certain events and people in his life. He re-writes his emotional history according to instructions emanating from the False Self. Thus, not only does the narcissist lose control of his future life (the movie) - he is gradually losing ground to the False Self in the battle to preserve the integrity and genuineness of his past experiences. Eroded between these two poles, the narcissist gradually disappears and is replaced by his disorder to the most complete extent.

 

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next: The Misanthropic Altruist (Philanthropy as Sadistic Narcissism)

• Watch the video on The Cult of the Narcissist

The narcissist is the guru at the centre of a cult. Like other gurus, he demands complete obedience from his flock: his spouse, his offspring, other family members, friends, and colleagues. He feels entitled to adulation and special treatment by his followers He punishes the wayward and the straying lambs. He enforces discipline, adherence to his teachings, and common goals. The less accomplished he is in reality - the more stringent his mastery and the more pervasive the brainwashing.

The - often involuntary - members of the narcissist's mini-cult inhabit a twilight zone of his own construction. He imposes on them a shared psychosis, replete with persecutory delusions, "enemies", mythical narratives, and apocalyptic scenarios if he is flouted.

The narcissist's control is based on ambiguity, unpredictability, fuzziness, and ambient abuse. His ever-shifting whims exclusively define right versus wrong, desirable and unwanted, what is to be pursued and what to be avoided. He alone determines the rights and obligations of his disciples and alters them at will.

The narcissist is a micro-manager. He exerts control over the minutest details and behaviours. He punishes severely and abuses withholders of information and those who fail to conform to his wishes and goals.

The narcissist does not respect the boundaries and privacy of his reluctant adherents. He ignores their wishes and treats them as objects or instruments of gratification. He seeks to control both situations and people compulsively.

He strongly disapproves of others' personal autonomy and independence. Even innocuous activities, such as meeting a friend or visiting one's family require his permission. Gradually, he isolates his nearest and dearest until they are fully dependent on him emotionally, sexually, financially, and socially.

He acts in a patronising and condescending manner and criticises often. He alternates between emphasising the minutest faults (devalues) and exaggerating the talents, traits, and skills (idealises) of the members of his cult. He is wildly unrealistic in his expectations - which legitimises his subsequent abusive conduct.

 

The narcissist claims to be infallible, superior, talented, skilful, omnipotent, and omniscient. He often lies and confabulates to support these unfounded claims. Within his cult, he expects awe, admiration, adulation, and constant attention commensurate with his outlandish stories and assertions. He reinterprets reality to fit his fantasies.

His thinking is dogmatic, rigid, and doctrinaire. He does not countenance free thought, pluralism, or free speech and doesn't brook criticism and disagreement. He demands - and often gets - complete trust and the relegation to his capable hands of all decision-making.

He forces the participants in his cult to be hostile to critics, the authorities, institutions, his personal enemies, or the media - if they try to uncover his actions and reveal the truth. He closely monitors and censors information from the outside, exposing his captive audience only to selective data and analyses.

The narcissist's cult is "missionary" and "imperialistic". He is always on the lookout for new recruits - his spouse's friends, his daughter's girlfriends, his neighbours, new colleagues at work. He immediately attempts to "convert" them to his "creed" - to convince them how wonderful and admirable he is. In other words, he tries to render them Sources of Narcissistic Supply.

Often, his behaviour on these "recruiting missions" is different to his conduct within the "cult". In the first phases of wooing new admirers and proselytising to potential "conscripts" - the narcissist is attentive, compassionate, empathic, flexible, self-effacing, and helpful. At home, among the "veterans" he is tyrannical, demanding, wilful, opinionated, aggressive, and exploitative.

As the leader of his congregation, the narcissist feels entitled to special amenities and benefits not accorded the "rank and file". He expects to be waited on hand and foot, to make free use of everyone's money and dispose of their assets liberally, and to be cynically exempt from the rules that he himself established (if such violation is pleasurable or gainful).

In extreme cases, the narcissist feels above the law - any kind of law. This grandiose and haughty conviction leads to criminal acts, incestuous or polygamous relationships, and recurrent friction with the authorities.

Hence the narcissist's panicky and sometimes violent reactions to "dropouts" from his cult. There's a lot going on that the narcissist wants kept under wraps. Moreover, the narcissist stabilises his fluctuating sense of self-worth by deriving Narcissistic Supply from his victims. Abandonment threatens the narcissist's precariously balanced personality.

Add to that the narcissist's paranoid and schizoid tendencies, his lack of introspective self-awareness, and his stunted sense of humour (lack of self-deprecation) and the risks to the grudging members of his cult are clear.

The narcissist sees enemies and conspiracies everywhere. He often casts himself as the heroic victim (martyr) of dark and stupendous forces. In every deviation from his tenets he espies malevolent and ominous subversion. He, therefore, is bent on disempowering his devotees. By any and all means.

The narcissist is dangerous.

 

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next: The Narcissist's Time

• Watch the video on Narcissist's Object Constancy

Narcissists often carry on talking (rather, lecturing) long after their interlocutors - bored stiff and resentful - have physically departed or mentally switched off. They are shocked to discover that they have been conversing with thin air for awhile. They are equally astounded when they are abandoned or shunned by spouses, friends, colleagues, the media, their fans, or audiences.

The root of this recurrent astonishment is the narcissist's perverse object constancy.

According to the great developmental psychologist, Margaret Mahler, between the ages of 24 and 36 months of life, the infant is finally able to cope with the mother's absence (by finding appropriate substitutes to her presence). It knows that she will return and trusts her to do so time and again.

The psychic image of the mother is internalized as a stable, reliable, and predictable object. As the infant's sense of time and verbal skills evolve, it becomes more immune to delayed gratification and tolerant of inevitable separation.

Piaget, the renowned child psychologist, concurred with Mahler and coined the term "object constancy" to describe the dynamics she observed.

As opposed to Mahler, Daniel Stern, another prominent psychoanalyst, proposes that the child is born with a sense of Self:

"Infants begin to experience a sense of an emergent self from birth. They are pre-designed to be aware of self - organising processes. They never experience a period of total self / other undifferentiation. There is no confusion of self and other in the beginning or at any point during infancy.

They are pre-designed to be selectively responsive to external social events and never experience an autistic like phase.

During the period of 2 - 6 months the infant consolidates the core sense of self as a separate, cohesive, bounded, physical unit with a sense of their own agency, affectivity and continuity in time. There is no symbiotic like phase. In fact the subjective experiences of union with another can occur only after a core self and a core other exists."

But even Stern accepts the existence of a distinct and separate "other" versus the nascent "self".

 

Pathological narcissism is a reaction to deficient bonding and dysfunctional attachment (Bowlby). Object relations in narcissists are infantile and chaotic (Winnicott, Guntrip). Many narcissists have no psychological-object constancy at all. In other words, many of them do not feel that other people are benign, reliable, helpful, constant, predictable, and trustworthy.

To compensate for this lack in ability (or willingness) to relate to real, live people, the narcissist invents and molds substitute-objects or surrogate-objects.

These are mental representations of meaningful or significant others (Sources of Narcissistic Supply). They have little or nothing to do with reality. These imagoes - images - are confabulations, works of fiction. They respond to the narcissist's needs and fears - and do not correspond to the persons they purport to stand for.

The narcissist internalizes these pliable representations, manipulates them, and interacts with them - not with the originals. The narcissist is entirely immersed in his world, talking to these "figurines", arguing with these substitutes, contracting with these surrogates, being admired by them.

Hence his dismay when confronted with real people, their needs, feelings, preferences, and choices.

Thus, the typical narcissist refrains from any meaningful discourse with his spouse and children, friends and colleagues. Instead, he spins a narrative in which these people - represented by mental avatars - admire him, find him fascinating, fervently wish to oblige him, love him, or fear him.

These "avatars" have little or nothing to do with the way his kin and kith REALLY feel about him. The protagonists in the narcissist's yarns do not incorporate veritable data about his wife, or offspring, or colleagues, or friends. They are mere projections of the narcissist's inner world. Thus, when the narcissist faces the real thing - he refuses to believe and accept the facts:

"My wife has always been so cooperative - whatever happened to her lately?"

(She was never cooperative - she was subservient or frightened into submission. But the narcissist didn't notice because he never actually "saw her".)

"My son always wanted to follow in my footsteps - I don't know what possesses him!"

(The narcissist's poor son never wanted to be a lawyer or a doctor. He always dreamed of being an actor or an artist. But the narcissist was not aware of it.)

"My friends used to listen to my stories enraptured - I have no idea why they no longer do so!"

(At first, his friends politely listened to the narcissist's interminable rants and ravings. Finally, they dropped from his social circle, one by one.)

"I was admired by the media - now I am constantly ignored!"

(At first, an object of derision and morbid fascination, the novelty wore off and the media moved on to other narcissists.)

Puzzled, hurt, and clueless - the narcissist withdraws further and further with every narcissistic injury. Finally, he is forced into choosing the delusional way out.

 

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next: Back to La-la Land Giving the Narcissist a Second Chance

• Watch the video on The Narcissist's Second Chance

Relationships with narcissists peter out slowly and tortuously. Narcissists do not provide closure.They stalk. They cajole, beg, promise, persuade, and, ultimately, succeed in doing the impossible yet again: sweep you off your feet, though you know better than to succumb to their spurious and superficial charms.

So, you go back to your "relationship" and hope for a better ending. You walk on eggshells. You become the epitome of submissiveness, a perfect Source of Narcissistic Supply, the ideal mate or spouse or partner or colleague. You keep your fingers crossed.

But how does the narcissist react to the resurrection of the bond?

It depends on whether you have re-entered the liaison from a position or strength - or of vulnerability and weakness.

The narcissist casts all interactions with other people in terms of conflicts or competitions to be won. He does not regard you as a partner - but as an adversary to be subjugated and defeated. Thus, as far as he is concerned, your return to the fold is a triumph, proof of his superiority and irresistibility.

If he perceives you as autonomous, dangerously independent, and capable of bailing out and abandoning him - the narcissist acts the part of the sensitive, loving, compassionate, and empathic counterpart. Narcissists respect strength, they are awed by it. As long as you maintain a "no nonsense" attitude, placing the narcissist on probation, he is likely to behave himself.

If, on the other hand, you have resumed contact because you have capitulated to his threats or because you are manifestly dependent on him financially or emotionally - the narcissist will pounce on your frailty and exploit your fragility to the maximum. Following a perfunctory honeymoon, he will immediately seek to control and abuse you.

 

In both cases, the narcissist's thespian reserves are exhausted and his true nature and feelings emerge. The facade crumbles and beneath it lurks the same old heartless falsity that is the narcissist. His gleeful smugness at having bent you to his wishes and rules, his all-consuming sense of entitlement, his sexual depravity, his aggression, pathological envy, and rage - all erupt uncontrollably.

The prognosis for the renewed affair is far worse if it follows a lengthy separation in which you have made a life for yourself with your own interests, pursuits, set of friends, needs, wishes, plans, and obligations, independent of your narcissistic ex and unrelated to him.

The narcissist cannot countenance your separateness. To him, you are a mere instrument of gratification or an extension of his bloated False Self. He resents your pecuniary wherewithal, is insanely jealous of your friends, refuses to accept your preferences or compromise his own, in envious and dismissive of your accomplishments.

Ultimately, the very fact that you have survived without his constant presence seems to deny him his much-needed Narcissistic Supply. He rides the inevitable cycle of idealisation and devaluation. He berates you, humiliates you publicly, threatens you, destabilises you by behaving unpredictably, fosters ambient abuse, and uses others to intimidate and humble you ("abuse by proxy").

You are then faced with a tough choice:

To leave again and give up all the emotional and financial investments that went into your attempt to resurrect the relationship - or to go on trying, subject to daily abuse and worse?

It is a well-known landscape. You have been here before. But this familiarity doesn't make it less nightmarish.

 

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next: The Cult of the Narcissist

If you're depressed despite normal efforts to treat your depression symptoms, a physical source of the depression should be considered.

Depression is a universally understood condition of sadness and despondency. Life has lost its luster and gloom prevails. Some sadness is an inherent part of weathering life's misfortunes. People normally recover from such low points and carry on. Other conditions of sadness may require lifestyle changes such as resolving a rocky marriage, dropping bad habits, or removing oppressive factors from one's life. Still other situations may require the counsel of a good friend or priest or minister - someone one can trust and discuss his or her troubles with.

However, sometimes people don't recover from life's setbacks. Or they become depressed over insignificant matters or for no reason at all. The feelings of sadness may simply slow them down or can debilitate them to the point where they weep continuously, cannot function in life, or may consider suicide

Looking for a Medical Cause for Depression

When a person remains depressed despite normal efforts to treat the depression, a physical source of the depression should be considered. This is particularly true in the case of debilitating or suicidal depression.

Physiological causes of depression are so common, in fact, that The American Assn. of Clinical Endocrinologists states, "The diagnosis of subclinical [without obvious signs] or clinical hypothyroidism must be considered in every patient with depression."

Physical sources of depression include:

• Nutritional deficiencies
• Lack of exercise
• Hypothyroidism
• Hyperthyroidism
• Fibromyalgia
• Candida (yeast infection)
• Poor adrenal function
• Other hormonal disorders including:
  • Cushing's Disease (excessive pituitary hormone production)
  • Addison's disease (low adrenal function)
  • High levels of parathyroid hormone
  • Low levels of pituitary hormones
• Hypoglycemia
• Food Allergies
• Heavy metals (such as mercury, lead, aluminum, cadmium, and thallium)
• Selenium toxicity
• Premenstrual syndrome
• Sleep disturbances
• Infections including:
  • AIDS
  • Influenza
  • Mononucleosis
  • Syphilis (late stage)
  • Tuberculosis
  • Viral hepatitis
  • Viral pneumonia
• Medical conditions including:
  • Heart problems
  • Lung disease
  • Diabetes
  • Multiple sclerosis
  • Rheumatoid arthritis
  • Chronic pain
  • Chronic inflammation
  • Cancer
  • Brain tumors
  • Head injury
  • Multiple sclerosis
  • Parkinson's disease
  • Stroke
  • Temporal lope epilepsy
  • Systemic lupus erythematosus
  • Liver disease
• Drugs including:
  • Tranquilizers and sedatives
  • Antipsychotic drugs
  • Amphetamines (withdrawal from)
  • Antihistamines
  • Beta-blockers
  • High blood pressure medications
  • Birth control pills
  • Anti-inflammatory agents
  • Corticosteroids (adrenal hormone agents
  • Cimetidine
  • Cycloserine (an antibiotic)
  • Indomethacin
  • Reserpine
  • Vinblastine
  • Vincristine

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The Importance of Exercise in Treating Depression Symptoms

A Duke University study points out the remarkable connection between depression and one's physical condition. A group of 156 elderly patients diagnosed with major depression were divided into three groups, including one whose only treatment was a brisk 30-minute walk or jog three times a week. After 16 weeks, 60.4% no longer met the criteria for a diagnosis of depression.

Duke University psychologist James Blumenthal published the results of his team's study in the Oct. 25, 1, issue of The Archives of Internal Medicine. "One of the conclusions we can draw from this," he said, "is that exercise may be just as effective as medication and may be a better alternative for certain patients.

Daily 30-minute walks are even better and faster-acting, according to a German study.

Nutritional Deficiencies As A Cause of Depression

A particular note should be made about nutritional deficiencies and their relationship to depression. According to the Encyclopedia of Natural Medicine, "A deficiency of any single nutrient can alter brain function and lead to depression, anxiety, and other mental disorders."

However, some nutritional deficiencies are more common than others.

Vitamin B₂ deficiency is not common but can be created, ironically enough, by certain antidepressant drugs called tricyclics>. This can lead to further depression.

Vitamin B₆ is commonly very low in people who are depressed. This is particularly true in people taking birth control pills or estrogen in other forms. Those who are deficient in this vitamin normally do well with B₆ supplements.

Vitamin B₉ is called folic acid and is the most common deficient vitamin. Studies have shown that 31-35% of depressed patients have folic acid deficiencies. The most common symptom of folic acid deficiency is, in fact, depression.

Vitamin B₁₂ works along with folic acid in a number of biochemical functions. Deficiency becomes more common over the age of 50. One study showed deficiency rates as follows: Between the ages of 60-69, 24%, ages 70-79, 32%, over 80, nearly 40%. Supplementation of folic acid and B₁₂ often produces dramatic results in people who are depressed because of deficiencies.

Vitamin C deficiency is not particularly common but can occur people with very poor diets or nonexistent intake of fruits and vegetables. Symptoms of a mild deficiency include fatigue, irritableness and "the blues." If not remedied, scurvy symptoms can develop.

Magnesium is a critical mineral used in sending messages along your nerves. By some estimates nearly 75% of Americans do not take in enough to meet minimum requirements. Magnesium deficiencies can result in muscle weakness and irritability.

Another deficiency can occur with amino acids, the building blocks that make up protein. One form of the amino acid methionine is called SAMe (S-adenosylmethionine). SAMe levels tend to be low in the elderly and in depressed people. SAMe supplements have been effective in alleviating depression. A common dosage of SAMe is to start with 1,600 mg a day - either 800 mg twice a day or 400 mg four times a day - for about two or three weeks, or until you start to feel the antidepressant effects. Then one gradually reduces the dosage to 800 mg or even 400-mg a day, based on one's depressive symptoms.

Tryptophan is another amino acid that affects depression. Many depressed people have low tryptophan levels. One supplement, 5-HTP, which contains a form of tryptophan, has been shown in numerous studies to be as effective as modern antidepressants (such as Prozac, , and Paxil) for less cost and with fewer and much milder side effects. A standard dosage of 5-HTP is 50-100 mg once or twice a day with meals.

Low fat diets can lead to depression if they are deficient in a specific fatty acid (the building block of fats) called omega-3. Omega-3 is common in certain seeds, canola oil, soybean oil, egg yolks, and cold-water ocean fish. Population studies in different countries have shown that decreased consumption of omega-3's correlates with increased rates of depression.

More information on the role of nutritional problems in depression.

Thyroid Problems Can Result in Depression

A study reported in the Feb. 28, 2000, issue of Archive of Internal Medicine revealed that, of more than 25,000 people given blood tests, 9.9% had thyroid problems they probably did not know about. Another 5.9% were being treated for thyroid problems. This means nearly 16% of the population had thyroid dysfunction. Depression is a common symptom of poor thyroid function.

Dr. Broda Barnes, author of Hypothyroidism: The Unsuspected Illness, estimated that as many as 40% of the public may have low thyroid function, much of which is not detectable by modern blood tests. He recommended a simple and more reliable body temperature test.

Dr. Barnes' self thyroid test, discussed in his book, is as follows: You take an old-fashioned mercury-type thermometer and shake it down and put it on the nightstand before going to bed (if you're going to do it on yourself - on someone else just shake it down below 95 degrees before you take the temp). In the morning on awakening, before arising or moving around, the person puts the thermometer snugly in his armpit for 10 minutes by the clock. If the temp is below 97.8, the person likely needs thyroid or, if they're on thyroid, they need more thyroid. The temp should be between 97.8-98.2. Dr. Barnes recommended Armour Thyroid which is natural. Most doctors don't use this test but alternative doctors do. You can get a list of them who will prescribe thyroid based on this test at the Broda Barnes Foundation at 203 261-2101.

A Note on Depression in the Elderly

A staggering number of the elderly are on antidepressant drugs because depression is rampant among the aged. While many factors can be involved - loss of loved ones, poor health, retirement, etc. - a primary cause of this epidemic is nutritional deficiencies. Not only do they eat poorly but they have trouble absorbing a number of vitamins (e.g. B₁₂) as their age increases.

Thyroid problems, as determined by blood tests, have been estimated to affect up to 20% of women over 60.

Lack of exercise, a common problem with seniors, can, as noted above, be a major source of depression.

Nutritional deficiencies, thyroid disorders, and enough exercise should be a top concern in any population of elderly people with "depression."

Summary

A host of physical ailments can lead to a condition of sadness, tearfulness, and hopelessness. These should be suspected and looked for in anyone who is depressed and has a known physical ailment or who experiences severe or unresolving depression.

next: Co-Occurrence of Depression With Cancer
~ depression library articles
~ all articles on depression

The following ADHD myths and factual responses have been collected from rebuttals to media articles about ADHD.

Myth #1: ADHD is a "phantom disorder".

FACT: The existence of a neurobiological disorder is not an issue to be decided by the media through public debate, but rather as a matter of scientific research. Scientific studies spanning 95 years summarized in the professional writings of Dr. Russell Barkley, Dr. Sam Goldstein, and others have consistently identified a group of individuals who have trouble with concentration, impulse control, and in some cases, hyperactivity. Although the name given to this group of individuals, our understanding of them, and the estimated prevalence of this group has changed a number of times over the past six decades, the symptoms have consistently been found to cluster together. Currently called Attention Deficit Hyperactivity Disorder, this syndrome has been recognized as a disability by the courts, the United States Department of Education, the Office for Civil Rights, the United States Congress, the National Institutes of Health, and all major professional medical, psychiatric, psychological, and educational associations.

Myth #2: Ritalin is like cocaine, and the failure to give youngsters drug holidays from Ritalin causes them to develop psychosis.

FACT: Methylphenidate (Ritalin) is a medically prescribed stimulant medication that is chemically different from cocaine. The therapeutic use of methylphenidate does NOT CAUSE addiction or dependence, and does not lead to psychosis. Some children have such severe ADD symptoms that it can be dangerous for them to have a medication holiday, for example a child who is so hyper and impulsive he'll run into traffic withoug stopping to look first. Hallucinations are an extremely rare side-effect of methylphenidate, and their occurrence has nothing to do with the presence or absence of medication holidays. Individuals with ADHD who are properly treated with stimulant medication such as Ritalin have a lower risk of developing problems with alcohol and other drugs than the general population. More importantly, fifty years of research has repeatedly shown that children, adolescents, and adults with ADHD safely benefit from treatment with methylphenidate.

Myth #3: No study has ever demonstrated that taking stimulant medications can cause any lasting behavioral or educational benefit to ADHD children.

FACT: Research has repeatedly shown that children, adolescents, and adults with ADHD benefit from therapeutic treatment with stimulant medications, which has been used safely and studied for more than 50 years. For example, The New York Times reviewed a recent study from Sweden showing positive long- term effects of stimulant medication therapy on children with ADHD. Readers interested in more studies on the effectiveness of ADHD medication should consult the professional writings of Dr. Russell Barkley, Drs. Gabrielle Weiss and Lily Hechtman, and Dr. Joseph Biederman.

Myth #4: ADHD kids are learning to make excuses, rather than take responsibility for their actions.

FACT: Therapists, educators, and physicians routinely teach children that ADHD is a challenge, not an excuse. Medication corrects their underlying chemical imbalance, giving them a fair chance of facing the challenges of growing up to become productive citizens. Accommodations for the disabled, as mandated by federal and state laws, are not ways of excusing them from meeting society's responsibilities, but rather make it possible for them to compete on a leveled playing field.

Myth #5: ADHD is basically due to bad parenting and lack of discipline, and all that ADHD children really need is old-fashioned discipline, not any of these phony therapies.

FACT: There are still some parent-bashers around who believe the century-old anachronism that child misbehavior is always a moral problem of the "bad child." Under this model, the treatment has been to "beat the Devil out of the child." Fortunately, most of us are more enlightened today. A body of family interaction research conducted by Dr. Russell Barkley and others has unequivocally demonstrated that simply providing more discipline without any other interventions worsens rather than improves the behavior of children with ADHD. One can't make a paraplegic walk by applying discipline. Similarly, one can't make a child with a biologically-based lack of self-control act better by simply applying discipline alone.

Myth #6: Ritalin is unsafe, causing serious weight loss, mood swings, Tourette's syndrome, and sudden, unexplained deaths.

FACT: Research has repeatedly shown that children, adolescents, and adults with ADHD benefit from treatment with Ritalin (also known as methylphenidate), which has been safely used for approximately 50 years. There are NO published cases of deaths from overdoses of Ritalin; if you take too much Ritalin, you will feel terrible and act strange for a few hours, but you will not die. This cannot be said about many other medications. The unexplained deaths cited in some articles are from a combination of Ritalin and other drugs, not from Ritalin alone. Further investigation of those cases has revealed that most of the children had unusual medical problems which contributed to their deaths. It is true that many children experience appetite loss, and some moodiness or "rebound effect" when Ritalin wears off. A very small number of children may show some temporary tics, but these do not become permanent. Ritalin does not permanently alter growth, and usually does not result in weight loss. Ritalin does not cause Tourette's syndrome, rather many youngsters with Tourette's also have ADHD. In some cases, Ritalin even leads to an improvement of the of tics in children who have ADHD and Tourette's.

Myth #7: Teachers around the country routinely push pills on any students who are even a little inattentive or overactive.

FACT: Teachers are well-meaning individuals who have the best interests of their students in mind. When they see students who are struggling to pay attention and concentrate, it is their responsibility to bring this to parents' attention, so parents can take appropriate action. The majority of teachers do not simply push pills- they provide information so that parents can seek out appropriate diagnostic help. We do agree with the position that teachers should not diagnose ADHD. However, being on the front lines with children, they collect information, raise the suspicion of ADHD, and bring the information to the attention of parents, who then need to have a full evaluation conducted outside the school. The symptoms of ADHD must be present in school and at home before a diagnosis is made; teachers do not have access to sufficient information about the child's functioning to make a diagnosis of ADHD or for that matter to make any kind of medical diagnosis.

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Myth #8: Efforts by teachers to help children who have attention problems can make more of a difference than medications such as Ritalin.

FACT: It would be nice if this were true, but recent scientific evidence from the multi-modal treatment trials sponsored by the National Institute of Mental Health suggests it is a myth. In these studies, stimulant medication alone was compared to stimulant medication plus a multi-modal psychological and educational treatment, as treatments for children with ADHD. The scientists found that the multi-modal treatment plus the medication was not much better than the medication alone. Teachers and therapists need to continue to do everything they can to help individuals with ADHD, but we need to realize that if we don't also alter the biological factors that affect ADHD, we won't see much change.

Myth #9: CH.A.D.D. is supported by drug companies, and along with many professionals, are simply in this field to make a quick buck on ADHD.

FACT: Thousands of parents and professionals volunteer countless hours daily to over 600 chapters of CH.A.D.D. around the U.S. and Canada on behalf of individuals with ADHD. CH.A.D.D. is very open about disclosing any contributions from drug companies. These contributions only support the organization's national conference, which consists of a series of educational presentations, 95% of which are on topics other than medications. None of the local chapters receive any of this money. It is a disgrace to impugn the honesty and efforts of all of these dedicated volunteers. CH.A.D.D. supports all known effective treatments for ADHD, including medication, and takes positions against unproven and costly remedies.

Myth #10: It is not possible to accurately diagnose ADD or ADHD in children or adults.

FACT: Although scientists have not yet developed a single medical test for diagnosing ADHD, clear-cut clinical diagnostic criteria have been developed, researched, and refined over several decades. The current generally accepted diagnostic criteria for ADHD are listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) published by the American Psychiatric Association (1995). Using these criteria and multiple methods to collect comprehensive information from multiple informants, ADHD can be reliably diagnosed in children and adults.

Myth #11: Children outgrow ADD or ADHD.

FACT: ADHD is not found just in children. We have learned from a number of excellent follow-up studies conducted over the past few decades that ADHD often lasts a lifetime. Over 70% of children diagnosed as having ADHD will continue to manifest the full clinical syndrome in adolescence, and 15-50% will continue to manifest the full clinical syndrome in adulthood. If untreated, individuals with ADHD may develop a variety of secondary problems as they move through life, including depression, anxiety, substance abuse, academic failure, vocational problems, marital discord, and emotional distress. If properly treated, most individuals with ADHD live productive lives and cope reasonably well with their symptoms.

Myth #12: Methylphenidate prescriptions in the U.S. have increased 600%.

FACT: The production quotas for methylphenidate increased 6-fold; however that DEA production quota is a gross estimate based on a number of factors, including FDA estimates of need, drug inventories at hand, EXPORTS, and industry sales expectations. One cannot conclude that a 6-fold increase in production quotas translates to a 6-fold increase in the use of methylphenidate among U.S. children any more than one should conclude that Americans eat 6 times more bread because U.S. wheat production increased 6-fold even though much of the grain is stored for future use and export to countries that have no wheat production. Further, of the approximately 3.5 million children who meet the criteria for ADHD, only about 50% of them are diagnosed and have stimulant medication included in their treatment plan. The estimated number of children taking methylphenidate for ADD suggested in some media stories fails to note that methylphenidate is also prescribed for adults who have ADHD, people with narcolepsy, and geriatric patients who receive considerable benefit from it for certain conditions associated with old age such as memory functioning. (see Pediatrics, December 1996, Vol. 98, No. 6)

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Common Myths About ADHD

From a UK Perspective: With thanks to Michelle Richardson (ADHD Nurse), Ryegate Children's Centre.

Myth:

Children naturally outgrow ADHD.

Fact:

In some children, the overactive behavior of ADHD decreases during the teen years. But inattention often becomes more challenging during early high school years when students must organize homework assignments and complete complex projects. Some children do not experience any symptoms of ADHD in adulthood, while some experience fewer symptoms. Others have no change in their symptoms from childhood to adulthood.

Myth:

ADHD is caused by too much white sugar, preservatives, and other artificial food additives. Removing these things from a child's diet can cure the disorder.

Fact:

Studies have shown that very few children with ADHD are helped by special diets. Most of the children who do respond to diets are very young or have food allergies. Sugar and food additives have been ruled out as causes for ADHD.

Myth:

Poor parenting is responsible for ADHD behaviors in children.

Fact:

ADHD is a physical disorder caused by differences in how the child's brain works. Anxiety-producing factors, such as family conflicts or disruptions, can aggravate the disorder, but they do not cause it.

Common Myths About ADHD Stimulant Medications

Myth:

Children treated with stimulant medications will become addicted or will be more likely to abuse other drugs.

Fact:

Stimulant medications are not addictive when used as directed. Studies have shown adequate treatment of ADHD may reduce the risk of substance abuse.

Myth:

Children must be taken off stimulant medications by the time they become teenagers.

Fact:

About 80% of children who need medications will need them as teenagers.

Myth:

Stimulant medications stunt growth.

Fact:

While stimulant medications may cause an initial, mild slowing of growth, this effect is temporary. Children treated with ADHD stimulant medications ultimately reach their normal height.

Myth:

Children build up a tolerance to stimulant medication. They end up needing more and more of it.

Fact:

While your child's medication may need to be adjusted occasionally, there's no evidence that children become tolerant to medication or require more of it to be effective.

Other contributors to this article: Becky Booth, Wilma Fellman, LPC, Judy Greenbaum, Ph.D., Terry Matlen, ACSW, Geraldine Markel, Ph.D., Howard Morris, Arthur L. Robin, Ph.D., Angela Tzelepis, Ph.D.

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Brand Names: NovoLog, NovoLog FlexPen, NovoLog PenFill
Generic Name: insulin aspart

Pronounced:IN su lin AS part

NovoLog Insulin Aspart, full prescribing information

What is NovoLog and what is it used for?

NovoLog contains insulin aspart. Insulin is a hormone that works by lowering levels of glucose (sugar) in the blood. Insulin aspart is a fast-acting form of insulin.

NovoLog is used to treat type 1 (insulin-dependent) diabetes in adults and children who are at least 2 years old. It is usually given together with a long-acting insulin.

NovoLog may also be used for other purposes not listed.

Important information about NovoLog

NovoLog is a fast-acting insulin that begins to work very quickly. After using it, you should eat a meal within 5 to 10 minutes.

Take care to keep your blood sugar from getting too low, causing hypoglycemia. Symptoms of low blood sugar may include headache, nausea, hunger, confusion, drowsiness, weakness, dizziness, blurred vision, fast heartbeat, sweating, tremor, or trouble concentrating. Carry a piece of non-dietetic hard candy or glucose tablets with you in case you have low blood sugar. Also be sure your family and close friends know how to help you in an emergency.

Also watch for signs of blood sugar that is too high (hyperglycemia). These symptoms include increased thirst, loss of appetite, fruity breath odor, increased urination, nausea, vomiting, drowsiness, dry skin, and dry mouth. Check your blood sugar levels and ask your doctor how to adjust your insulin doses if needed

Never share an injection pen or cartridge with another person. Sharing injection pens or cartridges can allow disease such as hepatitis or HIV to pass from one person to another.

Before using NovoLog

Do not use NovoLog if you are allergic to insulin, or if you are having an episode of hypoglycemia (low blood sugar).

Before using NovoLog, tell your doctor if you have liver or kidney disease.

Tell your doctor about all other medications you use, including any oral (taken by mouth) diabetes medications.

NovoLog is only part of a complete program of treatment that may also include diet, exercise, weight control, foot care, eye care, dental care, and testing your blood sugar. Follow your diet, medication, and exercise routines very closely. Changing any of these factors can affect your blood sugar levels.

Your doctor will need to check your progress on a regular basis. Do not miss any scheduled appointments.

FDA pregnancy category B. NovoLog is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether NovoLog passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

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How should I use NovoLog?

Use NovoLog exactly as it was prescribed for you. Do not use it in larger amounts or for longer than recommended by your doctor. Follow the directions on your prescription label.

NovoLog is given as an injection (shot) under your skin, using a needle and syringe or an insulin pump. Your doctor, nurse, or pharmacist will give you specific instructions on how and where to inject this medicine. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles and syringes.

NovoLog is a fast-acting medication that begins to work very quickly. After using NovoLog, you should eat a meal within 5 to 10 minutes.

NovoLog should be thin, clear, and colorless. Do not use the medication if it has looks cloudy, has changed colors, or has any particles in it. Call your doctor for a new prescription.

Choose a different place in your injection skin area each time you use NovoLog. Do not inject into the same place two times in a row.

If you use this medication with an insulin pump, do not mix or dilute NovoLog with any other insulin. Call your doctor at once if you think your infusion pump is not working properly.

Use each disposable needle only one time. Throw away used needles in a puncture-proof container (ask your pharmacist where you can get one and how to dispose of it). Keep this container out of the reach of children and pets.

Some insulin needles can be used more than once, depending on needle brand and type. But a reused needle must be properly cleaned, recapped, and inspected for bending or breakage. Reusing needles also increases your risk of infection. Ask your doctor or pharmacist whether you are able to reuse your insulin needles.

Infusion pump tubing, catheters, and the needle location on your skin should be changed every 48 hours. Throw away any medication leftover in the reservoir.

Never share an injection pen or cartridge with another person. Sharing injection pens or cartridges can allow disease such as hepatitis or HIV to pass from one person to another.

Check your blood sugar carefully during a time of stress or illness, if you travel, exercise more than usual, or skip meals. These things can affect your glucose levels and your insulin dose needs may also change.

Watch for signs of blood sugar that is too high (hyperglycemia). These symptoms include increased thirst, loss of appetite, fruity breath odor, increased urination, nausea, vomiting, drowsiness, dry skin, and dry mouth. Check your blood sugar levels and ask your doctor how to adjust your insulin doses if needed.

Ask your doctor how to adjust your NovoLog dose if needed. Do not change your dose without first talking to your doctor. Carry an ID card or wear a medical alert bracelet stating that you have diabetes, in case of emergency. Any doctor, dentist, or emergency medical care provider who treats you should know that you are diabetic.

Storing unopened vials, cartridges, or injection pens: Keep in the carton and store in a refrigerator, protected from light. Throw away any insulin not used before the expiration date on the medicine label. Unopened vials, cartridges, or injection pens may also be stored at room temperature for up to 28 days, away from heat and bright light. Throw away any insulin not used within 28 days. Storing after your first use: Keep the "in-use" vials, cartridges, or injection pens at room temperature and use within 28 days. Do not refrigerate.

Do not freeze NovoLog, and throw away the medication if it has become frozen.

What happens if I miss a dose?

Since NovoLog is used before meals, you may not be on a timed dosing schedule. Whenever you use NovoLog, be sure to eat a meal within 5 to 10 minutes. Do not use extra NovoLog to make up a missed dose.

It is important to keep NovoLog on hand at all times. Get your prescription refilled before you run out of medicine completely.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine. An insulin overdose can cause life-threatening hypoglycemia.

Symptoms of severe hypoglycemia include extreme weakness, blurred vision, sweating, trouble speaking, tremors, stomach pain, confusion, seizure (convulsions), or coma.

What should I avoid while using NovoLog?

Do not change the brand of insulin aspart or syringe you are using without first talking to your doctor or pharmacist. Avoid drinking alcohol. Your blood sugar may become dangerously low if you drink alcohol while using NovoLog. Do not expose NovoLog to high heat. Throw the medication away if it becomes hotter than 98 degrees F.

NovoLog side effects

Get emergency medical help if you have any of these signs of insulin allergy: itching skin rash over the entire body, wheezing, trouble breathing, fast heart rate, sweating, or feeling like you might pass out.

Call your doctor if you have a serious side effect such as:

• swelling in your hands or feet; or
• low potassium (confusion, uneven heart rate, extreme thirst, increased urination, leg discomfort, muscle weakness or limp feeling).

Hypoglycemia, or low blood sugar, is the most common side effect of NovoLog. Symptoms of low blood sugar may include headache, nausea, hunger, confusion, drowsiness, weakness, dizziness, blurred vision, fast heartbeat, sweating, tremor, trouble concentrating, confusion, or seizure (convulsions). Watch for signs of low blood sugar. Carry a piece of non-dietetic hard candy or glucose tablets with you in case you have low blood sugar.

NovoLog can also cause hypokalemia (low potassium levels in the blood). Call your doctor at once if you have symptoms such as dry mouth, increased thirst, increased urination, uneven heartbeats, muscle pain or weakness, leg pain or discomfort, or confusion.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect NovoLog?

Using certain medicines can make it harder for you to tell when you have low blood sugar. Tell your doctor if you use any of the following:

• albuterol (Proventil, Ventolin);
• clonidine (Catapres);
• reserpine;
• guanethidine (Ismelin); or
• a beta-blocker such as atenolol (Tenormin), bisoprolol (Zebeta), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal, InnoPran), timolol (Blocadren) and others.

There are many other medicines that can increase or decrease the effects of NovoLog on lowering your blood sugar. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor. Keep a list with you of all the medicines you use and show this list to any doctor or other healthcare provider who treats you.

Where can I get more information?

• Your pharmacist can provide more information about NovoLog.
• Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use NovoLog only for the indication prescribed.

last updated 10/2007

NovoLog Insulin Aspart, full prescribing information

Detailed Info on Signs, Symptoms, Causes, Treatments of Diabetes

back to: Browse all Medications for Diabetes

Learn about the types of music therapy and how music therapy is used in the treatment of various psychiatric disorders.

Music has soothed the souls of human beings for ages. It also has helped people recover from ailments since ancient times. Today, there is a widespread interest in the use of music therapy in treating psychiatric disorders. This article describes the various types of music therapy in use today and also offers insight into how music therapy can be incorporated into the management of psychiatric disorders and as an element of psychotherapy. (Altern Ther Health Med. 2004;11(6):52-53.)

Music is an ancient art that has soothed minds for centuries. Music helps people regain inner peace and is the voice that binds people together. It has been used to treat the sick since ancient times and frequently is used to cure depression. Songs offer people solace in adversity and joy in prosperity. They are sung on birthdays and even at the death of a loved one. Music is accepted as a universal means to express one's emotions. It was an essential component of ancient healing. A drum was beaten when treatment was offered to a patient, and a successful recovery was announced with trumpets.¹ Great philosophers have assigned important roles to music in the expression of their emotions and teachings.² Music was used to treat psychiatric illness in ancient Greek and Roman cultures.³ More recently, reports have indicated the usefulness of music therapy in managing psychiatric disorders.⁴ Music has been used in psychosis and neurosis and now is being used in addressing organic disorders such as dementia.^5,6 There is a wealth of literature on music therapy in all fields, but sadly, renowned psychiatry textbooks fail to mention music therapy as a treatment modality, and many contain no information about it at all. The purpose of this article is to offer insight into the various types of music therapy and review some of the literature on the use of music therapy in psychiatry.

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Background Music Therapy

Background music therapy is a form of therapy in which music is heard for an average of 8 to 12 hours per day as part of a hospital routine. It is transmitted via audiotapes and radio. The aim of this therapy is to create a calm environment amid the chaos in the hospital. This plays a useful role in allaying anxiety and relaxing patients in critical care.⁷

Contemplative Music

Contemplative music therapy helps patients appreciate the significance of music and art in general. Before music is played for patients, they are given a biography of the composer and other details about the music. This may be administered in a group setting or individually. This facilitates the uncovering of morbid experiences, termed communicative music therapy, and causes emotional enlivenment, termed reactive musical therapy. In contemplative therapy, both the music that soothes as well as the group setting and the group therapy used bring out morbid experiences of the patients. This therapy also aims to soothe agitation and alleviate sadness.⁸

Combined Music

In combined music therapy, music therapy is used in conjunction with other therapeutic procedures. Unlike background music therapy, it calls for the patient to select musical compositions that enhance therapeutic outcome and suit the patient. Sometimes in this form of music therapy, hypnosis is conducted while the subject listens to the music. This music is often accompanied by suggestion under hypnosis that improves the therapeutic outcome. In combined music therapy, the patient is asked to select music he likes as it will soothe him better, and here music is used as an adjuvant to various other therapies. The patient may or may not like the music chosen by the therapist and hence he is given the choice so that therapy is adhered to. This form of music therapy has been used in combination with cerebral electrosleep therapy and behavior therapy methods such as autogenic training.⁹

Executive Music

Executive music therapy consists of individual or group singing and playing musical instruments. Patients with long hospital stays are the best candidates for this form of therapy. It strengthens patients' self-confidence and their feelings of worth among others. Executive music therapy can be incorporated into the occupational therapy routine.¹⁰

Executive Iatromusic

In executive iatromusic therapy, a musician performs in children's psychiatric units. This form of therapy frequently is used in managing emotionally disturbed, mentally retarded, and dyslexic children.^11-13

Creative Music

In creative music therapy, patients write songs, compose music, and play instruments as a form of catharsis. Grief over a deceased loved one, oppression, and repressed feelings and fears often are well expressed in music and song.¹⁴

References

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The Use of Music Therapy in Psychiatric Disorders

Music therapy has been used effectively in both adults and children with psychiatric disorders. It has been used to modify the behavior of children with autism and pervasive developmental disorders with moderate success.¹⁵ It has been used to reduce agitation in patients with dementia by soothing them and eliminating the social isolation of these patients.^16,17 Music therapy has been used in patients with Parkinson's disease to improve motor skills and emotional problems.¹⁸ There is ample evidence of the usefulness of music therapy in alleviating grief and in combating bouts of depression.^19-21

Conclusions

Music no doubt plays a pivotal role in the lives of human beings. Incorporating music therapy into regular therapy programs for psychiatric disorders can help speed recovery and also help make therapy a more positive experience. Music therapy is a valuable but relatively unexplored asset in the field of psychiatry and psychotherapy.

References

1. Radin P. Music and medicine among primitive peoples. In: Schullian DM, Schoen M, eds. Music and Medicine. Freeport, NY: Books for Libraries; 1971:3-24.

2. The Internet Encyclopedia of Philosophy. Xunzi (Hsün Tzu). Available at: http://www.iep.utm.edu/x/xunzi.htm. Accessed Oct 19, 2005.

3. Meinecke, B. Music and medicine in classical antiquity. In: Schullian DM, Schoen M, eds. Music and Medicine. Freeport, NY: Books for Libraries; 1971:47-95.

4. Covington H. Therapeutic music for patients with psychiatric disorders. Holist Nurs Pract. 2001;15:59-69.

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5. Brotons M, Marti P. Music therapy with Alzheimer's patients and their caregivers: A pilot project. J Music Ther. 2003;40:138-150.

6. Gregory D. Music listening for maintaining attention of older adults with cognitive impairments. J Music Ther. 2002;39:244-264.

7. Richards K, Nagel C, Markie M, Elwell J, Barone C. Use of complementary and alternative therapies to promote sleep in critically ill patients. Crit Care Nurs Clin North Am. 2003;15:329-340.

8. Schmolz A. Zur Methode der Einzelmusiktherapie. In Musiktherapie by von Kohler & Jena, G. 1971, Pp 83-88.

9. Schultz LH. Autogenic Training. Stuttgart, Thieme, 1960.

10. Keen AW. Using Music as therapy tool to motivate troubled adolescents. Soc Work Health Care. 2004; 39: 361-373.

11. Rainey Perry MM. Relating improvisational music therapy with severely and multiply disabled children to communication development. J Music Ther. 2003;40:227-246.

12. Overy, K. Dyslexia and music. From timing deficits to musical interventions. Ann NY Acad Sci. 2003;999:497-505.

13. Layman DL, Hussey DL, Laing SJ. Music therapy assessment for severely emotionally disturbed children: A pilot study. J Music Ther. 2002;39:164-187.

14. O'Callahn CC. Pain, music creativity and music therapy in palliative care. AM J Hsop Palliative Care. 1996;13(2):43-49.

15. Brownell MD. Musically adapted social stories to modify behavior in students with autism: Four case studies. J Music Ther. 2002;39:117-144.

16. Lou MF. The use of music to decrease agitated behaviour of the demented elderly: The state of the science. Scand J Caring Sci. 2001;15:165-173.

17. Gotell E, Brown S, Ekman SL. Caregiver singing and background music in dementia care. West J Nurs Res. 2002;24:195-216.

18. Pacchetti C, Mancini F, Aglieri R, Fundaro C, Martignoni E, Nappi, G. Active music therapy in Parkinson's disease: An integrative method for motor and emotional rehabilitation. Psychosom Med. 2000;62:386-393.

19. Smeijsters H, van Den Hurk J. Music therapy helping to work through grief and finding a personal identity. J Music Ther. 1999;36:222-252.

20. Ernst E, Rand JL, Stevinson C. Complementary therapies for depression: an overview. Arch Gen Psychiatry. 1998;55:1026-1032.

21. Lai YM. Effects of music listening on depressed women in Taiwan. Issues Ment Health Nurs. 1999;20:229-246.

back to: Alternative Medicine Home ~ Alternative Medicine Treatments

Lindsey Kent MD PhD
Developmental Psychiatry Section, Douglas House 18 Trumpington Road, University of Cambridge, Cambridge, CB2 2AH, UK mailto:lk255@cam.ac.uk
Current Psychiatry Reports 2004, 6:143-148 (published 1 April 2004)

Abstract

In the past few years, interest in the molecular genetics of attention deficit hyperactivity disorder (ADHD) has grown enormously, with many groups searching for susceptibility genes, often through large collaborative efforts facilitated by the International ADHD Genetics Consortium. Association findings for several candidate genes within the dopaminergic system, the DRD4 and DRD5 receptor genes and the dopamine transporter gene, DAT1, have been well replicated, and the first of several ongoing genome linkage scan study results have been published. Current challenges in this field are to identify the actual functional variant(s) in these genes conferring susceptibility and other genetic and environmental risk factors for ADHD.

Lindsey Kent , MBChB., PhD. MRC Psych
University Lecturer
I am a child and adolescent psychiatrist with research interests in the biological underpinnings of Attention Deficit Hyperactivity Disorder and related conditions. My particular interests are concerned with the genetics of hyperactivity and attention disorders. In addition to searching for susceptibility genes, a further research aim is to identify meaningful biological phenotypes for ADHD, which may assist gene identification strategies. I am part of the international ADHD molecular genetic consortium and collaborate with a number of other research groups including the neuropsychiatric genetics groups in Trinity College Dublin and University of Wales, College of Medicine.

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Brand Name: Duetact
Generic Name: Pioglitazone Hydrochloride and Glimepiride

Contents:

Description
Pharmacology
Indications and Usage
Contraindications
Warnings
Precautions
Adverse Reactions
Overdose
Dosage and Administration
How Supplied
References
Ophthalmology Data

Duetact, pioglitazone hydrochloride and glimepiride patient information (in plain English)

• Thiazolidinediones, including pioglitazone, which is a component of Duetact, cause or exacerbate congestive heart failure in some patients (see Warnings, Pioglitazone hydrochloride). After initiation of Duetact, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to the current standards of care. Furthermore, discontinuation of Duetact must be considered.
• Duetact is not recommended in patients with symptomatic heart failure. Initiation of Duetact in patients with established NYHA Class III or IV heart failure is contraindicated (see Contraindications and Warnings, Pioglitazone hydrochloride).

Description

Duetact™ (pioglitazone hydrochloride and glimepiride) tablets contain two oral antihyperglycemic agents used in the management of type 2 diabetes: pioglitazone hydrochloride and glimepiride. The concomitant use of pioglitazone and a sulfonylurea, the class of drugs that includes glimepiride, has been previously approved based on clinical trials in patients with type 2 diabetes inadequately controlled on a sulfonylurea. Additional efficacy and safety information about pioglitazone and glimepiride monotherapies may be found in the prescribing information for each individual drug.

Pioglitazone hydrochloride is an oral antihyperglycemic agent that acts primarily by decreasing insulin resistance. Pioglitazone is used in the management of type 2 diabetes. Pharmacological studies indicate that pioglitazone improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Pioglitazone improves glycemic control while reducing circulating insulin levels.

Pioglitazone ( ±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, biguanides, or the α-glucosidase inhibitors. The molecule contains one asymmetric center, and the synthetic compound is a racemate. The two enantiomers of pioglitazone interconvert in vivo. The structural formula is as shown:

Pioglitazone Hydrochloride

Pioglitazone hydrochloride is an odorless, white crystalline powder that has a molecular formula of C₁₉H₂₀N₂O₃S-HC_l and a molecular weight of 392.90. It is soluble in N,N-dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether.

Glimepiride 1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyl] sulfonyl]-3-(trans-4-methylcyclohexyl)-urea is an oral blood glucose-lowering drug of the sulfonylurea class and is used in the management of type 2 diabetes. The molecule is the trans-isomer with respect to the cyclohexyl substituents. The chemical structure is as shown:

Glimepiride

Glimepiride is a white to yellowish-white crystalline, odorless, to practically odorless powder, that has a molecular formula of C₂4H₃₄N₄O₅S and a molecular weight of 490.62. It is soluble in dimethylsulfoxide, slightly soluble in acetone, very slightly soluble in acetonitrile and methanol, and practically insoluble in water.

Duetact is available as a tablet for oral administration containing 30 mg pioglitazone hydrochloride (as the base) with 2 mg glimepiride (30 mg/2 mg) or 30 mg pioglitazone hydrochloride (as the base) with 4 mg glimepiride (30 mg/4 mg) formulated with the following excipients: povidone USP, croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF, hydroxypropyl cellulose NF, polysorbate 80 NF, and microcrystalline cellulose NF.

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Clinical Pharmacology

Mechanism of Action

Duetact

Duetact combines two antihyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: pioglitazone hydrochloride, a member of the thiazolidinedione class, and glimepiride, a member of the sulfonylurea class. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas sulfonylureas are insulin secretogogues that act primarily by stimulating release of insulin from functioning pancreatic beta cells.

Pioglitazone hydrochloride

Pioglitazone depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.

Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.

Glimepiride

The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as glimepiride. This is supported by both preclinical and clinical studies demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. These findings are consistent with the results of a long-term, randomized, placebo-controlled trial in which glimepiride therapy improved postprandial insulin/C-peptide responses and overall glycemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels. However, as with other sulfonylureas, the mechanism by which glimepiride lowers blood glucose during long-term administration has not been clearly established.

Pharmacokinetics and Drug Metabolism

Absorption and Bioavailability

Duetact

Bioequivalence studies were conducted following a single dose of the Duetact 30 mg/2 mg and 30 mg/4 mg tablets and concomitant administration of ACTOS (30 mg) and glimepiride (2 mg or 4 mg) under fasting conditions in healthy subjects.

Based on the area under the curve (AUC) and maximum concentration (C_max) of both pioglitazone and glimepiride, Duetact 30 mg/2 mg and 30 mg/4 mg were bioequivalent to ACTOS 30 mg concomitantly administered with glimepiride (2 mg or 4 mg, respectively) (Table 1).

Table 1. Mean (SD) Pharmacokinetic Parameters for Duetact

Regimen		N	AUC(0-inf) (ng· h/mL)	N	Cmax (ng/mL)	N	Tmax (h)	N	T1/2 (h)
30 mg/2 mg Duetact	pioglitazone	32	10116 (3641)	34	986 (433)	34	2.12 (1.10)	32	10.43 (5.08)
	glimepiride	34	871 (342)	34	168 (57.1)	34	2.53 (0.73)	34	8.23 (4.18)
30 mg pioglitazone + 2 mg glimepiride tablets	pioglitazone	32	11870 (3779)	34	1011 (406)	34	2.22 (1.38)	32	11.83 (4.39)
	glimepiride	34	863 (340)	34	190 (61.6)	34	2.29 (1.17)	34	6.47 (2.76)
30 mg/4 mg Duetact	pioglitazone	36	10676 (3031)	37	1103 (317)	37	1.84 (0.96)	36	9.64 (3.63)
	glimepiride	36	2435 (3063)	37	308 (110)	37	2.71 (0.67)	36	11.01 (5.34)
30 mg pioglitazone + 4 mg glimepiride tablets	pioglitazone	36	12179 (3481)	37	1188 (342)	37	2.17 (1.06)	36	10.47 (4.65)
	glimepiride	36	2432 (3217)	37	360 (133)	37	2.73 (1.15)	36	9.56 (4.32)

Food did not change the systemic exposures to glimepiride or pioglitazone following administration of Duetact. The presence of food did not significantly alter the time to peak serum concentration of glimepiride. However, for pioglitazone, there was a delay in time to peak concentration from 1.6 to 3.6 hours when administered with food. This food-induced delay in time to reach maximum serum concentration (T_max) was also associated with a 9% decrease in the maximum serum concentration (C_max) of pioglitazone. These changes are not likely to be clinically significant.

Pioglitazone hydrochloride

Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption.

Glimepiride

After oral administration, glimepiride is completely (100%) absorbed from the GI tract. Studies with single oral doses in normal subjects and with multiple oral doses in patients with type 2 diabetes have shown significant absorption of glimepiride within 1 hour after administration and Cmax at 2 to 3 hours. When glimepiride was given with meals, the mean Tmax was slightly increased (12%) and the mean Cmax and the total area under the serum concentration-time curve (AUC) were slightly decreased (8% and 9%, respectively).

Distribution

Pioglitazone hydrochloride

The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein bound (> 99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound (> 98%) to serum albumin.

Glimepiride

After intravenous (IV) dosing in normal subjects, Vd/F was 8.8 L (113 mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than 99.5%.

Metabolism

Pioglitazone hydrochloride

Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglitazone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M-III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC.

In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see Precautions, Drug Interactions, Pioglitazone hydrochloride). Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.

Glimepiride

Glimepiride is completely metabolized by oxidative biotransformation after either an IV or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). CYP2C9 has been shown to be involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M1, but not M2, possesses about 1/3 of the pharmacological activity as compared to its parent in an animal model; however, whether the glucose-lowering effect of M1 is clinically meaningful is not clear.

Excretion and Elimination

Pioglitazone hydrochloride

Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.

The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/f, calculated to be 5 to 7 L/hr.

Glimepiride

When 14C-glimepiride was given orally, approximately 60% of the total radioactivity was recovered in the urine in 7 days and M1 (predominant) and M2 accounted for 80-90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and M1 and M2 (predominant) accounted for about 70% of that recovered in feces. No parent drug was recovered from urine or feces. After IV dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite has been observed.

Special Populations

Renal Insufficiency

Pioglitazone hydrochloride

The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended.

Glimepiride

A single-dose, open-label study was conducted in 15 patients with renal impairment. Glimepiride (3 mg) was administered to 3 groups of patients with different levels of mean creatinine clearance (CLcr); (Group I, CLcr = 77.7 mL/min, n = 5), (Group II, CLcr = 27.7 mL/min, n = 3), and (Group III, CLcr = 9.4 mL/min, n = 7). Glimepiride was found to be well tolerated in all 3 groups. The results showed that glimepiride serum levels decreased as renal function decreased. However, M1 and M2 serum levels (mean AUC values) increased 2.3 and 8.6 times from Group I to Group III. The apparent terminal half-life (T1/2) for glimepiride did not change, while the half-lives for M1 and M2 increased as renal function decreased. Mean urinary excretion of M1 plus M2 as percent of dose, however, decreased (44.4%, 21.9%, and 9.3% for Groups I to III).

A multiple-dose titration study was also conducted in 16 patients with type 2 diabetes and with renal impairment using doses ranging from 1-8 mg daily for 3 months. The results were consistent with those observed after single doses. All patients with a CLcr less than 22 mL/min had adequate control of their glucose levels with a dosage regimen of only 1 mg daily. The results from this study suggested that a starting dose of 1 mg glimepiride may be given to patients with type 2 diabetes and kidney disease, and the dose may be titrated based on fasting blood glucose levels (see Dosage and Administration, Special Patient Populations).

Hepatic Insufficiency

Pioglitazone hydrochloride

Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values.

Therapy with Duetact should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2.5 times the upper limit of normal (see Precautions, General: Pioglitazone hydrochloride, Hepatic Effects).

Glimepiride

No studies were performed in patients with hepatic insufficiency.

Elderly

Pioglitazone hydrochloride

In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant.

Glimepiride

Comparison of glimepiride pharmacokinetics in patients with type 2 diabetes ≤65 years and those >65 years was performed in a study using a dosing regimen of 6 mg daily. There were no significant differences in glimepiride pharmacokinetics between the two age groups. The mean AUC at steady-state for the older patients was about 13% lower than that for the younger patients; the mean weight-adjusted clearance for the older patients was about 11% higher than that for the younger patients.

Pediatrics

No pharmacokinetic studies of Duetact were performed in pediatric patients.

Gender

Pioglitazone hydrochloride

As monotherapy and in combination with sulfonylurea, metformin, or insulin, pioglitazone improved glycemic control in both males and females. The mean C_max and AUC values were increased 20% to 60% in females. In controlled clinical trials, hemoglobin A1C (A1C) decreases from baseline were generally greater for females than for males (average mean difference in A1C 0.5%). Since therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.

Glimepiride

There were no differences between males and females in the pharmacokinetics of glimepiride when adjustment was made for differences in body weight.

Ethnicity

Pioglitazone hydrochloride

Pharmacokinetic data among various ethnic groups are not available.

Glimepiride

No pharmacokinetic studies to assess the effects of race have been performed, but in placebo-controlled studies of glimepiride in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 536), blacks (n = 63), and Hispanics (n = 63).

Other Populations

Glimepiride

There were no important differences in glimepiride metabolism in subjects identified as phenotypically different drug-metabolizers by their metabolism of sparteine. The pharmacokinetics of glimepiride in morbidly obese patients were similar to those in the normal weight group, except for a lower C_max and AUC. However, since neither C_max nor AUC values were normalized for body surface area, the lower values of C_max and AUC for the obese patients were likely the result of their excess weight and not due to a difference in the kinetics of glimepiride.

Drug-Drug Interactions

Co-administration of pioglitazone (45 mg) and a sulfonylurea (5 mg glipizide) administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide. Glimepiride and glipizide have similar metabolic pathways and are mediated by CYP2C9; therefore, drug-drug interaction between pioglitazone and glimepiride is considered unlikely. Specific pharmacokinetic drug interaction studies with Duetact have not been performed, although such studies have been conducted with the individual pioglitazone and glimepiride components.

Pioglitazone hydrochloride

The following drugs were studied in healthy volunteers with co-administration of pioglitazone 45 mg once daily. Results are listed below:

Oral Contraceptives: Co-administration of pioglitazone (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and C_max respectively. There were no significant changes in norethindrone AUC (0-24h) and C_max. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown.

Midazolam: Administration of pioglitazone for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam C_max and AUC.

Nifedipine ER: Co-administration of pioglitazone for 7 days with 30 mg nifedipine ER administered orally once daily for 4 days to male and female volunteers resulted in a ratio of least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 - 0.95) for C_max and 0.88 (0.80 - 0.96) for AUC. In view of the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown.

Ketoconazole: Co-administration of pioglitazone for 7 days with ketoconazole 200 mg administered twice daily resulted in a ratio of least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06 - 1.23) for C_max, 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for C_min.

Atorvastatin Calcium: Co-administration of pioglitazone for 7 days with atorvastatin calcium (LIPITOR®) 80 mg once daily resulted in a ratio of least square mean (90% CI) values for unchanged pioglitazone of 0.69 (0.57 - 0.85) for C_max, 0.76 (0.65 - 0.88) for AUC and 0.96 (0.87 - 1.05) for C_min. For unchanged atorvastatin, the ratio of least square mean (90% CI) values were 0.77 (0.66 - 0.90) for C_max, 0.86 (0.78 - 0.94) for AUC and 0.92 (0.82 - 1.02) for C_min.

Cytochrome P450: See Precautions, Drug Interactions, Pioglitazone hydrochloride

Gemfibrozil: Concomitant administration of gemfibrozil (oral 600 mg twice daily), an inhibitor of CYP2C8, with pioglitazone (oral 30 mg) in 10 healthy volunteers pre-treated for 2 days prior with gemfibrozil (oral 600 mg twice daily) resulted in pioglitazone exposure (AUC0-24) being 226% of the pioglitazone exposure in the absence of gemfibrozil (see Precautions, Drug Interactions, Pioglitazone hydrochloride).¹

Rifampin: Concomitant administration of rifampin (oral 600 mg once daily), an inducer of CYP2C8 with pioglitazone (oral 30 mg) in 10 healthy volunteers pre-treated for 5 days prior with rifampin (oral 600 mg once daily) resulted in a decrease in the AUC of pioglitazone by 54% (see Precautions, Drug Interactions, Pioglitazone hydrochloride).²

In other drug-drug interaction studies, pioglitazone had no significant effect on the pharmacokinetics of fexofenadine, metformin, digoxin, warfarin, ranitidine, or theophylline.

Glimepiride

The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including nonsteroidal anti-inflammatory drugs and other drugs that are highly protein bound, such as salicylates, sulfonamides, chloramphenicol, coumarins, probenecid, monoamine oxidase inhibitors, and beta adrenergic blocking agents. Due to the potential drug interaction between these drugs and glimepiride, the patient should be observed closely for hypoglycemia when these drugs are co-administered. Conversely, when these drugs are withdrawn, the patient should be observed closely for loss of glycemic control.

Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, and isoniazid. Due to the potential drug interaction between these drugs and glimepiride, the patient should be observed closely for loss of glycemic control when these drugs are co-administered. Conversely, when these drugs are withdrawn, the patient should be observed closely for hypoglycemia.

Aspirin: Co-administration of aspirin (1 g three times daily) and glimepiride led to a 34% decrease in the mean glimepiride AUC and, therefore, a 34% increase in the mean CL/f. The mean C_max had a decrease of 4%. Blood glucose and serum C-peptide concentrations were unaffected and no hypoglycemic symptoms were reported. Pooled data from clinical trials showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of aspirin and other salicylates.

Cimetidine/Ranitidine: Co-administration of either cimetidine (800 mg once daily) or ranitidine (150 mg twice daily) with a single 4-mg oral dose of glimepiride did not significantly alter the absorption and disposition of glimepiride, and no differences were seen in hypoglycemic symptomatology. Pooled data from clinical trials showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of H2-receptor antagonists.

Propranolol: Concomitant administration of propranolol (40 mg three times daily) and glimepiride significantly increased C_max, AUC, and T1/2 of glimepiride by 23%, 22%, and 15%, respectively, and it decreased CL/f by 18%. The recovery of M1 and M2 from urine, however, did not change. The pharmacodynamic responses to glimepiride were nearly identical in normal subjects receiving propranolol and placebo. Pooled data from clinical trials in patients with type 2 diabetes showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of beta-blockers. However, if beta-blockers are used, caution should be exercised and patients should be warned about the potential for hypoglycemia.

Warfarin: Concomitant administration of glimepiride (4 mg once daily) did not alter the pharmacokinetic characteristics of R- and S-warfarin enantiomers following administration of a single dose (25 mg) of racemic warfarin to healthy subjects. No changes were observed in warfarin plasma protein binding. Glimepiride treatment did result in a slight, but statistically significant, decrease in the pharmacodynamic response to warfarin. The reductions in mean area under the prothrombin time (PT) curve and maximum PT values during glimepiride treatment were very small (3.3% and 9.9%, respectively) and are unlikely to be clinically important.

Ramipril: The responses of serum glucose, insulin, C-peptide, and plasma glucagon to 2 mg glimepiride were unaffected by co-administration of ramipril (an ACE inhibitor) 5 mg once daily in normal subjects. No hypoglycemic symptoms were reported. Pooled data from clinical trials in patients with type 2 diabetes showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of ACE inhibitors.

Miconazole: A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known. There is a potential interaction of glimepiride with inhibitors (e.g. fluconazole) and inducers (e.g. rifampicin) of cytochrome P450 2C9.

Although no specific interaction studies were performed with glimepiride, pooled data from clinical trials showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of calcium-channel blockers, estrogens, fibrates, NSAIDS, HMG CoA reductase inhibitors, sulfonamides, or thyroid hormone.

Pharmacodynamics and Clinical Effects

Pioglitazone hydrochloride

Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin levels, and lower A1C values. Based on results from an open-label extension study, the glucose-lowering effects of pioglitazone appear to persist for at least one year. In controlled clinical studies, pioglitazone in combination with a sulfonylurea had an additive effect on glycemic control.

Patients with lipid abnormalities were included in placebo-controlled monotherapy clinical studies with pioglitazone. Overall, patients treated with pioglitazone had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL cholesterol and total cholesterol compared to the placebo group. A similar pattern of results was seen in 16-week and 24-week combination therapy studies of pioglitazone with a sulfonylurea.

Glimepiride

A mild glucose-lowering effect first appeared following single oral doses as low as 0.5-0.6 mg in healthy subjects. The time required to reach the maximum effect (i.e., minimum blood glucose level [T_min]) was about 2 to 3 hours. In patients with type 2 diabetes, both fasting and 2-hour postprandial glucose levels were significantly lower with glimepiride (1, 2, 4, and 8 mg once daily) than with placebo after 14 days of oral dosing. The glucose-lowering effect in all active treatment groups was maintained over 24 hours.

In larger dose-ranging studies, blood glucose and A1C were found to respond in a dose-dependent manner over the range of 1 to 4 mg/day of glimepiride. Some patients, particularly those with higher fasting plasma glucose (FPG) levels, may benefit from doses of glimepiride up to 8 mg once daily. No difference in response was found when glimepiride was administered once or twice daily.

In two 14-week, placebo-controlled studies in 720 subjects, the average net reduction in A1C for patients treated with 8 mg of glimepiride once daily was 2.0% in absolute units compared with placebo-treated patients. In a long-term, randomized, placebo-controlled study of patients with type 2 diabetes unresponsive to dietary management, glimepiride therapy improved postprandial insulin/C-peptide responses, and 75% of patients achieved and maintained control of blood glucose and A1C. Efficacy results were not affected by age, gender, weight, or race. In long-term extension trials with previously-treated patients, no meaningful deterioration in mean fasting plasma glucose (FPG) or A1C levels was seen after 2 1/2 years of glimepiride therapy.

Glimepiride therapy is effective in controlling blood glucose without deleterious changes in the plasma lipoprotein profiles of patients treated for type 2 diabetes.

Clinical Studies

There have been no clinical efficacy studies conducted with Duetact. However, the efficacy and safety of the separate components have been previously established. The co-administration of pioglitazone and a sulfonylurea, including glimepiride, has been evaluated for efficacy and safety in two clinical studies. These clinical studies established an added benefit of pioglitazone in glycemic control of patients with inadequately controlled type 2 diabetes while on sulfonylurea therapy. Bioequivalence of Duetact with co-administered pioglitazone and glimepiride tablets was demonstrated at the 30 mg/2 mg and 30 mg/4 mg dosage strengths (see Clinical Pharmacology, Pharmacokinetics and Drug Metabolism, Absorption and Bioavailability).

Clinical Studies of Pioglitazone Add-On Therapy in Patients Not Adequately Controlled on a Sulfonylurea

Two treatment-randomized, controlled clinical studies in patients with type 2 diabetes were conducted to evaluate the safety and efficacy of pioglitazone plus a sulfonylurea. Both studies included patients receiving a sulfonylurea, either alone or in combination with another antihyperglycemic agent, who had inadequate glycemic control. Excluding the sulfonylurea agent, all other antihyperglycemic agents were discontinued prior to starting study treatment. In the first study, 560 patients were randomized to receive 15 mg or 30 mg of pioglitazone or placebo once daily in addition to their current sulfonylurea regimen for 16 weeks. In the second study, 702 patients were randomized to receive 30 mg or 45 mg of pioglitazone once daily in addition to their current sulfonylurea regimen for 24 weeks.

In the first study, the addition of pioglitazone 15 mg or 30 mg once daily to treatment with a sulfonylurea after 16 weeks significantly reduced the mean A1C by 0.88% and 1.28% and the mean FPG by 39.4 mg/dL and 57.9 mg/dL, respectively, from that observed with sulfonylurea treatment alone. In the second study, the mean reductions from baseline at Week 24 in A1C were 1.55% and 1.67% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 51.5 mg/dL and 56.1 mg/dL, respectively. Based on these reductions in A1C and FPG (Table 2), the addition of pioglitazone to sulfonylurea resulted in significant improvements in glycemic control irrespective of the sulfonylurea dosage.

Table 2. Glycemic Parameters in 16-Week and 24-Week Pioglitazone Hydrochloride + Sulfonylurea Combination Studies

Parameter	Placebo + sulfonylurea	Pioglitazone 15 mg + sulfonylurea		Pioglitazone 30 mg + sulfonylurea
16-Week Study
* significant change from baseline p ≤ 0.050 †significant difference from placebo plus sulfonylurea, p ≤ 0.050 (a) patients who achieved an A1C ≤ 6.1% or ≥ 0.6% decrease from baseline (b) patients who achieved a decrease in FPG by ≥ 30 mg/dL
A1C (%) Baseline mean Mean change from baseline at 16 weeks Difference in change from placebo + sulfonylurea	N=181 9.86 0.06	N=176 10.01 -0.82*† -0.88		N=182 9.93 -1.22*† -1.28
Responder rate (%) (a)	23.8	56.8		74.2
FPG (mg/dL) Baseline mean Mean change from baseline at 16 weeks Difference in change from placebo + sulfonylurea Responder rate (%) (b)	N=182 236 5.6 22.0	N=179 246.8 -33.8*† -39.4 55.3		N=186 238.9 -52.3*† -57.9 67.7
Parameter	Pioglitazone 30 mg + sulfonylurea		Pioglitazone 45 mg + sulfonylurea
24-Week Study
A1C (%) Baseline mean Mean change from baseline at 24 weeks	N=340 9.77 -1.55*		N=332 9.85 -1.67*
Responder rate (%) (a)	77.4		79.5
FPG (mg/dL) Baseline mean Mean change from baseline at 24 weeks	N=338 214.4 -51.5*		N=329 217.2 -56.1*
Responder rate (%) (b)	63.6		71.1

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Indications and Usage

Duetact is indicated as an adjunct to diet and exercise as a once-daily combination therapy to improve glycemic control in patients with type 2 diabetes who are already treated with a combination of pioglitazone and a sulfonylurea or whose diabetes is not adequately controlled with a sulfonylurea alone, or for those patients who have initially responded to pioglitazone alone and require additional glycemic control.

Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy.

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Contraindications

Initiation of Duetact in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated (see Boxed Warning).

In addition, Duetact is contraindicated in patients with:

1. Known hypersensitivity to pioglitazone, glimepiride or any other component of Duetact.
2. Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.

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Warnings

Glimepiride

SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes, 19 supp. 2: 747-830, 1970).

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2-1/2 times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glimepiride tablets and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

Pioglitazone hydrochloride

Cardiac Failure and Other Cardiac Effects

Pioglitazone, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of pioglitazone must be considered. Patients with NYHA Class III and IV cardiac status were not studied during pre-approval clinical trials and pioglitazone is not recommended in these patients (see Boxed Warning and Contraindications).

In one 16-week U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, pioglitazone at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%).

In this study, two of the 191 patients receiving 15 mg pioglitazone plus insulin (1.1%) and two of the 188 patients receiving 30 mg pioglitazone plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week dose-controlled study in which pioglitazone was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0.9% (3/345) of patients on 45 mg reported CHF as a serious adverse event.

Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin.

In type 2 diabetes and congestive heart failure (systolic dysfunction)

A 24-week post-marketing safety study was performed to compare pioglitazone (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean A1C 8.8% at baseline) with NYHA Class II and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on pioglitazone compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with pioglitazone was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed.

Pioglitazone should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation (see Dosage and Administration, Special Patient Populations).

Prospective Pioglitazone Clinical Trial In Macrovascular Events (PROactive)

In PROactive, 5238 patients with type 2 diabetes and a prior history of macrovascular disease were treated with ACTOS (n=2605), force-titrated up to 45 mg once daily, or placebo (n=2633) (see Adverse Reactions). The percentage of patients who had an event of serious heart failure was higher for patients treated with ACTOS (5.7%, n=149) than for patients treated with placebo (4.1%, n=108). The incidence of death subsequent to a report of serious heart failure was 1.5% (n=40) in patients treated with ACTOS and 1.4% (n=37) in placebo-treated patients. In patients treated with an insulin-containing regimen at baseline, the incidence of serious heart failure was 6.3% (n=54/864) with ACTOS and 5.2% (n=47/896) with placebo. For those patients treated with a sulfonylurea-containing regimen at baseline, the incidence of serious heart failure was 5.8% (n=94/1624) with ACTOS and 4.4% (n=71/1626) with placebo.

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Precautions

General

Pioglitazone hydrochloride

Pioglitazone exerts its antihyperglycemic effect only in the presence of insulin. Therefore, Duetact should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Hypoglycemia: Patients receiving pioglitazone in combination with insulin or oral hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary.

Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with pioglitazone as monotherapy or in combination with sulfonylureas or metformin vs. placebo-treated patients. In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with pioglitazone in combination with insulin (see Warnings, Pioglitazone hydrochloride, Cardiac Failure and Other Cardiac Effects). Patients with NYHA Class III and IV cardiac status were not studied in pre-approval pioglitazone clinical trials. Pioglitazone is not indicated in patients with NYHA Class III or IV cardiac status.

In postmarketing experience with pioglitazone, cases of congestive heart failure have been reported in patients both with and without previously known heart disease.

Edema: In all U.S. clinical trials with pioglitazone, edema was reported more frequently in patients treated with pioglitazone than in placebo-treated patients and appears to be dose related (see Adverse Reactions, Pioglitazone hydrochloride). In postmarketing experience, reports of initiation or worsening of edema have been received. Since thiazolidinediones, including pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, Duetact should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure (see Boxed Warning, Warnings, Pioglitazone hydrochloride, and Precautions, Information for Patients).

Weight Gain: Dose related weight gain was observed with pioglitazone alone and in combination with other hypoglycemic agents (Table 3). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Table 3. Weight Changes (kg) from Baseline During Double-Blind Clinical Trials with Pioglitazone

			Control Group (Placebo)	pioglitazone 15 mg	pioglitazone 30 mg	pioglitazone 45 mg
			Median (25th/75thpercentile)	Median (25th/75thpercentile)	Median (25th/75thpercentile)	Median (25th/75thpercentile)
Note: Trial durations of 16 to 26 weeks
Monotherapy			-1.4 (-2.7/0.0) n=256	0.9 (-0.5/3.4) n = 79	1.0 (-0.9/3.4) n=188	2.6 (0.2/5.4) n = 79
Combination Therapy		Sulfonylurea Metformin Insulin	-0.5 (-1.8/0.7) n=187 -1.4 (-3.2/0.3) n=160 0.2 (-1.4/1.4) n=182	2.0 (0.2/3.2) n=183 N/A 2.3 (0.5/4.3) n=190	3.1 (1.1/5.4) n=528 0.9 (-0.3/3.2) n=567 3.3 (0.9/6.3) n=522	4.1 (1.8/7.3) n=333 1.8 (-0.9/5.0) n=407 4.1 (1.4/6.8) n=338

Ovulation: Therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. Thus, adequate contraception in premenopausal women should be recommended while taking Duetact. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known.

Hematologic: Across all clinical studies with pioglitazone, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects (see Adverse Reactions, Laboratory Abnormalities,Pioglitazone hydrochloride,Hematologic). Duetact may cause decreases in hemoglobin and hematocrit.

Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects were treated with pioglitazone. In U.S. clinical studies, over 4700 patients with type 2 diabetes received pioglitazone. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies.

During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with pioglitazone and 2 of 793 (0.25%) placebo-treated patients had ALT values ≥ 3 times the upper limit of normal. The ALT elevations in patients treated with pioglitazone were reversible and were not clearly related to therapy with pioglitazone.

In postmarketing experience with pioglitazone, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established.

Pending the availability of the results of additional large, long-term controlled clinical trials and additional postmarketing safety data on pioglitazone, it is recommended that patients treated with Duetact undergo periodic monitoring of liver enzymes.

Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with Duetact in all patients and periodically thereafter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with Duetact should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.

Therapy with Duetact should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2.5 times the upper limit of normal) at baseline or any time during therapy with Duetact should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with Duetact in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the upper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced, Duetact therapy should be discontinued.

Macular Edema: Macular edema has been reported in post-marketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been diagnosed on routine ophthalmologic examination. Some patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. It is unknown whether or not there is a causal relationship between pioglitazone and macular edema. Patients with diabetes should have regular eye exams by an ophthalmologist, per the Standards of Care of the American Diabetes Association. Additionally, any diabetic who reports any kind of visual symptom should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings (see Adverse Reactions).

Fractures: In a randomized trial (PROactive) in patients with type 2 diabetes (mean duration of diabetes 9.5 years), an increased incidence of bone fracture was noted in female patients taking pioglitazone. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and remained during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in fracture rates was observed in men treated with pioglitazone 1.7% (30/1735) versus placebo 2.1% (37/1728). The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone and attention should be given to assessing and maintaining bone health according to current standards of care.

General

Glimepiride

Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Patients with impaired renal function may be more sensitive to the glucose-lowering effect of glimepiride. A starting dose of 1 mg of glimepiride once daily followed by appropriate dose titration is recommended in those patients (see Dosage and Administration, Special Patient Populations). Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. Combined use of glimepiride with insulin or metformin may increase the potential for hypoglycemia.

Loss of control of blood glucose: When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. The effectiveness of any oral hypoglycemic drug, including Duetact, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug.

Laboratory Tests

FPG and A1C measurements should be performed periodically to monitor glycemic control and therapeutic response to Duetact.

Liver enzyme monitoring is recommended prior to initiation of therapy with Duetact in all patients and periodically thereafter per the clinical judgment of the health care professional (see Precautions, General:Pioglitazone hydrochloride, Hepatic Effects and Adverse Reactions, Laboratory Abnormalities,Pioglitazone hydrochloride, Serum Transaminase Levels).

Information for Patients

Patients should be instructed regarding the importance of adhering to dietary instructions, a regular exercise program, and regular testing of blood glucose and A1C. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. Patients should also be informed of the potential risks and advantages of Duetact and of alternative modes of therapy.

Prior to initiation of Duetact therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members (see Precautions, General: Pioglitazone hydrochloride and Glimepiride, Hypoglycemia). Combination therapy of Duetact with other antihyperglycemic agents may also cause hypoglycemia.

Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on Duetact should immediately report these symptoms to their physician.

Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter per the clinical judgment of the health care professional. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine.

Therapy with a thiazolidinedione, including the active pioglitazone component of the Duetact tablet, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking Duetact. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Thus, adequate contraception in premenopausal women should be recommended. Patients who become pregnant while on Duetact or are planning a pregnancy should be advised to discuss with their physician a regimen appropriate for maintaining adequate glycemic control (see Precautions, Pregnancy: Pregnancy Category C).

Patients should be told to take a single dose of Duetact once daily with the first main meal and instructed that any change in dosing should be made only if directed by their physician (see Dosage and Administration, Maximum Recommended Dose).

Drug Interactions

Pioglitazone hydrochloride

In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate.

An enzyme inhibitor of CYP2C8 (such as gemfibrozil) may significantly increase the AUC of pioglitazone and an enzyme inducer of CYP2C8 (such as rifampin) may significantly decrease the AUC of pioglitazone. Therefore, if an inhibitor or inducer of CYP2C8 is started or stopped during treatment with pioglitazone, changes in diabetes treatment may be needed based on clinical response (see Clinical Pharmacology, Drug-Drug Interactions, Pioglitazone hydrochloride).

Glimepiride

(see Clinical Pharmacology, Drug-Drug Interactions, Glimepiride)

Carcinogenesis, Mutagenesis, Impairment of Fertility

Duetact

No animal studies have been conducted with Duetact. The following data are based on findings in studies performed with pioglitazone or glimepiride individually.

Pioglitazone hydrochloride

A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m2). Drug-induced tumors were not observed in any organ except for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m2). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m2). No drug-induced tumors were observed in any organ.

During prospective evaluation of urinary cytology involving more than 1800 patients receiving pioglitazone in clinical trials up to one year in duration, no new cases of bladder tumors were identified. In two 3 year studies in which pioglitazone was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking pioglitazone compared to 5/3679 (0.14%) in patients not taking pioglitazone. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six cases (0.16%) on pioglitazone and two (0.05%) on placebo.

Pioglitazone hydrochloride was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay.

No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone hydrochloride daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m²).

Glimepiride

Studies in rats at doses of up to 5000 ppm in complete feed (approximately 340 times the maximum recommended human dose, based on surface area) for 30 months showed no evidence of carcinogenesis. In mice, administration of glimepiride for 24 months resulted in an increase in benign pancreatic adenoma formation which was dose related and is thought to be the result of chronic pancreatic stimulation. The no-effect dose for adenoma formation in mice in this study was 320 ppm in complete feed, or 46-54 mg/kg body weight/day. This is about 35 times the maximum human recommended dose of 8 mg once daily based on surface area.

Glimepiride was non-mutagenic in a battery of in vitro and in vivo mutagenicity studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis, mouse micronucleus test).

There was no effect of glimepiride on male mouse fertility in animals exposed up to 2500 mg/kg body weight (>1,700 times the maximum recommended human dose based on surface area). Glimepiride had no effect on the fertility of male and female rats administered up to 4000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area).

Animal Toxicology

Pioglitazone hydrochloride

Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone hydrochloride (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respectively, based on mg/m2). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m2). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m2), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m2).

Glimepiride

Reduced serum glucose values and degranulation of the pancreatic beta cells were observed in beagle dogs exposed to 320 mg glimepiride/kg/day for 12 months (approximately 1,000 times the recommended human dose based on surface area). No evidence of tumor formation was observed in any organ. One female and one male dog developed bilateral subcapsular cataracts. Non-GLP studies indicated that glimepiride was unlikely to exacerbate cataract formation. Evaluation of the co-cataractogenic potential of glimepiride in several diabetic and cataract rat models was negative and there was no adverse effect of glimepiride on bovine ocular lens metabolism in organ culture.

Pregnancy

Pregnancy Category C

Duetact

Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Duetact should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

There are no adequate and well-controlled studies in pregnant women with Duetact or its individual components. No animal studies have been conducted with the combined products in Duetact. The following data are based on findings in studies performed with pioglitazone or glimepiride individually.

Pioglitazone hydrochloride

Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m2, respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m2). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m2). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m2).

Glimepiride

Teratogenic Effects: Glimepiride did not produce teratogenic effects in rats exposed orally up to 4000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area) or in rabbits exposed up to 32 mg/kg body weight (approximately 60 times the maximum recommended human dose based on surface area). Glimepiride has been shown to be associated with intrauterine fetal death in rats when given in doses as low as 50 times the human dose based on surface area and in rabbits when given in doses as low as 0.1 times the human dose based on surface area. This fetotoxicity, observed only at doses inducing maternal hypoglycemia, has been similarly noted with other sulfonylureas, and is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride.

Nonteratogenic Effects: In some studies in rats, offspring of dams exposed to high levels of glimepiride during pregnancy and lactation developed skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. Significant concentrations of glimepiride were observed in the serum and breast milk of the dams as well as in the serum of the pups. These skeletal deformations were determined to be the result of nursing from mothers exposed to glimepiride.

Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. Patients who are planning a pregnancy should consult their physician, and it is recommended that they change over to insulin for the entire course of pregnancy and lactation.

Nursing Mothers

No studies have been conducted with the combined components of Duetact. In studies performed with the individual components, pioglitazone was secreted in the milk of lactating rats and significant concentrations of glimepiride were observed in the serum and breast milk of the dams and serum of the pups. It is not known whether pioglitazone or glimepiride are secreted in human milk. However, other sulfonylureas are excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, and because of the effects on nursing animals, Duetact should not be administered to a woman breastfeeding. If Duetact is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered (see Precautions, Pregnancy: Pregnancy Category C, Glimepiride, Nonteratogenic Effects).

Pediatric Use

Safety and effectiveness of Duetact in pediatric patients have not been established.

Elderly Use

Pioglitazone hydrochloride

Approximately 500 patients in placebo-controlled clinical trials of pioglitazone were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients.

Glimepiride

In U.S. clinical studies of glimepiride, 608 of 1986 patients were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Comparison of glimepiride pharmacokinetics in patients with type 2 diabetes ≤65 years (n=49) and those >65 years (n=42) was performed in a study using a dosing regimen of 6 mg daily. There were no significant differences in glimepiride pharmacokinetics between the two age groups (see Clinical Pharmacology, Special Populations, Elderly: Glimepiride).

Glimepiride is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Elderly patients are particularly susceptible to hypoglycemic action of glucose-lowering drugs. In elderly, debilitated, or malnourished patients, or in patients with renal and hepatic insufficiency, the initial dosing, dose increments, and maintenance dosage should be conservative based upon blood glucose levels prior to and after initiation of treatment to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents (see Clinical Pharmacology, Special Populations, Renal Insufficiency: Glimepiride; PRECAUTIONS, General: Glimepiride, Hypoglycemia and Dosage and Administration, Special Patient Populations).

Adverse Reactions

The adverse events reported in at least 5% of patients in the controlled 16-week clinical studies between placebo plus a sulfonylurea and pioglitazone (15 mg and 30 mg combined) plus sulfonylurea-treatment arms were upper respiratory tract infection (15.5% and 16.6%), accidental injury (8.6% and 3.5%) and combined edema/peripheral edema (2.1% and 7.2%), respectively.

The incidence and type of adverse events reported in at least 5% of patients in any combined treatment group from the 24-week study comparing pioglitazone 30 mg plus a sulfonylurea and pioglitazone 45 mg plus a sulfonylurea are shown in Table 4; the rate of adverse events resulting in study discontinuation between the two treatment groups was 6.0% and 9.7%, respectively.

Table 4. Adverse Events That Occurred in ≥ 5% of Patients in Any Treatment Group During the 24-Week Study

Adverse Event	Pioglitazone 30 mg+ sulfonylurea N=351 n (%)	Pioglitazone 45 mg+ sulfonylurea N=351 n (%)
Hypoglycemia	47 (13.4)	55 (15.7)
Upper Respiratory Tract Infection	43 (12.3)	52 (14.8)
Weight Increased	32 (9.1)	47 (13.4)
Edema Lower Limb	20 (5.7)	43 (12.3)
Headache	25 (7.1)	14 (4.0)
Urinary Tract Infection	20 (5.7)	24 (6.8)
Diarrhea	21 (6.0)	15 (4.3)
Nausea	18 (5.1)	14 (4.0)
Pain in Limb	19 (5.4)	14 (4.0)

In U.S. double-blind studies, anemia was reported in ≤ 2% of patients treated with pioglitazone plus a sulfonylurea (see Precautions, General: Pioglitazone hydrochloride).

Pioglitazone hydrochloride

Over 8500 patients with type 2 diabetes have been treated with pioglitazone in randomized, double-blind, controlled clinical trials. This includes 2605 high-risk patients with type 2 diabetes treated with pioglitazone from the PROactive clinical trial. Over 6000 patients have been treated for 6 months or longer, and over 4500 patients for one year or longer. Over 3000 patients have received pioglitazone for at least 2 years.

Most clinical adverse events were similar between groups treated with pioglitazone in combination with a sulfonylurea and those treated with pioglitazone monotherapy. Other adverse events reported in at least 5% of patients in controlled clinical studies between placebo and pioglitazone monotherapy included myalgia (2.7% and 5.4%), tooth disorder (2.3% and 5.3%), diabetes mellitus aggravated (8.1% and 5.1%) and pharyngitis (0.8% and 5.1%), respectively.

In monotherapy studies, edema was reported for 4.8% (with doses from 7.5 mg to 45 mg) of patients treated with pioglitazone versus 1.2% of placebo-treated patients. Most of these events were considered mild or moderate in intensity (see Precautions, General: Pioglitazone hydrochloride, Edema).

Prospective Pioglitazone Clinical Trial In Macrovascular Events (PROactive)

In PROactive, 5238 patients with type 2 diabetes and a prior history of macrovascular disease were treated with ACTOS (n=2605), force-titrated up to 45 mg daily, or placebo (n=2633), in addition to standard of care. Almost all subjects (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, ARBs, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates). Patients had a mean age of 61.8 years, mean duration of diabetes 9.5 years, and mean A1C 8.1%. Average duration of follow-up was 34.5 months. The primary objective of this trial was to examine the effect of ACTOS on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in the cardiovascular composite endpoint (see table 5 below). Although there was no statistically significant difference between ACTOS and placebo for the 3-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with ACTOS.

Table 5. Number of First and Total Events for Each Component within the Cardiovascular Composite Endpoint

	Placebo N=2633		ACTOS N=2605
Cardiovascular Events	First Events (N)	Total events (N)	First Events (N)	Total events (N)
Any event	572	900	514	803
All-cause mortality	122	186	110	177
Non-fatal MI	118	157	105	131
Stroke	96	119	76	92
ACS	63	78	42	65
Cardiac intervention	101	240	101	195
Major leg amputation	15	28	9	28
Leg revascularization	57	92	71	115

Postmarketing reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received (see Precautions, General: Pioglitazone hydrochloride).

Glimepiride

Adverse events that occurred in controlled clinical trials with placebo and glimepiride monotherapy, other than hypoglycemia, headache and nausea, also included dizziness (0.3% and 1.7%) and asthenia (1.0% and 1.6%), respectively.

Gastrointestinal Reactions: Vomiting, gastrointestinal pain, and diarrhea have been reported with glimepiride, but the incidence in placebo-controlled trials was less than 1%. In rare cases, there may be an elevation of liver enzyme levels. In isolated instances, impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis, which may also lead to liver failure have been reported with sulfonylureas, including glimepiride.

Dermatologic Reactions:Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in less than 1% of glimepiride-treated patients. These may be transient and may disappear despite continued use of glimepiride. If those hypersensitivity reactions persist or worsen, the drug should be discontinued. Porphyria cutanea tarda, photosensitivity reactions, and allergic vasculitis have been reported with sulfonylureas.

Metabolic Reactions: Hepatic porphyria reactions and disulfiram-like reactions have been reported with sulfonylureas; however, no cases have yet been reported with glimepiride tablets. Cases of hyponatremia have been reported with glimepiride and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH.

Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas.

Other Reactions: Changes in accommodation and/or blurred vision may occur with the use of glimepiride. In placebo-controlled trials of glimepiride, the incidence of blurred vision with placebo was 0.7%, and with glimepiride, 0.4%. This is thought to be due to changes in blood glucose, and may be more pronounced when treatment is initiated. This condition is also seen in untreated diabetic patients, and may actually be reduced by treatment.

Laboratory Abnormalities

Pioglitazone hydrochloride

Hematologic:Pioglitazone may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with pioglitazone appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone. These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with pioglitazone therapy and have rarely been associated with any significant hematologic clinical effects (see Precautions, General: Pioglitazone hydrochloride, Hematologic).

Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with pioglitazone had ALT values ≥ 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with pioglitazone, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with pioglitazone were withdrawn from clinical trials in the U.S. due to abnormal liver function tests.

In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see Precautions, General: Pioglitazone hydrochloride, Hepatic Effects).

CPK Levels: During required laboratory testing in clinical trials with pioglitazone, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive pioglitazone, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to pioglitazone therapy is unknown.

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Overdose

Pioglitazone hydrochloride

During controlled clinical trials, one case of overdose with pioglitazone was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.

In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms.

Glimepiride

Overdosage of sulfonylureas, including glimepiride, can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, because hypoglycemia may recur after apparent clinical recovery.

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Dosage and Administration

General

The use of antihyperglycemic therapy in the management of type 2 diabetes should be individualized on the basis of effectiveness and tolerability. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia.

Dosage Recommendations

Selecting the starting dose of Duetact should be based on the patient's current regimen of pioglitazone and/or sulfonylurea. Those patients who may be more sensitive to antihyperglycemic drugs should be monitored carefully during dose adjustment. After initiation of Duetact, patients should be carefully monitored for adverse events related to fluid retention (see Boxed Warning and Warnings, Pioglitazone hydrochloride). It is recommended that a single dose of Duetact be administered once daily with the first main meal.

Starting dose for patients currently on glimepiride monotherapy

Based on the usual starting dose of pioglitazone (15 mg or 30 mg daily), Duetact may be initiated at 30 mg/2 mg or 30 mg/4 mg tablet strengths once daily, and adjusted after assessing adequacy of therapeutic response.

For patients with type 2 diabetes and systolic dysfunction, see Dosage and Administration, Special Patient Populations.

Starting dose for patients currently on pioglitazone monotherapy

Based on the usual starting doses of glimepiride (1 mg or 2 mg once daily), and pioglitazone 15 mg or 30 mg, Duetact may be initiated at 30 mg/2 mg once daily, and adjusted after assessing adequacy of therapeutic response.

For patients who are not currently on glimepiride and may be more sensitive to hypoglycemia, see Dosage and Administration, Special Patient Populations.

Starting dose for patients switching from combination therapy of pioglitazone plus glimepiride as separate tablets

Duetact may be initiated with 30 mg/2 mg or 30 mg/4 mg tablet strengths based on the dose of pioglitazone and glimepiride already being taken. Patients who are not controlled with 15 mg of pioglitazone in combination with glimepiride should be carefully monitored when switched to Duetact.

Starting dose for patients currently on a different sulfonylurea monotherapy or switching from combination therapy of pioglitazone plus a different sulfonylurea (e.g. glyburide, glipizide, chlorpropamide, tolbutamide, acetohexamide)

No exact dosage relationship exists between glimepiride and the other sulfonylurea agents. Therefore, based on the maximum starting dose of 2 mg glimepiride, Duetact should be limited initially to a starting dose of 30 mg/2 mg once daily, and adjusted after assessing adequacy of therapeutic response.

Any change in diabetic therapy should be undertaken with care and appropriate monitoring as changes in glycemic control can occur. Patients should be observed carefully for hypoglycemia (1-2 weeks) when being transferred to Duetact, especially from longer half-life sulfonylureas (e.g. chlorpropamide) due to potential overlapping of drug effect.

Sufficient time should be given to assess adequacy of therapeutic response. Ideally, the response to therapy should be evaluated using A1C, which is a better indicator of long-term glycemic control than FPG alone. A1C reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with Duetact for a period of time adequate to evaluate change in A1C (8-12 weeks) unless glycemic control as measured by FPG deteriorates.

Special Patient Populations

Duetact is not recommended for use in pregnancy, nursing mothers or for use in pediatric patients.

In elderly, debilitated, or malnourished patients, or in patients with renal or hepatic insufficiency, the initial dosing, dose increments, and maintenance dosage of Duetact should be conservative to avoid hypoglycemic reactions. These patients should be started at 1 mg of glimepiride prior to prescribing Duetact. During initiation of Duetact therapy and any subsequent dose adjustment, patients should be observed carefully for hypoglycemia (see PRECAUTIONS, General: Glimepiride, Hypoglycemia).

Therapy with Duetact should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy (see PRECAUTIONS, General: Pioglitazone hydrochloride, Hepatic Effects and CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency: Pioglitazone hydrochloride). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with Duetact and periodically thereafter (see Precautions, General: Pioglitazone hydrochloride, Hepatic Effects and PRECAUTIONS, Laboratory Tests).

The lowest approved dose of Duetact therapy should be prescribed to patients with type 2 diabetes and systolic dysfunction only after titration from 15 mg to 30 mg of pioglitazone has been safely tolerated. If subsequent dose adjustment is necessary, patients should be carefully monitored for weight gain, edema, or signs and symptoms of CHF exacerbation (see Warnings, Pioglitazone hydrochloride, Cardiac Failure and Other Cardiac Effects).

Maximum Recommended Dose

Duetact tablets are available as a 30 mg pioglitazone plus 2 mg glimepiride or a 30 mg pioglitazone plus 4 mg glimepiride formulation for oral administration. The maximum recommended daily dose for pioglitazone is 45 mg and the maximum recommended daily dose for glimepiride is 8 mg

Duetact should therefore not be given more than once daily at any of the tablet strengths.

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How Supplied

Duetact is available in 30 mg pioglitazone plus 2 mg glimepiride or 30 mg pioglitazone plus 4 mg glimepiride tablets as follows:

30 mg/2 mg tablet: white to off-white, round, convex, uncoated tablet, debossed with 30/2 on one side and 4833G on the other, available in:

NDC 64764-302-30 Bottles of 30

NDC 64764-302-90 Bottles of 90

30 mg/4 mg tablet: white to off-white, round, convex, uncoated tablet, debossed with 30/4 on one side and 4833G on the other, available in:

NDC 64764-304-30 Bottles of 30

NDC 64764-304-90 Bottles of 90

Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed and protect from moisture and humidity.

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References

1. Deng, LJ, et al. Effect of gemfibrozil on the pharmacokinetics of pioglitazone. Eur J Clin Pharmacol 2005; 61: 831-836, Table 1.
2. Jaakkola, T, et al. Effect of rifampicin on the pharmacokinetics of pioglitazone. Br J Clin Pharmacol 2006; 61:1 70-78.

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Human Ophthalmology Data

Glimepiride

Ophthalmic examinations were carried out in over 500 subjects during long-term studies using the methodology of Taylor and West and Laties et al. No significant differences were seen between glimepiride and glyburide in the number of subjects with clinically important changes in visual acuity, intraocular tension, or in any of the five lens-related variables examined.

Ophthalmic examinations were carried out during long-term studies using the method of Chylack et al. No significant or clinically meaningful differences were seen between glimepiride and glipizide with respect to cataract progression by subjective LOCS II grading and objective image analysis systems, visual acuity, intraocular pressure, and general ophthalmic examination.

Rx only

ACTOS® and DuetactTM are trademarks of Takeda Pharmaceutical Company Limited and used under license by Takeda Pharmaceuticals America, Inc.

Distributed by:

Takeda Pharmaceuticals America, Inc.

Deerfield, IL 60015

© 2006 Takeda Pharmaceuticals America, Inc.

05-1140 September 2007

Last Updated: 09/07

Duetact, pioglitazone hydrochloride and glimepiride patient information (in plain English)

Detailed Info on Signs, Symptoms, Causes, Treatments of Diabetes

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The information in this monograph is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects. This information is generalized and is not intended as specific medical advice. If you have questions about the medicines you are taking or would like more information, check with your doctor, pharmacist, or nurse.

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