School-Related Medical Issues 2016-17
John L. Digges, MD, PhD, MPH, FAAP
Dr. Digges practiced general and behavioral pediatrics in Oklahoma and California for 14 years. For ten of the past 12 years, he has served as the Forensic (Child Abuse) Pediatrician for Kern County, California; and he has had a private practice limited to ADHD consultations for the past 12 years. He has been a CME surveyor for the Institute of Medical Quality (CMA) since 2000, and is a recent past-President of the Kern County Medical Society. Dr. Digges has been at the DCN since August, 2008.
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ADHD and Concerta
We have a 7 year old male student with ADHD, who showed significant improvement after he was started on Concerta last year. His dose was gradually increased to 36mg over a few weeks, and he has been doing well for several months.
Recently after returning from Winter Break, his old symptoms have returned. We thought he was just having trouble getting back into the school routine, but his distractibility, difficulty initiating work both in school and for homework, and his impulsive behaviors have resurfaced and persisted. Can you offer any possible explanations?
When I hear of an ADHD student having experienced improvement on medication followed by a noticeable return of ADHD symptoms, I wonder about any changes which may have occurred. For your student, has there been any significant change in his life (injury, illness, incarceration or death of a family member; loss of employment of one or both parents; having to move residences; etc.)? Has the school situation changed significantly (new teacher, best friend moved away, being bullied, course material overwhelming, etc.)? An acute loss or other stressor can cause substantial disruption in a child’s routine, and may divert their interest and energy away from school work. If discreet inquiry reveals the child has experienced such a loss or stressor, providing the child with access to resources and emotional support to address the loss/stressor can be quite helpful. Is he continuing to take his medications as prescribed? After experiencing success on the medication, children (or parents) sometimes believe they can maintain the improvement without the medication, and stop taking it.
Another possible cause relates to the specific medication he was prescribed. All stimulant preparations used to treat ADHD can be viewed as consisting of first, a molecule and second, a release mechanism; each of which will affect the efficacy of the preparation. The product he was prescribed, Concerta, is the brand name for d,l-methylphenidate, and employs the OROS (osmotic release oral system) delivery method. If the physician writes the prescription so that it allows for generic substitution, there have been 3 preparations from which the pharmacist could choose. There is one generic that uses the same molecule and the same release mechanism, but there are two generic products that use the same molecule but a different release mechanism.
The OROS release mechanism consists of a non-soluble tablet which has a laser drilled hole at one end, 3 equal sized chambers internally, and a coating applied to the outside of the tablet which contains 22% of the total dose. An additional 26% of the total dose is contained in a slurry in the first chamber, while 52% of the total dose is compressed into a slurry in the second chamber. The third chamber contains a non-soluble fiber matrix (“push compartment”).
After the tablet is swallowed, the coating with 22% of the total dose dissolves rather quickly, and the medication then enters the blood stream in about 45 minutes or so. Once the coating has dissolved, the tablet becomes semi-permeable to water, allowing water to enter into the third compartment and interact with the matrix. The matrix then starts to expand at a predictable rate, pushing the medication slurry through the opening adjacent to the 1st compartment. The 26% contained in this compartment leaves the tablet over a ~3-4 hour period, followed by the 52% in the second compartment also being pushed out over a ~3-4 hour period. This elegant arrangement allows for a smooth upslope of medication in the blood for about 6-9 hours after ingestion.
It is this period of “upslope” of the pharmacokinetic curve which is associated with the improvements seen in focus and resistance to distraction. (The reduction in non-goal-directed motor activity excess is attributed to the higher concentration of medicine in the system, so it roughly equates to the middle portion of the curve). Tablet preparations which do not employ the OROS system generally produce a similar upslope of the curve for the first 2 hours, but then produce a plateau for the next 4-5 hours. This results in improved focus for the first 2 hours, but is typically followed by a period where the concentration is high enough to reduce non-goal-directed motor activity excess; but the lack of upslope results in a lack of improvement in the symptoms of inattention, easy distractibility, and difficulty with both initiating and completing work.
In November 2014, the FDA recognized the lack of equivalence between the two non-OROS generics and the brand name Concerta (made by Janssen) or the OROS generic (made by Janssen but marketed by Actavis under a licensing agreement). The FDA changed their therapeutic equivalence code from “AB” (equivalence) to “BX” (data are insufficient to determine therapeutic equivalence). Additionally, the FDA requested the other two manufacturers to either voluntarily withdraw their products from the market, or within six months, provide data to confirm bioequivalence. They did neither, but pharmacists were permitted to continue to fill “Concerta” prescriptions that allowed for generic substitution with the two non-bioequivalent products. In November of 2016, the FDA proposed to withdraw approval of the two non-equivalent products, a process likely to result in only OROS products being able to be sold as bioequivalent to Concerta.
It is possible, then, that the child’s increase in ADHD symptoms may reflect a change in the preparation he received from the pharmacy at his most recent refill. The Concerta-equivalent product will have either Janssen or Actavis on the label, and the tablet will have “ALZA” imprinted on it. If the label has another company listed and the tablets do not have “ALZA” imprinted on them, then the tablet is not bio-equivalent with Concerta.
I hope this is helpful, both for your student and potentially for other students that have been affected by the substitution of non-bioequivalent products for Concerta.
John L. Digges, MD, PhD, MPH, FAAP Behavioral Pediatrician, Diagnostic Center North, Fremont, California
Making sense of a child with features of ASD, ADHD and Williams Syndrome (WS), but none of the facial features typically associated with WS
We have an 8 year old student who functions cognitively at about the kindergarten to first grade level. His strengths seem to be in rote memory recall and expressive language. He has been diagnosed with Attention Deficit/Hyperactivity Disorder (ADHD) and also has some autistic-like features. He is very hyperactive, easily distractible, unable to complete assigned work, and seems oblivious that the ringing bell means it’s time to line up. He has enormous difficulty transitioning from one activity to the next, and he is quite impulsive. He also perseverates a lot, often displays echolalia, flaps his hands frequently when excited, tantrums and screams loudly when he doesn’t get his way, swats at others when annoyed by them, and seems to exist in a world of his own. He typically spends time outside engaging in sensory-stimulating activities, such as repetitively throwing small pieces of bark into the air and watching them fall to the ground. While inside, he appears enthralled by watching the sand fall from the top portion of the container to the bottom through the narrowed orifice of the hourglass timer.
Despite having features consistent with autism, he seems to be very social. He will point to preferred objects to attract the attention of others, appears to enjoy sharing with others and sometimes talking with peers or adults, but often he just seems to be talking to no one in particular. These comments that are unrelated to the task at hand are very disruptive in the classroom, and comments appear to contribute to his being ignored by his peers or being referred to as “weird.”
His pediatrician believes he has Williams Syndrome and not autism, but confirmatory genetics studies have not yet been completed. My concern is that when I Google Williams Syndrome, the description provided seems to fit our student, but he does not look anything like the pictures they show as being characteristic of Williams Syndrome. Could you help us make sense of this confusing picture?
Perhaps I can. Children with Williams Syndrome (WS) are missing variable portions of a particular region located on the long arm of the 7th chromosome (7q11.23). This region is suspected of coding for about 20 or so genes. The variable presentation of WS is believed to reflect which specific genes are missing (deleted) from the normal 7th chromosome. For example, the absence of the gene known as GTF2IRD1 is believed to be responsible for producing the characteristic facial features of WS: broad forehead, prominent “starburst” or white lacey pattern on the colored portion of the eye (iris) in blue and green eyed children, shortened distance between each corner of the eye (short palpebral fissure), puffiness around the eyes/full cheeks, small upturned nose, depressed nasal bridge, prominent/full lips, an open mouth, and small chin. Children missing a portion of 7q11.23 but still retaining GTF2IRD1 could have WS but lack the characteristic facial findings.
Features such as strong rote memory skills, well developed spoken language, outgoing and engaging personality coupled with displaying an extreme interest in other people are all consistent with WS. Children with WS will often manifest mild to moderate intellectual disability, learning problems, hyperactivity, distractibility, impulsivity, anxiety and phobias. Fine motor skills and spatial relations are often weak in children with WS.
Other characteristics frequently seen in children with WS include some type of heart or great vessel problem, elevated calcium levels in the blood, feeding difficulties in early childhood, abnormal dentition, problems involving kidney structure or function, hernias, joint laxity, and ultra-sensitive hearing (hyperacusis, or painful sensations associated with certain sound frequencies or intensity). Many children with WS, in addition to their extreme sociability and politeness, will often display heighted interest in or ability involving music.
With respect to autistic features, there are numerous reports of overlap between characteristics of WS and autistic spectrum disorder (ASD). Individuals in both groups display language delays, developmental delays, problems with motor skills, hypersensitivity to sounds, perseveration, and the tendency to be “picky” eaters. However, the two groups represent polar opposites when it comes to “social profile,” with the WS children displaying hypersociability and the ASD children characterized by social avoidance. Whereas excessive sociability and an extreme interest in interacting with people represent the core behavioral features of WS, impairments in social functioning and verbal communication are consistently observed in children with ASD. Children with WS typically possess elaborate vocabularies and affect-rich expressive language, whereas children with ASD almost universally manifest a deficit in the “communicative use” of language.
It would appear that your student’s excessively social personality would preclude a formal diagnosis of autism; but together with his developmental delays, ADHD-like symptoms and well developed speech, may very well be consistent with Williams Syndrome. This diagnosis can be confirmed by array CGH (comparative genomic hybridization) testing. Knowing the diagnosis can also alert the physician and family to check for comorbid conditions associated with it.
Thank you for your question, and I hope this helps.
John L. Digges, MD, PhD, MPH, FAAP
Diagnostic Center - Northern California
Multiple considerations may affect “correct” dosage of ADHD medications.
My 9 year old son has been on 50 mg of Strattera for about 2 years. Within the past two weeks, our family and the school saw changes in his behavior. I took him to his doctor and my son weighed 70 pounds. The doctor changed his dose to 80 mg per day. Is this too much?
Thank you for your question. The answer is not straight forward, as it depends upon the particular circumstances and what is meant by “too much.”
I will assume your son is being treated for ADHD, but I do have a few questions.
Do you know whether he was diagnosed with predominantly inattentive presentation or combined presentation?
Has he been diagnosed with/treated for any other physical or mental health conditions?
What non-pharmacologic strategies are in place to support your son’s presumed executive function deficits?
Has he been treated previously with any other medications for his ADHD? If so, what was his response?
Is he currently taking any other medications in addition to his Strattera?
Have there been any significant changes in his physical or social environment or his emotional status recently?
Has he experienced a high number of A.C.E.’s (adverse childhood events)?
The 50 mg per day dose he was taking while he weighed 70 pounds (~32 kg) works out to ~1.6 mg/kg/day. An 80 mg per day dose for a ~32 kg boy works out to ~2.5 mg/kg/day. According to the prescribing information available on-line for Strattera (2007), the recommendation from the manufacturer (Eli Lilly) for dosing atomoxetine in children and adolescents is to not exceed 1.4 mg/kg/day or 100 mg, whichever is less. Studies have been conducted using does as high as 2.0 mg/kg/day, with no untoward effects observed on the higher doses. However, there was no additional benefit noted from doses in excess of 1.2 mg/kg/day. A dose of 2.5 mg/kg/day is above the dose for which there are safety data available for children and adolescents.
If your son had co-existing conditions such as bipolar disorder or schizophrenia, or displayed unacceptable side effects to multiple trials of various stimulant preparations, or was unable to tolerate guanfacine; and appeared to have significant symptom reduction only in response to atomoxetine, then it might be reasonable to exceed the recommended dosage guidelines in order to provide symptom relief. I would have recommended a more gradual titration; however, such as 1-2 months on 60 mg/day (~1.8 mg/kg/day). When your son weighs 80 pounds (~36 kg), a dose of 70 mg/day would equal ~1.9 mg/kg/day.
The questions I raised about non-pharmacological strategies in place, environmental stressors that your son may be experiencing, and whether he was exposed to adverse childhood events were to explore whether appropriate supportive strategies were already in place, whether any environmental stressors might be contributing to the behavior changes you and the school observed, or whether exposure to trauma during his early development might be affecting his behavior. If for example, he was not receiving adequate accommodations to support his efforts to deal with his ADHD symptoms, then initiating them might lead to a reduction in his symptoms and improvement in his behavior. If he had been exposed to bullying or had suffered significant emotional loss, then I would suggest that those concerns be addressed and appropriate interventions be directed towards relieving the stress he has been experiencing. If he had indeed experienced a high number of adverse childhood events, then referral to a specialist in this area might also result in improvements in his behavior.
Finally, after appropriate non-pharmacological strategies are in place, and assuming your son did not have contraindications to stimulant medication or guanfacine, then I would recommend that you and your physician enter into a discussion about the possibility of considering either of these classes of preparations instead of trying doses of atomoxetine in excess of those for which we have at least some safety data. I hope these comments are of some help to you and your son.
John L. Digges, MD, PhD, MPH, FAAP
Diagnostic Center North