Daytrana

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Daytrana is a transdermal patch developed and marketed by Noven Pharmaceuticals, Inc. that was approved in April 2006. In the literature, Daytrana is most commonly referred to as methylphenidate transdermal system (MTS).

Daytrana is approved by the Food and Drug Administration (FDA) as a once daily treatment of pediatric patients—ages 6 to 17—with attention deficit hyperactivity disorder (ADHD). However, off-label prescriptions in older patients are not uncommon. It is mainly prescribed as a second-line treatment for ADHD when traditional oral forms are not well-tolerated or if patients have difficulty with compliance.

Noven's original FDA submission indicated that it should be used for 12 hours; when the FDA rejected the submission they requested evidence that a shorter time period was safe and effective; Noven provided such evidence and Daytrana was approved for the aforementioned indication over a 9-hour period.[1]

Transdermal versus oral administration[edit]

Orally administered methylphenidate is subject to first-pass metabolism, by which the levo-isomer is extensively metabolized. By circumventing this first-pass metabolism, the relative concentrations of l-threo-methylphenidate are much higher with transdermal administration (50-60% of those of dexmethylphenidate instead of about 14-27%).[2][3]

Contraindications[edit]

Methylphenidate is contraindicated for individuals using monoamine oxidase inhibitors (e.g., phenelzine and tranylcypromine), or individuals with agitation, tics, or glaucoma, or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals.[4]

The US FDA gives methylphenidate a pregnancy category of C, and women are advised to only use the drug if the benefits outweigh the potential risks.[5] Not enough animal and human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development. In 2007, empirical literature included 63 cases of prenatal exposure to methylphenidate across three empirical studies.[6]

Adverse effects[edit]

Daytrana has a side effect profile comparable to other medications containing methylphenidate. The patch should not be worn for longer than 9 hours, even if a new patch was placed due to the previous patch falling off.

Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Methylphenidate was ranked 13th in dependence, 12th in physical harm, and 18th in social harm.[7]

Methylphenidate is generally well tolerated.[8][9] The most commonly observed adverse effects with a frequency greater than placebo include appetite loss, dry mouth, anxiety/nervousness, nausea, and insomnia. Gastrointestinal adverse effects may include abdominal pain and weight loss. Nervous system adverse effects may include akathisia (agitation/restlessness), irritability, dyskinesia (tics), lethargy (drowsiness/fatigue), and dizziness. Cardiac adverse effects may include palpitations, changes in blood pressure and heart rate (typically mild), tachycardia (rapid resting heart rate), and Raynaud's phenomenon (reduced blood flow to the hands and feet).[10] Ophthalmologic adverse effects may include blurred vision and dry eyes, with less frequent reports of diplopia and mydriasis.[11] Other adverse effects may include depression, emotional lability, confusion, and bruxism. Hyperhidrosis (increased sweating) is common. Chest pain is rarely observed.[12]

There is some evidence of mild reductions in growth rate with prolonged treatment in children, but no causal relationship has been established and reductions do not appear to persist long-term.[13] Hypersensitivity (including skin rash, urticaria, and fever) is sometimes reported. The Daytrana patch has a much higher rate of dermal reactions than oral methylphenidate.[14]

Methylphenidate can worsen psychosis in psychotic patients, and in very rare cases it has been associated with the emergence of new psychotic symptoms.[15] It should be used with extreme caution in patients with bipolar disorder due to the potential induction of mania or hypomania.[16] There have been very rare reports of suicidal ideation, but evidence does not support a link.[13] Logorrhea is occasionally reported. Libido disorders, disorientation, and hallucinations are very rarely reported. Priapism is a very rare adverse event that can be potentially serious.[17]

USFDA-commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of methylphenidate or other ADHD stimulants.[18]

Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch for adverse effects is recommended.[19]

Interactions[edit]

Methylphenidate may inhibit the metabolism of coumarin anticoagulants, certain anticonvulsants, and some antidepressants (tricyclic antidepressants and selective serotonin reuptake inhibitors). Concomitant administration may require dose adjustments, possibly assisted by monitoring of plasma drug concentrations.[9] There are several case reports of methylphenidate inducing serotonin syndrome with concomitant administration of antidepressants.[20][21][22][23]

When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatic transesterification,[24][25] not unlike the hepatic formation of cocaethylene from cocaine and alcohol. The reduced potency of ethylphenidate and its minor formation means it does not contribute to the pharmacological profile at therapeutic doses and even in overdose cases ethylphenidate concentrations remain negligible.[26][25]

Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.[27]

Liver toxicity from methylphenidate is extremely rare, but limited evidence suggests that intake of β-adrenergic agonists with methylphenidate may increase the risk of liver toxicity.[28]

Mechanism of action[edit]

Methylphenidate is a central nervous system stimulant and Daytrana is the long acting transdermal patch formulation. Methylphenidate works in the CNS to selectively inhibit the presynaptic reuptake of dopamine and norepinephrine. It has been demonstrated to block dopamine transporter molecules and increase extracellular levels of dopamine in the striatum of healthy adults.[29]

Pharmacokinetics[edit]

In patients using Daytrana a 39 nanograms/mL peak serum concentration of methylphenidate be has been found to occur between 7.5 and 10.5 hours after administration.[30] However the onset to peak effect is 2 hours and the clinical effects remain up to 2 hours after patch has been removed. The absorption of Daytrana is increased when the transdermal patch is applied onto inflamed skin or skin that has been exposed to heat. The absorption lasts for approximately 9 hours after application (onto normal, unexposed to heat, and uninflammed skin). 90% of the medication is excreted in the urine as metabolites and unchanged drug.[30]

In pregnancy[edit]

The Food and Drug Administration has labeled Daytrana as a Category C medication in pregnancy,[31] and so it was found to have adverse effects in the fetus when studied in animals. However, there have not been enough studies performed in humans that show that the benefits of using Daytrana are outweighed by potential adverse effects.[citation needed]

Footnotes[edit]

  1. ^ http://www.fda.gov/ohrms/dockets/AC/05/briefing/2005-4195B1_01_04-Noven-Appendix-3.pdf
  2. ^ Heal DJ, Pierce DM (2006). "Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system". CNS Drugs. 20 (9): 713–738 (Page:730). doi:10.2165/00023210-200620090-00002. PMID 16953648. 
  3. ^ Anderson Vanessa R.; Lesley J. Scott (2006). "Methylphenidate Transdermal System In Attention-Deficit Hyperactivity Disorder in Children". Drugs. 66 (8): 1117–1126. doi:10.2165/00003495-200666080-00007. PMID 16789796. 
  4. ^ "DAYTRANA" (PDF). United States Food and Drug Administration. Noven Pharmaceuticals, Inc. October 2013. Retrieved 13 June 2014. 
  5. ^ Methylphenidate Use During Pregnancy and Breastfeeding. Drugs.com. Retrieved on 30 April 2011.
  6. ^ Humphreys C, Garcia-Bournissen F, Ito S, Koren G (2007). "Exposure to attention deficit hyperactivity disorder medications during pregnancy". Canadian Family Physician. 53 (7): 1153–5. PMC 1949295Freely accessible. PMID 17872810. 
  7. ^ Nutt, D; King, LA; Saulsbury, W; Blakemore, C (24 March 2007). "Development of a rational scale to assess the harm of drugs of potential misuse". Lancet. 369 (9566): 1047–53. doi:10.1016/S0140-6736(07)60464-4. PMID 17382831. 
  8. ^ Didoni, A; Sequi, M; Panei, P; Bonati, M; Lombardy ADHD Registry, Group (October 2011). "One-year prospective follow-up of pharmacological treatment in children with attention-deficit/hyperactivity disorder". European journal of clinical pharmacology. 67 (10): 1061–7. doi:10.1007/s00228-011-1050-3. PMID 21538145. 
    "Ritalin Side Effects". Retrieved 22 June 2015. 
    "Biphentin product monograph" (PDF). Purdue Pharma. Archived from the original (PDF) on 22 June 2015. Retrieved 22 June 2015. 
    Huss, M; Ginsberg, Y; Tvedten, T; Arngrim, T; Philipsen, A; Carter, K; Chen, CW; Kumar, V (January 2014). "Methylphenidate hydrochloride modified-release in adults with attention deficit hyperactivity disorder: a randomized double-blind placebo-controlled trial". Advances in therapy. 31 (1): 44–65. doi:10.1007/s12325-013-0085-5. PMC 3905180Freely accessible. PMID 24371021. 
  9. ^ a b "Concerta product monograph" (PDF). Janssen Pharmaceuticals. Retrieved 4 December 2016. 
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  12. ^ Stein; et al. (1998). "Sleep disturbances in children with Attention-Deficit/Hyperactivity Disorder a comparative study with healthy siblings". Journal of Learning Disabilities. 31 (6): 572–578. doi:10.1177/002221949803100607. 
  13. ^ a b Cortese, S; Holtmann, M; Banaschewski, T; Buitelaar, J; Coghill, D; Danckaerts, M; Dittmann, RW; Graham, J; Taylor, E; Sergeant, J; European ADHD Guidelines, Group (March 2013). "Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents". Journal of child psychology and psychiatry, and allied disciplines. 54 (3): 227–46. doi:10.1111/jcpp.12036. PMID 23294014. 
  14. ^ Findling, RL; Dinh, S (March 2014). "Transdermal therapy for attention-deficit hyperactivity disorder with the methylphenidate patch (MTS)". CNS Drugs. 28 (3): 217–28. doi:10.1007/s40263-014-0141-y. PMC 3933749Freely accessible. PMID 24532028. 
  15. ^ Kraemer M, Uekermann J, Wiltfang J, Kis B (July 2010). "Methylphenidate-induced psychosis in adult attention-deficit/hyperactivity disorder: report of 3 new cases and review of the literature". Clin Neuropharmacol. 33 (4): 204–6. doi:10.1097/WNF.0b013e3181e29174. PMID 20571380. 
  16. ^ Wingo, AP; Ghaemi, SN (2008). "Frequency of stimulant treatment and of stimulant-associated mania/hypomania in bipolar disorder patients". Psychopharmacology bulletin. 41 (4): 37–47. PMID 19015628. 
  17. ^ "Methylphenidate ADHD Medications: Drug Safety Communication – Risk of Long-lasting Erections". U.S. Food and Drug Administration. 17 December 2013. Retrieved 17 December 2013. 
  18. ^ "FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in children and young adults". United States Food and Drug Administration. 20 December 2011. Retrieved 4 November 2013. 
    Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast PG, Cheetham TC, Murray KT, Quinn VP, Stein CM, Callahan ST, Fireman BH, Fish FA, Kirshner HS, O'Duffy A, Connell FA, Ray WA (November 2011). "ADHD drugs and serious cardiovascular events in children and young adults". N. Engl. J. Med. 365 (20): 1896–1904. doi:10.1056/NEJMoa1110212. PMC 4943074Freely accessible. PMID 22043968. 
    "FDA Drug Safety Communication: Safety Review Update of Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in adults". United States Food and Drug Administration. 15 December 2011. Retrieved 4 November 2013. 
    Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast PG, Cheetham TC, Quinn VP, Dublin S, Boudreau DM, Andrade SE, Pawloski PA, Raebel MA, Smith DH, Achacoso N, Uratsu C, Go AS, Sidney S, Nguyen-Huynh MN, Ray WA, Selby JV (December 2011). "ADHD medications and risk of serious cardiovascular events in young and middle-aged adults". JAMA. 306 (24): 2673–2683. doi:10.1001/jama.2011.1830. PMC 3350308Freely accessible. PMID 22161946. 
  19. ^ Gordon N (1999). "Attention deficit hyperactivity disorder: possible causes and treatment". Int. J. Clin. Pract. 53 (7): 524–8. PMID 10692738. 
  20. ^ Ishii, M; Tatsuzawa, Y; Yoshino, A; Nomura, S (April 2008). "Serotonin syndrome induced by augmentation of SSRI with methylphenidate". Psychiatry and clinical neurosciences. 62 (2): 246. doi:10.1111/j.1440-1819.2008.01767.x. PMID 18412855. 
  21. ^ Türkoğlu, S (2015). "Serotonin syndrome with sertraline and methylphenidate in an adolescent". Clinical Neuropharmacology. 38 (2): 65–6. doi:10.1097/WNF.0000000000000075. PMID 25768857. 
  22. ^ Park, YM; Jung, YK (30 May 2010). "Manic switch and serotonin syndrome induced by augmentation of paroxetine with methylphenidate in a patient with major depression". Progress in neuro-psychopharmacology & biological psychiatry. 34 (4): 719–20. doi:10.1016/j.pnpbp.2010.03.016. PMID 20298736. 
  23. ^ Bodner, RA; Lynch, T; Lewis, L; Kahn, D (February 1995). "Serotonin syndrome". Neurology. 45 (2): 219–23. doi:10.1212/wnl.45.2.219. PMID 7854515. 
  24. ^ Patrick KS, González MA, Straughn AB, Markowitz JS (2005). "New methylphenidate formulations for the treatment of attention-deficit/hyperactivity disorder". Expert Opinion on Drug Delivery. 2 (1): 121–43. doi:10.1517/17425247.2.1.121. PMID 16296740. 
  25. ^ a b Markowitz JS, DeVane CL, Boulton DW, Nahas Z, Risch SC, Diamond F, Patrick KS (2000). "Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol". Drug Metabolism and Disposition. 28 (6): 620–4. PMID 10820132. 
  26. ^ Markowitz JS, Logan BK, Diamond F, Patrick KS (1999). "Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion". Journal of Clinical Psychopharmacology. 19 (4): 362–6. doi:10.1097/00004714-199908000-00013. PMID 10440465. 
  27. ^ Patrick KS, Straughn AB, Minhinnett RR, Yeatts SD, Herrin AE, DeVane CL, Malcolm R, Janis GC, Markowitz JS (March 2007). "Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics". Clinical Pharmacology and Therapeutics. 81 (3): 346–53. doi:10.1038/sj.clpt.6100082. PMC 3188424Freely accessible. PMID 17339864. 
  28. ^ Roberts SM, DeMott RP, James RC (1997). "Adrenergic modulation of hepatotoxicity". Drug Metab. Rev. 29 (1–2): 329–53. doi:10.3109/03602539709037587. PMID 9187524. 
  29. ^ http://www.adhd-institute.com/disease-management/pharmacological-therapy/mechanism-of-action/
  30. ^ a b "Product Information: DAYTRANA(R) transdermal patch, methylphenidate transdermal patch" (PDF). 2010. Archived from the original (PDF) on 2014-08-01. 
  31. ^ Methylphenidate Use During Pregnancy and Breastfeeding. Drugs.com. Retrieved on 30 April 2011.

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