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This question asks that we answer with 2-dimensional thinking. This issue will never be solved by 2D thinking. What happens if we look at it with 3D thinking?What do we all want? We want good health. We want it all the time and available to us competently and affordably as intervention is needed, rich and poor alike. Ideally, we will be able to choose a physician relationship based on trust and know that that care provider will not be limited to fifteen minutes twice a year of well-care.When the first clinic opens up near me that I can join for a nominal monthly fee, say $100 a month or maybe even as low as $60… perhaps a family plan for $200 or so a month, I will join. How does that work? In return for that retainer, I would expect to be on a wellness regimen, seeing the doctor as necessary to put me on a track to good health, including nutrition and weight-loss counseling and programs, fitness and exercise too, and mental optimization.Some of these programs I might have to pay extra for, if I choose them, and there might not be a physician involved in those aspects, but certainly someone knowledgeable. If the clinic offered chiropractic and acupuncture as options, that would be a big plus for me because, despite my strong skepticism in both cases, they have proven to have unique value for certain issues. All programs would feed into a file that says whether I am on track and what the best way is to get me there.That is likely to involve nutrition advice or disease-avoidance based on my genetic profile. Should I be overweight or sedentary, perhaps I pay a higher fee for the risk I represent.But what if, God forbid, something terrible happens to me? Do I have to pay out of pocket? No, the clinic would insure all of its patients against calamitous health issues as part of what your fees go for.Does that not sound better, ideal even?I wrote a history of a medical school a decade back. The chief of the surgical department told me a story about taking a group of med students to an Hispanic free clinic where there was a woman with a six-week-old that was not prospering. He put his students to the task of figuring out what was wrong, which involved making a makeshift scale, sniffing soiled diapers, abdominal palpitation and so on.The students swiftly concluded there was no infection; the baby must be on the wrong formula. One of the clinic staff was sent out to her car to fetch the formula—sure enough, she’d been given formula for 12-months-and-up. A change of formula, and the follow-up with her showed the baby doing just fine. Then he added, “Do you know what that workup would have cost in-hospital? At least $2000.”Based on that story, I asked several physicians I interviewed to indulge me in a hypothetical. Physicians, who must always focus like a laser on the here-and-now, hate what-if scenarios. But I got three to go along. “Would it be possible to operate clinics that were not just free but that paid people to come for regular checkups on a break-even basis or even turning a profit?”All three eventually agreed it would be possible… theoretically, but very complicated. As one put it, “Do you realize how many laws you would have to change?”“Do you realize how many laws you would have to change?” traces back to the first government foray into the practice of medicine, the Flexner Report of 1910 and associated congressional hearings. Given that this was the Progressive Era, the thrust was to make certain that medicine remained a profession for Anglo-Saxon Protestant males. It shut down all medical schools not operating on the Prussian Koch school of medicine.* (Osteopathic medicine’s five schools survived the onslaught and became home to women, Jews and Catholics who wished to pursue medicine in the US. That included some blacks, though two all-black medical schools were allowed to survive, with two others shut down, on the thinking that would supply sufficient medical care to black communities.)The hearings also opened the door to the inherently costly “gatekeeper” model of medicine in which patient access to medicines and specialty services comes solely via their primary physician. They also put the American Medical Association firmly in charge, making it the nation’s first large-scale lobbying association (and the origin of most of those laws that need changing).I was out for a run one gorgeous day on the San Francisco Peninsula more than three decades ago when an athletically built red-headed gentleman fell in beside me. The discussion quickly turned to diet, and I laughed him off and told him I had never reduced my intake of butter, bacon, eggs and cream. Rather, I watched my intake of sweeter carbs and eliminated sugar from my diet.He told me I was an idiot asking for a heart attack. “There’s nothing wrong with sugar,” he blurted, “it’s just quick energy.” I thought this awfully presumptuous and asked him how heart attacks were unheard of among cultures that ate lots of animal fats or in Mediterranean diets and what about diabetes?The man started getting red in the face, his voice rising as he announced, “I happen to be a cardiologist. When I say you should watch your fat intake, you should listen.” His hands were now balled up in fists, so I simply veered left and went my own way without another word.For years, on the rare occasions I told that story, listeners would often chime in with him, “He’s right.” Now we all know he was wrong, dead wrong, as in people died because of his willingness to dispense pure ignorance.The Koch school of microbial medicine produced heroic advances, the wonder of the world. It has also produced antibiotic resistant “bugs.” It has caused a lot of other areas of medicine to be ignored to the point that, while a plague of resistant pathogens now stands as a distinct menace, our big problems are no longer medical.Thanks to my wife’s employment, I was privy more than two decades back to a Kaiser Permanente study of profitability by member cohort. It showed that all of medical care was profitable.Guys like me who saw a doctor once a decade were quite profitable (they still didn’t approve of us… our thinking might catch on)Those who came to scheduled check-ups and followed doctors orders were the A students, and profitableThose with cancer, diabetes, lung diseases, heart disease, who followed their regimens… profitableWho wasn’t profitable?Those with sedentary to abusive lifestyles—incipient chronics—who failed to follow doctors’ orders (or, as in the case of my cardiologist running buddy, followed doctors’ ill-informed advice)Wary members, usually immigrants new to the system, who hold off presenting until the condition has become acuteA surprisingly large cohort of hypochondriacs, people who see the doctor multiple unnecessary times each year on flimsy pretextsAll of the cost overruns owed to behavioral problems! Foremost among the staggering cost of American medicine is the fact our present system has no incentive (except for Health Maintenance Organizations like Kaiser) to curb bad behaviors. Most of the government programs being pushed are not for medical care; they are insisting that all of us subsidize bad behavior.A local ENT, or ear, nose and throat doctor, a decade back requested my help with an announcement of being the recipient of a prestigious grant to develop a process that would take a common inner-ear problem from being addressed by referral to a specialist, a $2000 procedure, and allow it to be handled by a nurse practitioner with a quick stop at a clinic for $80.The reason he wanted my help was to craft it in a way that played up the prestigious aspect without giving away any hint that he was about to take an appreciable amount of cash out of the practices of his peers.When I was interviewing lots of physicians, they all, one way and another, were thankful for being in a cutting-edge profession. But then would come a revelation like, “When Tagamet came out, I lost half my gastric surgeries. I had a very tough year.” “When colonoscopy came on the scene, I lost all of my exploratory bowel surgeries. I almost went out of business.” “When the Beta-Blockers came out…” and so on.Those were all boons for us patients, but doctors are not aligned with our best interests. Having to revamp their practices and learn new skills is a hardship.My next younger brother visited more than sixty physicians over a fifteen-year period from his late twenties to his mid forties seeking to find out the source of his ceaseless nerve pain. Several primary-care docs offered to refer him to a psychiatrist. Several more scolded him for seeking pain killers and ordered him out of their offices. Most simply said there was nothing they could do for him.Finally he chanced upon a physician trained in Nigeria who had come here for a medical-research PhD. After reciting his symptoms, the man said, “You are describing the classic symptoms of Lyme disease, but surely, as many physicians as you say you have seen, you’ve been tested for that.”“No, I’ve never even heard of it.”Lyme disease has been a top emphasis of continuing medical education year-after-year for decades, since before he contracted it. The earlier the diagnosis, the more successful the treatment. My brother didn’t get a diagnosis until it was well into secondary stage and his quality of life was quite compromised. More than five dozen American primary-care docs failed my late brother utterly and completely.The winds of change need desperately to blow through the medical profession.The American College of Lifestyle Medicine is the new kid in town. They represent just one of the zephyrs that need to blow. We’ve reached the point, foretold by the Kaiser study mentioned above, where lifestyle issues, correctable by a change in lifestyle, account for some eighty percent of medical costs.But with government involvement and a lobbyist organization devoted to damping the winds of change as much as possible, those helpful breezes cannot blow. When I view proposals like the Patient Protection and Affordable Care Act, with my entrepreneurial mindset I see one thing only—a last-ditch effort to lock in the practice of medicine in this country in its present sorry state, an effort to keep subsidizing lower-quality care at unaffordable prices.What is necessary is a system that aligns costs and interests. A system thatputs the cost for poor lifestyle choices on those responsible, forcing changereduces the tremendous overhead of insurance-driven paymentsincentivizes physicians to innovate in the best interest of patientsdemands care providers stay up-to-date on the broad scope of health issues, not just medical onesrequires physicians to tackle rather than boot problem caseshave physicians pay for the insurance so that better patient outcomes produce lower operating costsis flexible in dealing with medical innovation and staying up on accurate informationprovides low-cost ways of profitably initiating lifestyle improvementsIf you look at the system I outlined at the outset, you will see that it has the potential to achieve all of these desirable realignments significantly reducing costs all around, substantially broadening the provision of care and making sure that our care providers have a financial stake in providing truly cutting-edge care to us so that we stay healthy and their balance sheet does too.* Well before the Flexner report, Sam Hahneman, the founder of homeopathic medicine, took to referring to the form of medicine that survived the Flexner shakeout as “allopathic” medicine, meaning “other than the problem.” It was an indictment of the tendency of western medicine to engage (expensively) in symptom management rather than address underlying issues, keeping illness a “cash cow.” The name stuck.

Kallmann syndrome and nIHH are treated with hormone replacement therapy, with the specific medications and doses tailored to the patient's needs. This treatment focuses first on inducing puberty and maintaining normal hormone levels. Later, the treatment may be changed to induce fertility.The early development of the hypothalamus and sense of smell in the human embryo are both affected in Kallmann sydnrome. The portion of the hypothalamus that produces GnRH originally forms as part of the nose and migrates during the early stages of embryonic development to join the rest of the hypothalamus. In Kallmann syndrome, both this portion of the hypothalamus and the smell-detecting (olfactory) neurons in the brain do not develop fully.When a person has the hormone deficiency characteristic of Kallmann syndrome but has a normal sense of smell, the condition is known as normosmic idiopathic hypogonadotropic hypogonadism (nIHH).Causes of Kallmann syndromeKallmann syndrome and nIHH are genetic conditions. They are caused by mutations in any of several different genes. Some, but not all, of these have been identified and the inheritance patterns mapped.Different gene mutations causing Kallmann syndrome and nIHH have different inheritance patterns.Some must be inherited from both parents (autosomal recessive inheritance). In these types, both parents may be carriers, which means they have no symptoms of the disease.Others can be inherited from either the mother or the father (autosomal dominant inheritance).In other types, females are carriers and males have (express) the condition (X-linked inheritance). In these types, the condition can be passed from mothers to sons but not from fathers to sons. Either parent can pass the condition to a daughter as a carrier.Researchers have more recently identified a fourth inheritance pattern in which mutations in more than one gene may combine to cause the condition (oligogenic inheritance).Researchers are working to identify all of the genetic mutations associated with Kallmann syndrome and nIHH.Signs and symptoms of Kallmann syndromeThe main symptom of Kallmann syndrome or nIHH is delayed or incomplete puberty. In Kallmann syndrome, this is paired with an impaired sense of smell, a condition present from birth but often not brought to a doctor’s attention until asked about it in the course of diagnosing the cause of delayed puberty.Other characteristics may also be present in children and adolescents with Kallmann syndrome or nIHH. These can include:Undescended, or partially descended, testiclesSmall penile sizeFacial defects, such as cleft lip or palateShort fingers or toes, especially the fourth fingerDevelopment of only one kidneyHearing lossColor blindnessAbnormal eye movementsAbnormal development of the teethMirror hand movements (bimanual synkinesis), in which the movements of one hand are mirrored by the movements of the otherTesting and diagnosis of Kallmann syndromeYour doctor will usually begin with a physical exam and with questions about any symptoms you may have noticed, especially those having to do with delayed puberty and impairments to the sense of smell. Because this is an inherited condition, the doctor may also ask about relatives who have experienced delayed puberty or problems with fertility.If signs indicate the possibility of Kallmann syndrome or nIHH, additional tests may include:Blood tests looking specifically at hormone levels in the peripheral veins that originate from the pituitary glandMagnetic resonance imaging (MRI) of the hypothalamus, pituitary gland and nose to look for anatomical abnormalitiesMolecular genetic testing to look for specific gene mutationsTreatment of Kallmann syndromeKallmann syndrome and nIHH are treated with hormone replacement therapy, with the specific medications and doses tailored to the patient’s needs. This treatment focuses first on inducing puberty and maintaining normal hormone levels. Later, the treatment may be changed to induce fertility.Medication may also be needed to restore bone health, as the same absence of hormones that leads to delayed puberty can also lead to a weakening of bone density and strength.Longer term, hormone replacement therapy for males may be reduced or withheld periodically to see if the body has reversed the condition and is producing normal levels of hormones. This reversal was found to occur in 10 to 15 percent of male patients in a study at one center.The details of referral to this specific group can be discussed with an endocrine provider in the CHOP Neuroendocrine Center.Follow-up careWhen medication is needed to supplement hormone production, periodic follow-up tests are needed to ensure that the treatment continues to work effectively. Dosage levels and the combination of medications may need to be adjusted over time.Kallmann SyndromeNORD gratefully acknowledges Maria I. Stamou, MD, Postdoctoral Research Fellow and Ravikumar Balasubramanian, MD, PhD, Instructor in Medicine, Harvard Reproductive Endocrine Sciences Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School; William F. Crowley, Jr., MD, Daniel K. Podolsky Professor of Medicine, Harvard Medical School, Director, Harvard Reproductive Sciences Center of Excellence, Director of Clinical Research, Massachusetts General Hospital, for the preparation of this report.Synonyms of Kallmann Syndromeidiopathic hypogonadotropic hypogonadism with anosmiaGeneral DiscussionKallmann syndrome (KS) is a rare genetic disorder in humans that is defined by a delay/absence of signs of puberty along with an absent/impaired sense of smell. A closely related disorder, normosmic idiopathic hypogonadotropic hypogonadism (nIHH), refers to patients with pubertal failure but with a normal sense of smell. Both KS and nIHH are due to an isolated deficiency of a key reproductive hormone called gonadotropin-releasing hormone (GnRH). KS and nIHH occurs in both sexes but males are more commonly diagnosed with this condition. Patients with KS/nIHH typically present at adolescence due to the delay in the onset of physical changes associated with puberty. KS patients are often aware of their lack of sense of smell but most may not have sought medical advice for this symptom. While these reproductive symptoms predominate in their presentation, non-reproductive features that may be present in KS/nIHH subjects include: facial abnormalities (eg. cleft lip/palate), absence of one kidney, shortened digits, deafness, eye movement abnormality etc. Typically, the diagnosis of KS/nIHH is made by a pediatric/adult endocrinologist. Following clinical examination, biochemical blood testing and various imaging tests are undertaken to confirm the diagnosis. As this is a genetic condition, testing for the various different genetic forms of this disease may also assist in making the diagnosis. For therapy, initially, hormone replacement therapy (testosterone in males; estrogen and progesterone in females) is used to induce secondary sexual characteristics. Once pubertal maturation is achieved, if KS and nIHH subjects wish to be fertile, either injections of pituitary hormones (the gonadotropins, LH and FSH) or in some instances, therapy with the synthetic peptide, GnRH, whose deficiency causes these syndromes, are required to induce the sex organs (testes or ovaries) to make sperm (males) or eggs (females). While both KS and nIHH are usually life-long in their nature, about 10-15% of patients may experience a recovery of their hormonal system, the reasons for which currently remain unclear.IntroductionNormal reproductive axis in humans The hypothalamus is a special area in the brain that is responsible for control of several hormones in the body. Reproductive function in humans is under the control of a group of ~ 1,200-1,500 cells (neurons) called GnRH (Gonadotropin-Releasing Hormone) neurons. At the time of puberty, these neurons coordinately secrete GnRH, a peptide hormone, in a series of discrete series of bursts or pulses. This pulsatile pattern of secretion of GnRH is the key to stimulating the production of two other glycoprotein hormones from the pituitary which is downstream from the hypothalamus, namely luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In turn, LH and FSH act on the sex organs or gonads in both sexes (testicles in men; ovaries in women) to do two things that are essential for human reproduction. The first is to stimulate the gonads to secrete sex steroids like testosterone in men and estrogen in women. The second is to produce the germ cells in the gonads (sperm in men and eggs in women). Pathophysiology of Kallmann syndrome (KS) and normosmic idiopathic hypogonadotropic hypogonadism (nIHH) GnRH is the master controller or 'pilot light' of reproduction. GnRH neurons are active in stimulating the reproductive axis at birth; become quiet during childhood; and initiate the awakening of the dormant reproductive axis of children at puberty. The GnRH neurons for these processes are unique amongst other hypothalamic neurons in the fact that they have a very complex developmental pattern. During the fetal period, these GnRH neurons originate in the olfactory placode (i.e. the early developing nose); then migrate along the fetal olfactory (smell-related) neurons that also originate in the nose; and eventually enter the brain ultimately wending their way to the hypothalamus, their ultimate residence during early gestation. In both sexes, these GnRH neurons are fully active and functional secreting GnRH soon after birth (neonatal period) and begin to secrete GnRH in a characteristic pulse pattern. However, this GnRH secretory activity, for reasons not entirely clear, becomes quiescent in childhood and mysteriously, reawakens again during adolescence marking the onset of puberty. Defects in either the development of GnRH neurons or their secretory function result in disruption of normal puberty. The condition of KS results when there is failure of the early development and/or migration of the GnRH neurons in the fetus. Therefore, when this migratory journey is interrupted due to various genetic defects, patients develop this unique combination of GnRH deficiency and anosmia (due to loss of olfactory neurons), that define this clinical syndrome. When GnRH deficiency results from either from defective GnRH secretion/action without any developmental migratory deficits, patients present with just GnRH deficiency without any smell defects. This group of patients is labeled as nIHH subjects, the nomosmic counterpart to KS. In both KS and nIHH patients, the rest of the hypothalamic and pituitary hormones are completely normal and the radiographic appearance of the hypothalamic-pituitary region is typically normal. Taken together, both KS and nIHH represent patients with "isolated GnRH deficiency" (IGD), which is the most precise pathophysiologic definition of this disorder. Historically, it was the KS form of IGD that was recognized first. As early as in the 19th century, the clinical association of anosmia and hypogonadism was recognized by a Spanish pathoglogist, Maestre de San Juan. However, it was Kallmann and Schoenfeld in 1944 who redefined this syndrome in the modern era. They showed the co-segregation of anosmia and hypogonadism in affected individuals from three families and therefore established the hereditary nature of this syndrome (i.e. passing from parents to offspring). Since then, this combination of hypogonadotropic hypogonadim and anosmia is described with the eponymous name, "Kallmann syndrome". However, even in Kallmann's first report, the presence of nIHH individuals was also recognized in some of these families as well as the presence of various non-reproductive clinical features. Since these early reports, both these clinical entities have been well studied and this report summarizes the clinical symptoms, causes, their associated non-reproductive phenotypes, the correct diagnostic work up, and the various treatment options for both KS and nIHH forms of IGD.Signs & SymptomsThe clinical hallmark of IGD is the failure of onset of puberty. This lack of pubertal maturation, i.e. hypogonadism, occurs in both sexes and is characterized by reduced blood levels of the sex hormone levels (testosterone and estrogen) as well as gonadotropins (LH and FSH) and infertility. In boys, the onset of normal pubertal development is heralded by testicular enlargement that is then followed by penile growth and the appearance of pubic hair. Affected men complain of absence of secondary sexual characteristics (facial hair growth, body hair growth, decreased pubic hair growth and genital enlargement) and a delayed growth spurt in comparison to their peers. In addition, an absence of sexual interest (libido) and poor sexual function (inability to attain or sustain an erection) may also be present. Unusual growth of breasts may also be rarely seen in these subjects although this more typically occurs during treatment of this condition and is often transient (see below).Clinical examinations in these subjects usually confirms the incomplete sexual maturation (e.g. prepubertal testicular volume [< 4ml]), a eunuchoid body habitus (disproportionally long arms when compared to height) and decreased muscle mass. The degree of pubertal maturation can vary considerably with some individuals lacking any sign of puberty whereas others may have partial pubertal features that do not progress normally. Although IGD in males is typically diagnosed at puberty, this diagnosis can be made in infancy due to a small genital size (micropenis/microphallus) and/or lack of descent of testes (undescended testes or referred to as cryptorchidism). As mentioned earlier, pulsatile GnRH secretion and evidence of a normal reproductive axis occurs during the neonatal period. Hence, timely biochemical testing during the first 6 months or so of life may also confirm the presence of hypogonadism with low gonadotropin levels, i.e. the biochemical hallmarks of this condition during this critical window of normal development. However, if this brief developmental window of diagnostic testing is missed, a definite diagnostic confirmation may have to wait until the expected time of puberty although the increasing knowledge of the genetic basis of this condition may enable confirmation by specific genetic testing (see below).In girls, the first sign of normal puberty is the onset of breast budding (thelarche), followed by a growth spurt, the appearance of pubic hair growth, and then only later, the onset of menstrual flow, i.e. menarche. IGD females typically report absence of breast development, an attenuated growth spurt, decreased pubic hair growth, and lack of initiation of menses (primary amenorrhea). However, some females may exhibit some evidence of a partial puberty with thelarche that fails to progress. Very occasionally, some IGD females may report onset of menses at the appropriate time period in adolescence that ceases after a few cycles. Clinical exam in IGD females usually confirms their immature sexual characteristics and enuchoid habitus. It is important to note that development of pubic hair can be normal in both sexes as it is controlled by secretion of androgens from the adrenal glands, i.e. adrenarche, which is unaffected in IGD subjects.As mentioned earlier, ~50% IGD subjects have KS and exhibit either anosmia (complete lack of smell) or hyposmia (reduced ability to smell). Many IGD subjects also exhibit a spectrum of other non-reproductive features and these features may offer clues to the underlying genetic etiology of IGD (see below). Commonly recognized non-reproductive features that may be present in IGD subjects include:·Midline facial defects such as cleft lip and/ or palate·Renal agenesis (One kidney does not develop)·Short metacarpals (short fingers, especially the 4th finger)·Deafness·Mirror movements (synkinesia)·Eye movement abnormalities·Poor balance due to cerebellar ataxia·Scoliosis (bent spine)CausesIGD is caused by mutations in a number of different genes and to-date, ~50% of patients have a demonstrable genetic mutation that is identifiable. While some genes primarily cause the KS form of IGD, others cause nIHH only, and some can cause both forms of this disorder. Mutations in genes that are thought to disrupt the development and migration of GnRH neurons from the olfactory epithelium to hypothalamus result in the KS phenotype. These include: KAL1, NELF, FGFR1, FGF8, PROK2, PROKR2, HS6ST1, CHD7, WDR11 and SEMA3A. Genes that primarily interfere with the normal secretion of GnRH (GNRH1, KISS1, KISS1R (GPR54), TAC3, TACR3) or its action on the pituitary (GNRHR) cause nIHH. The “overlap genes” ie. the ones that cause both KS and nIHH include FGFR1, FGF8, PROK2, PROKR2, HS6ST1, CHD7, WDR11 and SEMA3A. Presumably, these genes may have multiple roles in GnRH biology including both migration and their normal secretory function.Each of these genes have varied pattern of affecting families, i.e. inheritance (the way that the disorder passes from parents to offspring). All forms of Mendelian inheritance (autosomal dominant, autosomal recessive, and X-lined recessive) as well more complex oligogenic inheritance patterns are now recognized. Understanding the genetic basis of the disorder is crucial not only for genetic counseling for determine the risk of transmission to the next generation, but also for fostering new gene discovery as well as bench-to-bedside research.General notes on inheritance of genetic diseases:Genes for any particular trait are located on chromosomes (rod-shaped organelles consisting of DNA in the nucleus of each cell) and each individual receives 23 chromosomes (22 autosomes and one sex-chromosome like the X and Y chromosomes), each from the father and the mother. Knowing which gene is located on which chromosome allows a prediction of the inheritance pattern of each gene and based on this pattern of inheritance, the probability of passing the disease from parents to their children. A brief summary of the common modes of inheritance are discussed below:Autosomal dominant inheritance: Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary and sufficient to cause a particular disease. Thus the risk of transmitting a dominant gene is the same for males and females and hence can be inherited from either parent. The risk of passing the abnormal gene from an affected parent to offspring is 50% for each pregnancy.Autosomal recessive inheritance: Recessive genetic disorders also affect both sexes equally but differ from dominant inheritance in that a disease only occurs when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms of that condition. Marriages within close relatives (consanguineous marriages) thus have a higher risk of having children with a recessive genetic disorder than unrelated parents, as they are more likely to carry the same abnormal gene. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. Although consanguineous families with intermarriage are much more likely to experience these recessive diseases, these disorders can also arise in non-consanguineous (i.e. non-related) parents who happen to carry mutations in the same gene.X-linked inheritance: In X-linked recessive inheritance, females with a mutation in a gene on the X chromosome usually do not display symptoms of the disease linked to the genetic mutation since females have two X chromosomes and the normal gene on the second X chromosome can compensate for the mutated one. However, since males have only one X chromosome that is inherited from their mother (i.e. they are hemizygous), if they inherit an X chromosome that contains a defective gene, they will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will then be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Hence any condition in which a father passes a disease on to his son is, by definition, not an X-linked condition.Oligogenic inheritance: Oligogenic inheritance refers to a newly recognized inheritance pattern in which mutations in more than one gene synergistically interact and function in an additive manner to cause a disease phenotype. Both genes may have mutations (i.e. this is a digenic condition) in only one copy (i.e. it is a bi-allelic condition) or occasionally, one gene may have two mutations, each in a different allele they carry and the other may harbor a single mutation giving triallelic-digenic inheritance. Approximately, 10-15% of IGD patients have been shown to display this form of inheritance.The genes linked to IGD include:KAL1The first gene found responsible for KS was initially localized to the distal portion of X chromosome (Xp22.3) by studying patients with a “contiguous gene syndrome” (i.e. multiple genes lost due to large deletion of a portion of a chromosome resulting in multiple clinical phenotypes). This cluster of phenotypes included: short stature, chondrodysplasia punctata, intellectual disability, icthyosis and KS. By mapping the genes within this large deletion, the KAL1 gene was identified as the cause of KS. KAL1 is an X-linked gene and IGD is inherited in an X-linked recessive manner. KAL1 is comprised by 14 exons and encodes a secreted extracellular matrix protein called anosmin-1. Anosmin-1 plays an important role in the neuronal migration of both the GnRH neurons as well as the olfactory structures. This dual defect results in the characteristic combination of GnRH deficiency and anosmia, respectively. In addition, patients with KAL1 mutations may have additional non-reproductive phenotypes such as unilateral renal agenesis (absence of one kidney) and mirror movements. It is known that anosmin is also involved in kidney development, thus explaining why some patients with KS have renal agenesis. In addition, anosmin is also important for the crossing of the neurons in the developing brain across the midline, and this accounts for the mirror movements. Although KAL1 is a prototypical X-linked recessive gene, it is now known that some female carriers of KAL1 gene may also manifest IGD, suggesting other genetic mechanisms in these female carriers.KISS1R (GPR54)/KISS1In 2003, two independent groups indentified autosomal recessive mutations in KISS1R (formerly called GPR54) as a cause of nIHH form of IGD. The KISS1R encodes the kisspeptin receptor, a cognate G-protein-couple receptor for the ligand, kisspeptin. Kisspeptin is a secreted neuropeptide and it is now well-established the kisspeptin signaling system is an upstream regulator of the GnRH neurons. Recently, mutations in the gene KISS1 encoding kisspeptin itself, was also found to underlie autosomal recessive nIHH. Both KISS1 and KISS1R mutations affect the secretion of GnRH rather than the migration of GnRH neurons, thus resulting in nIHH exclusively. These human genetic observations and other supportive data from both humans and other species, now confirm that kisspeptin signaling is the most robust stimulator of GnRH secretion known currently.FGF8/FGFR1Using an IGD patient with a chromosomal breakpoint on 8p11.2-p11.1, FGFR1 (KAL2), a gene encoding the tyrosine kinase receptor, fibroblast growth factor receptor 1, was identified as a cause of KS. Subsequently, this was confirmed and in addition, mutations in FGFR1 were also identified in nIHH subjects, thus implicating this gene as an “overlap” gene causing both forms of IGD. Since then a large number of mutations of this gene have been uncovered as a cause of IGD. In mice that lack FGFR1, although the connection between the olfactory axons and the forebrain does occur, the olfactory bulb that is responsible for the sense of smell cannot evaginate from the epithelial wall. This observation could explain GnRH neuronal and olfactory migrational defect in patients with mutations in the FGFR1. Although there are 23 known FGF ligands, using the crystallographic modeling information of these ligands and by studying a single FGFR1 mutation, FGF8 was then identified as the ligand responsible for GnRH neuronal migration and mutations in FGF8 have now indentified in IGD patients. Typically, although both FGF8 and FGFR1 mutations are inherited in an autosomal dominant manner considerable variable penterance/expressivity characterizes pedigrees with these mutations. Amongst their clinical characteristics, patients with mutations in this pathway exhibit unique non-reproductive features such as dental agenesis, midline facial defects (cleft lip/palate) and digital bony abnormalities.PROK2/PROKR2 (Prokineticin 2/Prokineticin 2 receptor)Following the demonstration of deletions of Prok2 and Prokr2 as genetic causes of KS in mice, mutations in their respective human homologs, PROK2 and PROKR2 have been identified to cause both KS and nIHH. Both these genes are critical regulators of both GnRH neuronal development as well as the GnRH release. It is important to recognize that the majority of those mutations in these two genes have been found in the heterozygous states in humans, whereas heterozygous mice for these mutations don’t present with a similar phenotype. In addition, human harboring mutations in PROK2 and PROKR2 also present with variable clinical characteristics, ranging from severe IGD to seemingly unaffected healthy subjects. This fact indicates that a combination of mutations in different genes may be required for the eventual expression the IGD phenotype and argues strongly for oligogenicity as the inheritance mode for the PROK2 pathway.GNRH1/GNRHRBoth GNRH1 and GNRHR are obvious candidate genes to cause IGD. IGD patients with mutations in GNRHR were the first to be described. GNRHR mutations are relatively common and cause the nIHH form of IGD. Studies in patients with GNRHR mutations reveal a heterogeneous clinical presentation, with both autosomal recessive and oligogenic inheritance patterns. After several years of investigation, GNRH1 mutations were eventually shown to be a cause of GnRH deficiency in 2009. While GNRHR mutations are fairly common, mutations in GNRH1 are extremely rare and mutations were only identified after genetic studies were done in over 400 patients with IGD. No specific non-reproductive feature is seen in this group of patients.TAC3 and TACR3Using homozygosity mapping in consanguineous pedigrees (families where couples marry with closely related individuals), two novel genes involved in tachykinin signaling, TAC3 (encoding neurokinin B) and its receptor (TACR3) were identified as causes of nIHH. Subsequently, mutations in these two genes were also identified in non-endogamous IGD patients and show the neurokinin pathway plays an important role both in ‘mini-puberty’ as well as the GnRH activation in puberty. However, longitudinal studies have revealed that several subjects with TAC3/TACR3 mutations eventually reverse their GnRH deficiency in adulthood, suggesting that this pathway may be dispensable for adult reproductive function. No specific non-reproductive feature is seen in this group of patients.CHD7Mutations in gene CHD7 cause a severe CHARGE syndrome (eye coloboma, heart anomalies, choanal atresia, growth and developmental retardation, genitourinary anomalies and ear abnormalities) (OMIM #214800). The “G” in CHARGE related to hypogonadism occurring secondary to IGD. Recently, milder allelic variants in CHD7 have been linked to a non-syndromic presentation of IGD (both KS and nIHH), and surprisingly accounts for ~7% of IGD patients. These mutations are typically inherited milder missense mutations vs. CHARGE syndrome mutations which are de novo truncating/frameshift mutations, suggesting a genotype-phenotype correlation (unpublished data from the author’s clinical center). IGD patients with CHD7 mutations may also have additional CHARGE related features and ~30% of patients may display hearing loss (unpublished data from the author’s clinical center). Therefore, physicians as well as genetic counselors should perform extensive clinical evaluation to exclude these features.NELFThe human nasal embryonic LHRH factor gene, NELF, has been shown to function as a guidance molecule for olfactory axon projections and neurophilic migration of GnRH cells in mice. Mutations in NELF have been identified in IGD patients (both KS and nIHH), primarily in an oligogenic inheritance pattern.WDR11The WDR11 gene encodes for WD Repeat Containing Protein 11. Heterozygous mutations in WDR11 were recently identified as a cause of IGD. While both KS and nIHH subjects harbored variants in WDR11, murine studies show interaction of WDR11 with EMX1, a homeodomain transcription factor in olfactory neuronal development, thus accounting for its implication in KS. The precise biologic role of WDR11 in neuroendocrine regulation of GnRH is yet to be established.HS6ST1Mutations in HS6ST1 gene, encoding heparan sulfate (HS) 6-O-sulfotransferase, a member if heparan sulfate (HS) polysaccharides were recently identified as an oligogenic cause of IGD (both KS and nIHH). HS6ST1 catalyzes the transfer of sulfate from 3-prime-phosphoadenosine 5-prime-phosphosulfate to position 6 of the N-sulfoglucosamine residue of heparan sulfate and plays a crucial role in cell-cell communication and neuronal development. Genetics experiments in the worm, (C. elegans) also revealed that reveal that HS cell specifically regulates neural branching in vivo in concert with other IHH-associated genes, such as KAL1, FGFR1 and FGF8. These findings are consistent with a model in which anosmin-1 can act as a modulatory coligand with FGF8 to activate the FGFR1 receptor in an HS-dependent manner.SEMA3AMost recently, mutations as well as partial deletions in SEMA3A, encoding a secreted axonal guidance molecule, semaphorin 3A, were identified in ~6% of KS patients. Semaphorin 3A, a class 3 semaphorin, activates the neuropilin-plexin-A1 holoreceptor complex and acts as an axonal repulsive cue to the axonal growth cone during embryonic development. Supportive data from both murine deletions of Sema3a as well as mice with specific mutation in the semaphorin binding domain of its receptor show abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain.In conclusion, IGD is caused by a large number of mutations in many different genes, which now explain ~50% of the genetic causes of the disorder. While most are inherited in a strict Mendelian pattern, several of these genes are shown to interact with each other in an oligogenic manner, which means that patients with IGD may carry mutations in more than one gene, contributing to the complexity of the disease as well as its inheritance to the next generations. Thus, IGD patients require formal genetic counseling to both assess the etiology of their condition as well as the risk of transmission to subsequent generations.Affected PopulationsBoth KS and nIHH are relatively rare, can affect both males and females, with a clear male predominance (~4:1). According to a recent retrospective study, to identify all diagnosed KS cases throughout Finland born during a defined time period, the minimal incidence of KS in Finland was approximately 1 in 48,000 newborns. There was a clear difference in estimates between boys (1 in 30,000) and girls (1 in 125,000). The reason for this sex ratio relates in part to the genetics and in part due to a bias of ascertainment wherein males with delayed puberty tend to seek care more frequently than do their female counterparts. A precise estimate of prevalence remains a challenge as there may be differences in different populations.Related DisordersOccasionally, GnRH deficiency may present as adult-onset GnRH deficiency, wherein there is a history of an age-appropriate normal puberty followed by decrease in libido and fertility in adult life. These patients have usually normal testicular size and historical or physical evidence of normal spontaneous maturation, with documented fertility in several cases.Delayed puberty is characterized by delay of initiating puberty, but subsequent normal progression of sexual development. In contrast with the incidence in general population (<1%), delayed puberty has been observed much more frequently in families of patients with GnRH deficiency.IGD must be also distinguished from other forms of functional deficiency of GnRH, which present more commonly in women in the setting of excessive extreme exercise, severe weight loss, stress or dietary restriction (e.g. anorexia nervosa). This form of GnRH deficiency is referred to as hypothalamic amenorrhea (HA) and recent evidence suggests that genetic mutations in genes causing IGD may also be present in these women.Structural lesions of hypothalamus, such as tumors can interfere in the normal pattern of GnRH secretion. It is for that reason that normal radiographic appearance of the pituitary and hypothalamus is required for the diagnosis of IGD.In addition, various multisystem disorders (syndromic patients) with overlapping features of KS/nIHH have been reported. These include: CHARGE Syndrome (due to CHD7 mutations (see above), adrenal hypoplasia congenita (AHC) (due to DAX1 mutations), congenital obesity syndromes (due to LEP/LEPR mutations), Bartlet-Biedl Syndrome (several genes) and Moebius Syndrome.DiagnosisThe diagnosis of Kallmann syndrome is based on the clinical evidence of arrested sexual maturation or hypogonadism and the incomplete sexual maturation by Tanner staging on physical examination. Tanner staging is an established way used during the physical examination by endocrinologists and pediatric endocrinologists worldwide to evaluate the maturation of the primary and secondary sexual characteristics:STAGE 1Pubic Hair. NoneMale Genitalia. Childhood appearance of testes, scrotum, and penis (testicular volume <4 mL)Female Breast Development. No breast bud, small areola, slight elevation of papillaSTAGE IIPubic Hair. Sparse hair that is long and slightly pigmentedMale Genitalia. Enlargement of testes; reddish discoloration of scrotumFemale Breast Development. Formation of the breast bud; areolar enlargementSTAGE IIIPubic Hair. Darker, coarser, curly hairMale Genitalia. Continued growth of testes and elongation of penisFemale Breast Development. Continued growth of the breast bud and areola; areola confluent with breastSTAGE IVPubic Hair. Adult hair covering pubisMale Genitalia. Continued growth of testes, widening of the penis with growth of the glans penis; scrotal darkeningFemale Breast Development. Continued growth; areola and papilla form secondary mound projecting above breast contourSTAGE VPubic Hair. Laterally distributed adult- type hairMale Genitalia. Mature adult genitalia (testicular volume >15mL)Female Breast Development. Mature (areola again confluent with breast contour; only papilla projects)Typically, Tanner staging in IGD patients show:·Stage I-II genitalia in males, stage I-II breasts in females·Stage II-III pubic hair in both males and females, since it is controlled in part by adrenal androgens·Pre-pubertal testicular volume (stage I; <4mL) in malesHowever, the degree of sexual maturation can vary considerably between subjects. Occasionally, males with IGD can present with a partial pubertal phenotype, termed as the ‘fertile eunuch syndrome’, first described in 1950’s by Paqualini and Bur. These patients are hypogonodal with eunuchoid body proportions but their testicular measurements and spermatogenesis are nearly normal, suggesting an element of spontaneous testicular maturation. Similarly, in females, partial phenotypes with variable degree of breast development and in some extreme cases, menses may occur which then ceases. These partial phenotypes may be seen across all genetic forms of the disease and indicate some attenuated activity of their GnRH neuronal secretory activity.Apart from the physical examination, biochemical testing is also critical for diagnosis of IGD. As GnRH is not measurable, serum concentration of the gonadotropins (LH and FSH (secreted by the pituitary) and sex steroids are used for diagnosis. In patients with IGD, LH and FSH serum concentrations can be either low or normal, which is highly inappropriate in the presence of low testosterone (in males) and estradiol (in females). In addition, radiographic imaging of the hypothalamus-pituitary region using MRI scans is undertaken to rule any anatomical structural abnormalities. In addition the MRI exam may also indicate the absence of the olfactory structures in KS patients.Sense of smell can be evaluated by history and by formal diagnostic smell tests, such as the University of Pennsylvania smell identification test (UPSIT). This “scratch and sniff” test evaluates an individual’s ability to identify 40 microencapsulated odorants and can be easily performed in most clinical settings. Identification of anosmia, hyposmia, or normosmia is based on the individual’s score, age at testing and gender and is interpreted using a standard normogram in the UPSIT manual.As it has been already mentioned, molecular genetic testing for specifying the genes responsible for each affected individual indicates the way that other family members can be affected. Currently, clinical molecular genetic testing for mutations in KAL1,GNRHR, KISS1R, FGFR1, PROKR2, PROK2, CHD7, FGF8, GNRH1 and TACR3 genes are available to confirm the diagnosis. (Genetic Testing Registry).Standard TherapiesTreatmentThe standard forms of medical treatment involve hormone replacement therapies and this is usually tailored the clinical need of the patients. Typically, once the diagnosis is made, in both sexes, treatment is aimed at inducing puberty and maintaining normal hormonal levels. Subsequently, treatment may also be need for inducing fertility for achieving pregnancy.In males, puberty is usually initiated using testosterone therapy and various formulations of testosterone are currently available for this purpose. The most commonly used modes of treatment include testosterone injections given intramuscularly every 2 or 3 weeks depending on the particular injection) or topical testosterone formulations (patches, gels, liquids etc). Once puberty is initiated, testosterone therapy is continued to maintain secondary sex characteristics as well as to normalize biochemical testosterone levels in the blood. When fertility is desired, gonadotropin therapy (hCG and human menopausal gonadotropins [hMG] or recombinant FSH [rFSH]) can be administered to stimulate testicular growth and initiate sperm production (spermatogenesis). Typically, sperm is rarely seen in the semen analysis until testicular volume reaches at least 8 mL. In most IGD individuals without a history of cryptorchidism (undescended testes), sperm function is usually normal and conception can occur even with relatively low sperm counts.In females, estrogen and progestin therapy is used to induce the secondary sex characteristics, whereas gonadotropins or pulsatile GnRH therapy can be utilized to stimulate production of mature egg cells (folliculogenesis). If spontaneous pregnancy fails to occur despite normal folliculogenesis, in vitro fertilization may be considered with conception rates reported to be approximately 30% per ovulatory cycle.In addition to treating hypogonadism, potential deterioration in bone health that may have resulted from periods of low circulating sex hormones should be addressed. Depending on the history (the timing of puberty, duration of hypogonadism, and other osteoporotic risk factors [e.g., glucocorticoid excess, smoking) and bone mineral density measurement, measurement, specific treatment for decreased bone mass should be considered.Finally, it is really important to be reminded that since ~10-15 % of male patients studied in a referral IGD clinical center have been noted to have reversal of their hypogonadism, IGD patients must be evaluated serially for evidence of this reversibility. Features indicative of reversal include: testicular volume growth despite being on testosterone therapy and normalization of testosterone levels without adequate hormone replacement.

Adderall DescriptionA single-entity amphetamine product combining the neutral sulfate salts of dextroamphetamine and amphetamine, with the dextro isomer of amphetamine saccharate and d, l-amphetamine aspartate. kindly email juicetrip at Protonmail dot com to purchase Adderall with and without prescription, not out of context reliable sources and legit.EACH TABLET CONTAINS5 mg7.5 mg10 mg12.5 mg15 mg20 mg30 mgDextroamphetamineSaccharate1.25 mg1.875 mg2.5 mg3.125 mg3.75 mg5 mg7.5 mgAmphetamine Aspartate Monohydrate Equivalent1.25 mg*1.875 mg†2.5 mg‡3.125 mg§3.75 mg¶5 mg#7.5 mgÞDextroamphetamineSulfate, USP1.25 mg1.875 mg2.5 mg3.125 mg3.75 mg5 mg7.5 mgAmphetamineSulfate, USP1.25 mg1.875 mg2.5 mg3.125 mg3.75 mg5 mg7.5 mgTotal Amphetamine Base Equivalence3.13 mg4.7 mg6.3 mg7.8 mg9.4 mg12.6 mg18.8 mgInactive Ingredients: colloidal silicon dioxide, compressible sugar, corn starch, magnesium stearate, microcrystalline cellulose and saccharin sodium.Colors: Adderall ® 5 mg is a white to off-white tablet, which contains no color additives.Adderall ® 7.5 mg and 10 mg contain FD&C Blue #1 Aluminum Lake as a color additive.Adderall ® 12.5 mg, 15 mg, 20 mg and 30 mg contain FD&C Yellow #6 Aluminum Lake as a color additive.Adderall - Clinical PharmacologyPharmacodynamicsAmphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Amphetamines are thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.PharmacokineticsAdderall® tablets contain d-amphetamine and l-amphetamine salts in the ratio of 3:1. Following administration of a single dose 10 or 30 mg of Adderall® to healthy volunteers under fasted conditions, peak plasma concentrations occurred approximately 3 hours post-dose for both d-amphetamine and l-amphetamine. The mean elimination half-life (t1/2) for d-amphetamine was shorter than the t1/2 of the l-isomer (9.77 to 11 hours vs. 11.5 to 13.8 hours). The PK parameters (Cmax, AUC0-inf) of d-and l-amphetamine increased approximately three-fold from 10 mg to 30 mg indicating dose-proportional pharmacokinetics.The effect of food on the bioavailability of Adderall® has not been studied.Metabolism and ExcretionAmphetamine is reported to be oxidized at the 4 position of the benzene ring to form 4-hydroxyamphetamine, or on the side chain α or β carbons to form alpha-hydroxy-amphetamine or norephedrine, respectively. Norephedrine and 4-hydroxy-amphetamine are both active and each is subsequently oxidized to form 4-hydroxy-norephedrine. Alpha-hydroxy-amphetamine undergoes deamination to form phenylacetone, which ultimately forms benzoic acid and its glucuronide and the glycine conjugate hippuric acid. Although the enzymes involved in amphetamine metabolism have not been clearly defined, CYP2D6 is known to be involved with formation of 4-hydroxy-amphetamine. Since CYP2D6 is genetically polymorphic, population variations in amphetamine metabolism are a possibility.Amphetamine is known to inhibit monoamine oxidase, whereas the ability of amphetamine and its metabolites to inhibit various P450 isozymes and other enzymes has not been adequately elucidated. In vitro experiments with human microsomes indicate minor inhibition of CYP2D6 by amphetamine and minor inhibition of CYP1A2, 2D6, and 3A4 by one or more metabolites. However, due to the probability of auto-inhibition and the lack of information on the concentration of these metabolites relative to in vivoconcentrations, no predications regarding the potential for amphetamine or its metabolites to inhibit the metabolism of other drugs by CYP isozymes in vivo can be made.With normal urine pHs approximately half of an administered dose of amphetamine is recoverable in urine as derivatives of alpha-hydroxy-amphetamine and approximately another 30% to 40% of the dose is recoverable in urine as amphetamine itself. Since amphetamine has a pKa of 9.9, urinary recovery of amphetamine is highly dependent on pH and urine flow rates. Alkaline urine pHs result in less ionization and reduced renal elimination, and acidic pHs and high flow rates result in increased renal elimination with clearances greater than glomerular filtration rates, indicating the involvement of active secretion. Urinary recovery of amphetamine has been reported to range from 1% to 75%, depending on urinary pH, with the remaining fraction of the dose hepatically metabolized. Consequently, both hepatic and renal dysfunction have the potential to inhibit the elimination of amphetamine and result in prolonged exposures. In addition, drugs that affect urinary pH are known to alter the elimination of amphetamine, and any decrease in amphetamine’s metabolism that might occur due to drug interactions or genetic polymorphisms is more likely to be clinically significant when renal elimination is decreasedIndications and Usage for AdderallAdderall® (Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate and Amphetamine Sulfate Tablets (Mixed Salts of a Single Entity Amphetamine Product)) is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and Narcolepsy.Attention Deficit Hyperactivity Disorder (ADHD)A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV®) implies the presence of hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; “on the go;” excessive talking; blurting answers; can't wait turn; intrusive. The Combined Type requires both inattentive and hyperactive-impulsive criteria to be met.Special Diagnostic ConsiderationsSpecific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of the required number of DSM-IV® characteristics.Need for Comprehensive Treatment ProgramAdderall® (Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate and Amphetamine Sulfate Tablets (Mixed Salts of a Single Entity Amphetamine Product)) is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician's assessment of the chronicity and severity of the child's symptoms.Long-Term UseThe effectiveness of Adderall®(Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate and Amphetamine Sulfate Tablets (Mixed Salts of a Single Entity Amphetamine Product)) for long-term use has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Adderall® (Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate and Amphetamine Sulfate Tablets (Mixed Salts of a Single Entity Amphetamine Product)) for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.ContraindicationsAdvanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma.Agitated states.Patients with a history of drug abuse.During or within 14 days following the administration of monoamine oxidase inhibitors (hypertensive crises may result).WarningsSerious Cardiovascular EventsSudden Death and Preexisting Structural Cardiac Abnormalities or Other Serious Heart ProblemsChildren and AdolescentsSudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems.Although some structural heart problems alone may carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drugAdultsSudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugsHypertension and Other Cardiovascular ConditionsStimulant medications cause a modest increase in average blood pressure (about 2 to 4 mmHg) and average heart rate (about 3 to 6 bpm) and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with preexisting hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmiaAssessing Cardiovascular Status in Patients Being Treated With Stimulant MedicationsChildren, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.Psychiatric Adverse EventsPreexisting PsychosisAdministration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with preexisting psychotic disorder.Bipolar IllnessParticular care should be taken in using stimulants to treat ADHD patients with comorbid bipolar disorder because of concern for possible induction of mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.Emergence of New Psychotic or Manic SymptomsTreatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients.AggressionAggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility.Long-Term Suppression of GrowthCareful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they will likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining weight as expected may need to have their treatment interrupted.SeizuresThere is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizure, in patients with prior EEG abnormalities in absence of seizures, and very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued.Peripheral Vasculopathy, Including Raynaud’s PhenomenonStimulants, including Adderall®, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.Serotonin SyndromeSerotonin syndrome, a potentially life-threatening reaction, may occur when amphetamines are used in combination with other drugs that affect the serotonergic neurotransmitter systems such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort .Amphetamines and amphetamine derivatives are known to be metabolized, to some degree, by cytochrome P450 2D6 (CYP2D6) and display minor inhibition of CYP2D6 metabolism . The potential for a pharmacokinetic interaction exists with the coadministration of CYP2D6 inhibitors which may increase the risk with increased exposure to Adderall®. In these situations, consider an alternative non-serotonergic drug or an alternative drug that does not inhibit CYP2D6Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).Concomitant use of Adderall® with MAOI drugs is contraindicatedDiscontinue treatment with Adderall® and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Adderall® with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate Adderall® with lower doses, monitor patients for the emergence of serotonin syndrome during drug initiation or titration, and inform patients of the increased risk for serotonin syndrome.Visual DisturbanceDifficulties with accommodation and blurring of vision have been reported with stimulant treatment.PrecautionsGeneralThe least amount of amphetamine feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage. Adderall® should be used with caution in patients who use other sympathomimetic drugs.TicsAmphetamines have been reported to exacerbate motor and phonic tics and Tourette’s syndrome. Therefore, clinical evaluation for tics and Tourette’s syndrome in children and their families should precede use of stimulant medications.Information for PatientsAmphetamines may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or vehicles; the patient should therefore be cautioned accordingly.Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with amphetamine or dextroamphetamine and should counsel them in its appropriate use. A patient Medication Guide is available for Adderall®.The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, Including Raynaud’s Phenomenon]Instruct patients beginning treatment with Adderall® about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red.Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes.Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking Adderall®.Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.Drug InteractionsAcidifying AgentsGastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid HCl, ascorbic acid, fruit juices, etc.) lower absorption of amphetamines.Urinary Acidifying Agents(ammonium chloride, sodium acid phosphate, etc.) increase the concentration of the ionized species of the amphetamine molecule, thereby increasing urinary excretion. Both groups of agents lower blood levels and efficacy of amphetamines.Adrenergic BlockersAdrenergic blockers are inhibited by amphetamines.Alkalinizing AgentsGastrointestinal alkalinizing agents (sodium bicarbonate, etc.) increase absorption of amphetamines. Coadministration of Adderall® and gastrointestinal alkalizing agents, such as antacids, should be avoided. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase blood levels and therefore potentiate the actions of amphetamines.Antidepressants, TricyclicAmphetamines may enhance the activity of tricyclic or sympathomimetic agents; d-amphetamine with desipramine or protriptyline and possibly other tricyclics cause striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated.CYP2D6 InhibitorsThe concomitant use of Adderall® and CYP2D6 inhibitors may increase the exposure of Adderall®compared to the use of the drug alone and increase the risk of serotonin syndrome. Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during Adderall® initiation and after a dosage increase. If serotonin syndrome occurs, discontinue Adderall® and the CYP2D6 inhibitor . Examples of CYP2D6 Inhibitors include paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir.Serotonergic DrugsThe concomitant use of Adderall® and serotonergic drugs increases the risk of serotonin syndrome. Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during Adderall® initiation or dosage increase. If serotonin syndrome occurs, discontinue Adderall® and the concomitant serotonergic drug(s) . Examples of serotonergic drugs include selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort.MAO InhibitorsMAOI antidepressants, as well as a metabolite of furazolidone, slow amphetamine metabolism. This slowing potentiates amphetamines, increasing their effect on the release of norepinephrine and other monoamines from adrenergic nerve endings; this can cause headaches and other signs of hypertensive crisis. A variety of neurological toxic effects and malignant hyperpyrexia can occur, sometimes with fatal results.AntihistaminesAmphetamines may counteract the sedative effect of antihistamines.AntihypertensivesAmphetamines may antagonize the hypotensive effects of antihypertensives.ChlorpromazineChlorpromazine blocks dopamine and norepinephrine receptors, thus inhibiting the central stimulant effects of amphetamines, and can be used to treat amphetamine poisoning.EthosuximideAmphetamines may delay intestinal absorption of ethosuximide.HaloperidolHaloperidol blocks dopamine receptors, thus inhibiting the central stimulant effects of amphetamines.Lithium CarbonateThe anorectic and stimulatory effects of amphetamines may be inhibited by lithium carbonate.MeperidineAmphetamines potentiate the analgesic effect of meperidine.Methenamine TherapyUrinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying agents used in methenamine therapy.NorepinephrineAmphetamines enhance the adrenergic effect of norepinephrine.PhenobarbitalAmphetamines may delay intestinal absorption of phenobarbital; coadministration of phenobarbital may produce a synergistic anticonvulsant action.PhenytoinAmphetamines may delay intestinal absorption of phenytoin; coadministration of phenytoin may produce a synergistic anticonvulsant action.PropoxypheneIn cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur.Proton Pump InhibitorsPPIs act on proton pumps by blocking acid production, thereby reducing gastric acidity. When Adderall XR® (20 mg single-dose) was administered concomitantly with the proton pump inhibitor, omeprazole (40 mg once daily for 14 days), the median Tmax of d-amphetamine was decreased by 1.25 hours (from 4 to 2.75 hours), and the median Tmax of l-amphetamine was decreased by 2.5 hours (from 5.5 to 3 hours), compared to Adderall XR® administered alone. The AUC and Cmax of each moiety were unaffected. Therefore, coadministration of Adderall® and proton pump inhibitors should be monitored for changes in clinical effect.Veratrum AlkaloidsAmphetamines inhibit the hypotensive effect of veratrum alkaloids.Drug/Laboratory Test InteractionsAmphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinationsCarcinogenesis/Mutagenesis and Impairment of FertilityNo evidence of carcinogenicity was found in studies in which d,l-amphetamine (enantiomer ratio of 1:1) was administered to mice and rats in the diet for 2 years at doses of up to 30 mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/kg/day in male and female rats. These doses are approximately 2.4, 1.5, and 0.8 times, respectively, the maximum recommended human dose of 30 mg/day [child] on a mg/m2body surface area basis.Amphetamine, in the enantiomer ratio present in Adderall® (immediate-release)(d- to l- ratio of 3:1), was not clastogenic in the mouse bone marrow micronucleus test in vivo and was negative when tested in the E. coli component of the Ames test in vitro. d, l-Amphetamine (1:1 enantiomer ratio) has been reported to produce a positive response in the mouse bone marrow micronucleus test, an equivocal response in the Ames test, and negative responses in the in vitrosister chromatid exchange and chromosomal aberration assays.Amphetamine, in the enantiomer ratio present in Adderall® (immediate-release)(d- to l- ratio of 3:1), did not adversely affect fertility or early embryonic development in the rat at doses of up to 20 mg/kg/day (approximately 5 times the maximum recommended human dose of 30 mg/day on a mg/m2 body surface area basis).PregnancyTeratogenic EffectsPregnancy Category CAmphetamine, in the enantiomer ratio present in Adderall® (d- to l- ratio of 3:1), had no apparent effects on embryofetal morphological development or survival when orally administered to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 6 and 16 mg/kg/day, respectively. These doses are approximately 1.5 and 8 times, respectively, the maximum recommended human dose of 30 mg/day [child] on a mg/m2 body surface area basis. Fetal malformations and death have been reported in mice following parenteral administration of d-amphetamine doses of 50 mg/kg/day (approximately 6 times that of a human dose of 30 mg/day [child] on a mg/m2basis) or greater to pregnant animals. Administration of these doses was also associated with severe maternal toxicity.A number of studies in rodents indicate that prenatal or early postnatal exposure to amphetamine (d- or d,l-), at doses similar to those used clinically, can result in long-term neurochemical and behavioral alterations. Reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual function.There are no adequate and well-controlled studies in pregnant women. There has been one report of severe congenital bony deformity, tracheo-esophageal fistula, and anal atresia (vater association) in a baby born to a woman who took dextroamphetamine sulfate with lovastatin during the first trimester of pregnancy. Amphetamines should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Nonteratogenic EffectsInfants born to mothers dependent on amphetamines have an increased risk of premature delivery and low birth weight. Also, these infants may experience symptoms of withdrawal as demonstrated by dysphoria, including agitation, and significant lassitude.Usage in Nursing MothersAmphetamines are excreted in human milk. Mothers taking amphetamines should be advised to refrain from nursing.Pediatric UseLong-term effects of amphetamines in children have not been well established. Amphetamines are not recommended for use in children under 3 years of age with Attention Deficit Hyperactivity Disorder described under INDICATION AND USAGEGeriatric UseAdderall® has not been studied in the geriatric population.Adverse ReactionsCardiovascularPalpitations, tachycardia, elevation of blood pressure, sudden death, myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use.Central Nervous SystemPsychotic episodes at recommended doses, overstimulation, restlessness, irritability, euphoria, dyskinesia, dysphoria, depression, tremor, tics, aggression, anger, logorrhea, dermatillomania.Eye DisordersVision blurred, mydriasis.GastrointestinalDryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects.AllergicUrticaria, rash, hypersensitivity reactions including angioedema and anaphylaxis. Serious skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.EndocrineImpotence, changes in libido, frequent or prolonged erections.SkinAlopecia.MusculoskeletaDrug Abuse and DependenceAdderall® (Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate and Amphetamine Sulfate Tablets (Mixed Salts of a Single Entity Amphetamine Product)) is a Schedule II controlled substance.Amphetamines have been extensively abused. Tolerance, extreme psychological dependence, and severe social disability have occurred. There are reports of patients who have increased the dosage to levels many times higher than recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with amphetamines include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia.OverdosageIndividual patient response to amphetamines varies widely. Toxic symptoms may occur idiosyncratically at low doses.SymptomsManifestations of acute overdosage with amphetamines include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia and rhabdomyolysis.Fatigue and depression usually follow the central stimulation.Cardiovascular effects include arrhythmias, hypertension or hypotension and circulatory collapse.Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually preceded by convulsions and coma.TreatmentConsult with a Certified Poison Control Center for up to date guidance and advice. Management of acute amphetamine intoxication is largely symptomatic and includes gastric lavage, administration of activated charcoal, administration of a cathartic and sedation. Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendation in this regard. Acidification of the urine increases amphetamine excretion, but is believed to increase risk of acute renal failure if myoglobinuria is present. If acute, severe hypertension complicates amphetamine overdosage, administration of intravenous phentolamine has been suggested. However, a gradual drop in blood pressure will usually result when sufficient sedation has been achieved. Chlorpromazine antagonizes the central stimulant effects of amphetamines and can be used to treat amphetamine intoxication.Adderall Dosage and AdministrationRegardless of indication, amphetamines should be administered at the lowest effective dosage, and dosage should be individually adjusted according to the therapeutic needs and response of the patient. Late evening doses should be avoided because of the resulting insomnia.Attention Deficit Hyperactivity DisorderNot recommended for children under 3 years of age. In children from 3 to 5 years of age, start with 2.5 mg daily; daily dosage may be raised in increments of 2.5 mg at weekly intervals until optimal response is obtained.In children 6 years of age and older, start with 5 mg once or twice daily; daily dosage may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. Only in rare cases will it be necessary to exceed a total of 40 mg per day. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.Where possible, drug administration should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued therapy.NarcolepsyUsual dose 5 mg to 60 mg per day in divided doses, depending on the individual patient response.Narcolepsy seldom occurs in children under 12 years of age; however, when it does, dextroamphetamine sulfate may be used. The suggested initial dose for patients aged 6 to 12 is 5 mg daily; daily dose may be raised in increments of 5 mg at weekly intervals until optimal response is obtained. In patients 12 years of age and older, start with 10 mg daily; daily dosage may be raised in increments of 10 mg at weekly intervals until optimal response is obtained. If bothersome adverse reactions appear (e.g., insomnia or anorexia), dosage should be reduced. Give first dose on awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.How is Adderall SuppliedAdderall® (Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate and Amphetamine Sulfate Tablets (Mixed Salts of a Single Entity Amphetamine Product)) is supplied as follows:5 mg: White to off-white, round, flat-faced beveled edge tablet with four partial bisects debossed with 5 on one side and debossed with dp on the other side. They are available in bottles of 100 tablets (NDC 57844-105-01).7.5 mg: Blue, oval, biconvex tablet with two partial bisects debossed with 7.5 on one side and one full bisect and two partial bisects debossed with d | p on the other side. They are available in bottles of 100 tablets (NDC 57844-117-01).10 mg: Blue, round, biconvex tablet with one full bisect and two partial bisects debossed with 1 | 0 on one side and debossed with dp on the other side. They are available in bottles of 100 tablets (NDC 57844-110-01).12.5 mg: Peach, round, flat-faced beveled edge tablet debossed with 12.5 on one side and one full bisect and two partial bisects debossed with d | p on the other side. They are available in bottles of 100 tablets (NDC 57844-112-01).15 mg: Peach, oval, biconvex tablet with two partial bisects debossed with 15 on one side and one full bisect and two partial bisects debossed with d | p on the other side. They are available in bottles of 100 tablets (NDC 57844-115-01).20 mg: Peach, round, biconvex tablet with one full bisect and two partial bisects debossed with 2 | 0 on one side and debossed with dp on the other side. They are available in bottles of 100 tablets (NDC 57844-120-01).30 mg: Peach, round, flat-faced beveled edge tablet with one full bisect and 2 partial bisects debossed with 3 | 0 on one side and dp on the other side. They are available in bottles of 100 tablets (NDC 57844-130-01).Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA.Distributed by:Teva Pharmaceuticals USA, Inc.Parsippany, NJ 07054Rev. I 3/2020MEDICATION GUIDEAdderall® (ADD-ur-all) (CII)(Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate and Amphetamine Sulfate Tablets (Mixed Salts of a Single Entity Amphetamine Product))Read the Medication Guide that comes with Adderall® before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about you or your child’s treatment with Adderall®.What is the most important information I should know about Adderall®?The following have been reported with use of Adderall® and other stimulant medicines.1. Heart-Related Problems:• sudden death in patients who have heart problems or heart defects• stroke and heart attack in adults• increased blood pressure and heart rateTell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems.Your doctor should check you or your child carefully for heart problems before starting Adderall®.Your doctor should check your or your child’s blood pressure and heart rate regularly during treatment with Adderall®.Call your doctor right away if you or your child have any signs of heart problems such as chest pain, shortness of breath, or fainting while taking Adderall®.2. Mental (Psychiatric) Problems:All Patients• new or worse behavior and thought problems• new or worse bipolar illness• new or worse aggressive behavior or hostilityChildren and Teenagers• new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptomsTell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression.Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking Adderall®, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious.3. Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, Including Raynaud’s Phenomenon]:Fingers or toes may feel numb, cool, painfulFingers or toes may change color from pale, to blue, to redTell your doctor if you have or your child has numbness, pain, skin color change, or sensitivity to temperature in your fingers or toes.Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking Adderall®.What is Adderall®?Adderall® is a central nervous system stimulant prescription medicine. It is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). Adderall® may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD.Adderall® should be used as a part of a total treatment program for ADHD that may include counseling or other therapies.Adderall® is also used in the treatment of a sleep disorder called narcolepsy.Adderall® is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep Adderall® in a safe place to prevent misuse and abuse. Selling or giving away Adderall® may harm others, and is against the law.Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol, prescription medicines or street drugs.Who should not take Adderall®?Adderall® should not be taken if you or your child:have heart disease or hardening of the arterieshave moderate to severe high blood pressurehave hyperthyroidismhave an eye problem called glaucomaare very anxious, tense, or agitatedhave a history of drug abuseare taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI.are sensitive to, allergic to, or had a reaction to other stimulant medicinesAdderall® is not recommended for use in children less than 3 years old.Adderall® may not be right for you or your child. Before starting Adderall® tell your or your child’s doctor about all health conditions (or a family history of) including:heart problems, heart defects, high blood pressuremental problems including psychosis, mania, bipolar illness, or depressiontics or Tourette’s syndromeliver or kidney problemscirculation problems in fingers and toesthyroid problemsseizures or have had an abnormal brain wave test (EEG)Tell your doctor if you or your child are pregnant, planning to become pregnant, or breastfeeding.Can Adderall® be taken with other medicines?Tell your doctor about all of the medicines that you or your child take including prescription and nonprescription medicines, vitamins, and herbal supplements. Adderall® and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking Adderall®.Your doctor will decide whether Adderall® can be taken with other medicines.Especially tell your doctor if you or your child take:anti-depression medicines including MAOIsblood pressure medicinesseizure medicinesblood thinner medicinescold or allergy medicines that contain decongestantsstomach acid medicinesKnow the medicines that you or your child take. Keep a list of your medicines with you to show your doctor and pharmacist.Do not start any new medicine while taking Adderall® without talking to your doctor first.How should Adderall® be taken?Take Adderall® exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child.Adderall® tablets are usually taken two to three times a day. The first dose is usually taken when you first wake in the morning. One or two more doses may be taken during the day, 4 to 6 hours apart.Adderall® can be taken with or without food.From time to time, your doctor may stop Adderall® treatment for a while to check ADHD symptoms.Your doctor may do regular checks of the blood, heart, and blood pressure while taking Adderall®. Children should have their height and weight checked often while taking Adderall®. Adderall® treatment may be stopped if a problem is found during these check-ups.If you or your child take too much Adderall®or overdose, call your doctor or poison control center right away, or get emergency treatment.What are possible side effects of Adderall®?See “What is the most important information I should know about Adderall®?” for information on reported heart and mental problems.Other serious side effects include:slowing of growth (height and weight) in childrenseizures, mainly in patients with a history of seizureseyesight changes or blurred visionserotonin syndrome. A potentially life-threatening problem called serotonin syndrome can happen when medicines such as Adderall® are taken with certain other medicines. Symptoms of serotonin syndrome may include:agitation, hallucinations, coma or other changes in mental statusproblems controlling your movements or muscle twitchingfast heartbeathigh or low blood pressuresweating or fevernausea or vomitingdiarrheamuscle stiffness or tightnessCommon side effects include:stomach achedecreased appetitenervousnessAdderall® may affect your or your child’s ability to drive or do other dangerous activities.Talk to your doctor if you or your child have side effects that are bothersome or do not go away.This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information.How should I store Adderall®?Store Adderall® in a safe place at room temperature, 20° to 25°C (68° to 77°F).Keep Adderall® and all medicines out of the reach of children.General information about Adderall®Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Adderall® for a condition for which it was not prescribed. Do not give Adderall®to other people, even if they have the same condition. It may harm them and it is against the law. This Medication Guide summarizes the most important information about Adderall®. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Adderall® that was written for healthcare professionals.What are the ingredients in Adderall®?Active Ingredient: dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate.Inactive Ingredients: colloidal silicon dioxide, compressible sugar, corn starch, magnesium stearate, microcrystalline cellulose and saccharin sodium. The 5 mg is a white to off-white tablet, which contains no color additives. The 7.5 mg and 10 mg also contain FD&C Blue #1 Aluminum Lake as a color additive. The 12.5 mg, 15 mg, 20 mg and 30 mg also contain FD&C Yellow #6 Aluminum Lake as a color additive.This Medication Guide has been approved by the U.S. Food and Drug Administration.Distributed by:Teva Pharmaceuticals USA, Inc.Parsippany, NJ 07054Rev. H 3/2020Package/Label Display PanelAdderall® 5 mg CII 100s Label TextNDC 57844-105-01CIIAdderall®(Dextroamphetamine Saccharate,Amphetamine Aspartate,Dextroamphetamine Sulfate andAmphetamine Sulfate Tablets)(Mixed Salts of a Single EntityAmphetamine Product)5 mgPHARMACIST: DISPENSE THEACCOMPANYING MEDICATIONGUIDE TO EACH PATIENT.Rx only100 TABLETSTEVAPackage/Label Display PanelAdderall® 7.5 mg CII 100s Label TextNDC 57844-117-01CIIAdderall®(Dextroamphetamine Saccharate,Amphetamine Aspartate,Dextroamphetamine Sulfate andAmphetamine Sulfate Tablets)(Mixed Salts of a Single EntityAmphetamine Product)7.5 mgPHARMACIST: DISPENSE THEACCOMPANYING MEDICATIONGUIDE TO EACH PATIENT.Rx only100 TABLETSTEVAPackage/Label Display PanelAdderall® 10 mg CII 100s Label TextNDC 57844-110-01CIIAdderall®(Dextroamphetamine Saccharate,Amphetamine Aspartate,Dextroamphetamine Sulfate andAmphetamine Sulfate Tablets)(Mixed Salts of a Single EntityAmphetamine Product)10 mgPHARMACIST: DISPENSE THEACCOMPANYING MEDICATIONGUIDE TO EACH PATIENT.Rx only100 TABLETSTEVAPackage/Label Display PanelAdderall® 12.5 mg CII 100s Label TextNDC 57844-112-01CIIAdderall®(Dextroamphetamine Saccharate,Amphetamine Aspartate,Dextroamphetamine Sulfate andAmphetamine Sulfate Tablets)(Mixed Salts of a Single EntityAmphetamine Product)12.5 mgPHARMACIST: DISPENSE THEACCOMPANYING MEDICATIONGUIDE TO EACH PATIENT.Rx only100 TABLETSTEVAPackage/Label Display PanelAdderall® 15 mg CII 100s Label TextNDC 57844-115-01CIIAdderall®(Dextroamphetamine Saccharate,Amphetamine Aspartate,Dextroamphetamine Sulfate andAmphetamine Sulfate Tablets)(Mixed Salts of a Single EntityAmphetamine Product)15 mgPHARMACIST: DISPENSE THEACCOMPANYING MEDICATIONGUIDE TO EACH PATIENT.Rx only100 TABLETSTEVAPackage/Label Display PanelAdderall® 20 mg CII 100s Label TextNDC 57844-120-01CIIAdderall®(Dextroamphetamine Saccharate,Amphetamine Aspartate,Dextroamphetamine Sulfate andAmphetamine Sulfate Tablets)(Mixed Salts of a Single EntityAmphetamine Product)20 mgPHARMACIST: DISPENSE THEACCOMPANYING MEDICATIONGUIDE TO EACH PATIENT.Rx only100 TABLETSTEVAPackage/Label Display PanelAdderall® 30 mg CII 100s Label TextNDC 57844-130-01CIIAdderall®(Dextroamphetamine Saccharate,Amphetamine Aspartate,Dextroamphetamine Sulfate andAmphetamine Sulfate Tablets)(Mixed Salts of a Single EntityAmphetamine Product)30 mgPHARMACIST: DISPENSE THEACCOMPANYING MEDICATIONGUIDE TO EACH PATIENT.Rx only100 TABLETSTEVAAdderalldextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate tabletProduct InformationProduct TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:57844-105Route of AdministrationORALDEA ScheduleCIIActive Ingredient/Active MoietyIngredient NameBasis of StrengthStrengthDEXTROAMPHETAMINE SACCHARATE(DEXTROAMPHETAMINE)DEXTROAMPHETAMINE SACCHARATE1.25 mgAMPHETAMINE ASPARTATE MONOHYDRATE(AMPHETAMINE)AMPHETAMINE ASPARTATE MONOHYDRATE1.25 mgDEXTROAMPHETAMINE SULFATE(DEXTROAMPHETAMINE)DEXTROAMPHETAMINE SULFATE1.25 mgAMPHETAMINE SULFATE(AMPHETAMINE)AMPHETAMINE SULFATE1.25 mgInactive IngredientsIngredient NameStrengthSILICON DIOXIDESUCROSEMALTODEXTRINSTARCH, CORNMAGNESIUM STEARATECELLULOSE, MICROCRYSTALLINESACCHARIN SODIUMProduct CharacteristicsColorWHITE (white to off-white)Score4 piecesShapeROUNDSize7mmFlavorImprint Code5;dpContainsPackaging#Item CodePackage Description1NDC:57844-105-01100 TABLET in 1 BOTTLEMarketing InformationMarketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End DateANDAANDA04042211/13/2014Adderalldextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate tabletProduct InformationProduct TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:57844-117Route of AdministrationORALDEA ScheduleCIIActive Ingredient/Active MoietyIngredient NameBasis of StrengthStrengthDEXTROAMPHETAMINE SACCHARATE(DEXTROAMPHETAMINE)DEXTROAMPHETAMINE SACCHARATE1.875 mgAMPHETAMINE ASPARTATE MONOHYDRATE(AMPHETAMINE)AMPHETAMINE ASPARTATE MONOHYDRATE1.875 mgDEXTROAMPHETAMINE SULFATE(DEXTROAMPHETAMINE)DEXTROAMPHETAMINE SULFATE1.875 mgAMPHETAMINE SULFATE(AMPHETAMINE)AMPHETAMINE SULFATE1.875 mgInactive IngredientsIngredient NameStrengthSILICON DIOXIDESUCROSEMALTODEXTRINSTARCH, CORNMAGNESIUM STEARATECELLULOSE, MICROCRYSTALLINESACCHARIN SODIUMFD&C BLUE NO. 1 ALUMINUM LAKEProduct CharacteristicsColorBLUEScore4 piecesShapeOVALSize10mmFlavorImprint Code7;5;d;pContainsPackaging#Item CodePackage Description1NDC:57844-117-01100 TABLET in 1 BOTTLEMarketing InformationMarketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End DateANDAANDA04042203/03/2015Adderalldextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate tabletProduct InformationProduct TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:57844-110Route of AdministrationORALDEA ScheduleCIIActive Ingredient/Active MoietyIngredient NameBasis of StrengthStrengthDEXTROAMPHETAMINE SACCHARATE(DEXTROAMPHETAMINE)DEXTROAMPHETAMINE SACCHARATE2.5 mgAMPHETAMINE ASPARTATE MONOHYDRATE(AMPHETAMINE)AMPHETAMINE ASPARTATE MONOHYDRATE2.5 mgDEXTROAMPHETAMINE SULFATE(DEXTROAMPHETAMINE)DEXTROAMPHETAMINE SULFATE2.5 mgAMPHETAMINE SULFATE(AMPHETAMINE)AMPHETAMINE SULFATE2.5 mgInactive IngredientsIngredient NameStrengthSILICON DIOXIDESUCROSEMALTODEXTRINSTARCH, CORNMAGNESIUM STEARATECELLULOSE, MICROCRYSTALLINESACCHARIN SODIUMFD&C BLUE NO. 1 ALUMINUM LAKEProduct CharacteristicsColorBLUEScore4 piecesShapeROUNDSize9mmFlavorImprint Code1;0;dpContainsPackaging#Item CodePackage Description1NDC:57844-110-01100 TABLET in 1 BOTTLEMarketing InformationMarketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End DateANDAANDA04042202/03/2014Adderalldextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate tabletProduct InformationProduct TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:57844-112Route of AdministrationORALDEA ScheduleCIIActive Ingredient/Active MoietyIngredient NameBasis of StrengthStrengthDEXTROAMPHETAMINE SACCHARATE(DEXTROAMPHETAMINE)DEXTROAMPHETAMINE SACCHARATE3.125 mgAMPHETAMINE ASPARTATE MONOHYDRATE(AMPHETAMINE)AMPHETAMINE ASPARTATE MONOHYDRATE3.125 mgDEXTROAMPHETAMINE SULFATE(DEXTROAMPHETAMINE)DEXTROAMPHETAMINE SULFATE3.125 mgAMPHETAMINE SULFATE(AMPHETAMINE)AMPHETAMINE SULFATE3.125 mgInactive IngredientsIngredient NameStrengthSILICON DIOXIDESUCROSEMALTODEXTRINSTARCH, CORNMAGNESIUM STEARATECELLULOSE, MICROCRYSTALLINESACCHARIN SODIUMFD&C YELLOW NO. 6Product CharacteristicsColorORANGE (peach)Score4 piecesShapeROUNDSize7mmFlavorImprint Code12;5;d;pContainsPackaging#Item CodePackage Description1NDC:57844-112-01100 TABLET in 1 BOTTLEMarketing InformationMarketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End DateANDAANDA04042206/18/2014Adderalldextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate tabletProduct InformationProduct TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:57844-115Route of AdministrationORALDEA ScheduleCIIActive Ingredient/Active MoietyIngredient NameBasis of StrengthStrengthDEXTROAMPHETAMINE SACCHARATE(DEXTROAMPHETAMINE)DEXTROAMPHETAMINE SACCHARATE3.75 mgAMPHETAMINE ASPARTATE MONOHYDRATE(AMPHETAMINE)AMPHETAMINE ASPARTATE MONOHYDRATE3.75 mgDEXTROAMPHETAMINE SULFATE(DEXTROAMPHETAMINE)DEXTROAMPHETAMINE SULFATE3.75 mgAMPHETAMINE SULFATE(AMPHETAMINE)AMPHETAMINE SULFATE3.75 mgInactive IngredientsIngredient NameStrengthSILICON DIOXIDESUCROSEMALTODEXTRINSTARCH, CORNMAGNESIUM STEARATECELLULOSE, MICROCRYSTALLINESACCHARIN SODIUMFD&C YELLOW NO. 6Product CharacteristicsColorORANGE (peach)Score4 piecesShapeOVALSize10mmFlavorImprint Code15;d;pContainsPackaging#Item CodePackage Description1NDC:57844-115-01100 TABLET in 1 BOTTLEMarketing InformationMarketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End DateANDAANDA04042206/30/2014Adderalldextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate tabletProduct InformationProduct TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:57844-120Route of AdministrationORALDEA ScheduleCIIActive Ingredient/Active MoietyIngredient NameBasis of StrengthStrengthDEXTROAMPHETAMINE SACCHARATE(DEXTROAMPHETAMINE)DEXTROAMPHETAMINE SACCHARATE5 mgAMPHETAMINE ASPARTATE MONOHYDRATE(AMPHETAMINE)AMPHETAMINE ASPARTATE MONOHYDRATE5 mgDEXTROAMPHETAMINE SULFATE(DEXTROAMPHETAMINE)DEXTROAMPHETAMINE SULFATE5 mgAMPHETAMINE SULFATE(AMPHETAMINE)AMPHETAMINE SULFATE5 mgInactive IngredientsIngredient NameStrengthSILICON DIOXIDESUCROSEMALTODEXTRINSTARCH, CORNMAGNESIUM STEARATECELLULOSE, MICROCRYSTALLINESACCHARIN SODIUMFD&C YELLOW NO. 6Product CharacteristicsColorORANGE (peach)Score4 piecesShapeROUNDSize9mmFlavorImprint Code2;0;dpContainsPackaging#Item CodePackage Description1NDC:57844-120-01100 TABLET in 1 BOTTLEMarketing InformationMarketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End DateANDAANDA04042202/11/2014Adderalldextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate tabletProduct InformationProduct TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:57844-130Route of AdministrationORALDEA ScheduleCIIActive Ingredient/Active MoietyIngredient NameBasis of StrengthStrengthDEXTROAMPHETAMINE SACCHARATE(DEXTROAMPHETAMINE)DEXTROAMPHETAMINE SACCHARATE7.5 mgAMPHETAMINE ASPARTATE MONOHYDRATE(AMPHETAMINE)AMPHETAMINE ASPARTATE MONOHYDRATE7.5 mgDEXTROAMPHETAMINE SULFATE(DEXTROAMPHETAMINE)DEXTROAMPHETAMINE SULFATE7.5 mgAMPHETAMINE SULFATE(AMPHETAMINE)AMPHETAMINE SULFATE7.5 mgInactive IngredientsIngredient NameStrengthSILICON DIOXIDESUCROSEMALTODEXTRINSTARCH, CORNMAGNESIUM STEARATECELLULOSE, MICROCRYSTALLINESACCHARIN SODIUMFD&C YELLOW NO. 6Product CharacteristicsColorORANGE (peach)Score4 piecesShapeROUNDSize10mmFlavorImprint Code3;0;dpContainsPackaging#Item CodePackage Description1NDC:57844-130-01100 TABLET in 1 BOTTLE