2017 in Review: New Drugs, Formulations and Clinical Guidelines

Author: Flavio Guzman, MD
Dr. Guzman has no conflicts of interest to disclose.
In this article, we look back at the most clinically relevant news of 2017 in the field of psychopharmacology.
In terms of new drugs, two drugs were approved for the treatment of tardive dyskinesia: valbenazine (Ingrezza) and deutetrabenazine (Austedo).
This publication also summarizes new formulations of ADHD medications and buprenorphine.
We also share key points from three guidelines of clinical interest: one on the use of psychotropic medications in pregnancy and the other two on mixed states and mixed depression.
Contents
New Drugs and Formulations Approved by the FDA in 2017 ………………………………………………………………………………… 1 Ingrezza (valbenazine)………………………………………………………………………………………………………………………………….. 1 Austedo (deutetrabenazine) ………………………………………………………………………………………………………………………….. 2 Opioids: An Injectable Buprenorphine Formulation and a Device for Withdrawal Symptoms…………………………………..2 Abilify MyCite (aripiprazole tablets with sensor) ……………………………………………………………………………………………….. 3 New ADHD Formulations: Adzenys ER, Cotempla XE-ODT, Mydayis ………………………………………………………………… 4
New Clinical Guidelines Published in 2017 …………………………………………………………………………………………………………. 5 Use of psychotropic medication in pregnancy and postpartum …………………………………………………………………………… 5 Bipolar disorder: mixed depression and mixed states ……………………………………………………………………………………….. 6
References …………………………………………………………………………………………………………………………………………………….. 6
New Drugs and Formulations Approved by the FDA in 2017 Ingrezza (valbenazine)
• Indication
o Treatment of adults with tardive dyskinesia
▪ Approval date: April 11, 2017 • Mechanism of action and pharmacology
o Valbenazine is a selective vesicular monoamine transporter 2 (VMAT2) inhibitor
o Valbenazine and its metabolite do not antagonize postsynaptic monoamine receptors in contrast to the
tetrabenazine formulations [1]
o It inhibits presynaptic packaging and release of dopamine into the synapse

• Adverse effects [2]

o The most common adverse effect of valbenazine in clinical trials was somnolence o Valbenazine can cause QT interval prolongation
Austedo (deutetrabenazine)
• Indications
o Chorea associated with Huntington’s disease o Tardive dyskinesia in adults
▪ Approval date: August 30, 2017 • Mechanism of action and pharmacology
o Deuetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor o Deutetrabenazine is a deuterated form of tetrabenazine
▪ The addition of deuterium increases the drug's duration of action • Adverse effects and contraindications [3]
o The most common adverse reactions of deutetrabenazine were nasopharyngeal symptoms and insomnia o May cause an increase in QT interval
o Deutetrabenazine is contraindicated in patients taking reserpine, MAOIs, tetrabenazine, or valbenazine
o Contraindicated in patients with hepatic impairment
Opioids: An Injectable Buprenorphine Formulation and a Device for Withdrawal Symptoms
Sublocade (buprenorphine extended-release) injection
• Formulation
o Once-monthly injectable buprenorphine
• Indication
o Treatment of moderate-to-severe opioid use disorder
• Administered monthly only by subcutaneous injection in the abdominal region [4] Comments by Joji Suzuki, MD
• This injectable formulation eliminates the need for daily adherence and addresses the concern of risk of buprenorphine diversion

• High cost is a concern

• Implementation of a long-acting formulation is more complex than sublingual formulations, requiring institutional
commitment
NSS-2 Bridge

• In November 2017 the FDA granted marketing authorization of the NSS-2 Bridge, a device designed to reduce the symptoms of opioid withdrawal

• About the device
o It contains a battery-powered chip that emits electrical pulses to stimulate branches of certain cranial
nerves
o Stimulation "may provide relief from opioid withdrawal symptoms" according to the FDA's news release
Abilify MyCite (aripiprazole tablets with sensor)
The FDA approved on November 13, 2017 a pill with a sensor that digitally tracks if patients have ingested their medication (aripiprazole).
How does this new system work?
[
Figure 1 Example of a digital medicine system. Photo: Proteus Digital Health
Example of a digital medicine system. Photo: Proteus Digital Health[/caption]
1. An aripiprazole tablet is embedded at the point of manufacture with an Ingestible Event Marker (IEM) sensor

2. The IEM sensor activates when in contact with stomach fluid and communicates to a wearable sensor, called the MyCite® Patch, which detects and records the date and time of the ingestion of the tablet

3. The information collected in the Patch is communicated to the mobile app

Comments
An editorial published this year in Expert Review of Neurotherapeutics comments on the practical aspects of Abilify MyCite.
"The patients included in the (registration) study clearly failed to represent ordinary patients with schizophrenia, those who we meet in daily clinical practice since they were all a stable population with mild intensity of psychotic symptoms as measured by Clinical Global Impression-Severity scale (CGI-S)." [5]
The authors pose several important questions, including:
• How does the clinician convince the paranoid patient that the digital medicine system is not monitoring his thoughts, actions, and life in general?

• What about privacy issues around the collection and storage of personal health data on smart devices?

  

• Is a study of 67 self-selected patients who volunteer for a clinical trial, an adequate representation of what happens in the real world?
They conclude the following:
"Given the time-intensive nature of the digital medicine system, and the fact that all it is able to do is identify nonadherent patients, it does not appear to be a good use of the busy clinicians’ time."
"This technology in no way provides a differential diagnosis of nonadherence. It would be far more productive for a clinician to spend a few minutes routinely inquiring about non-adherence in all their patients including doing a plasma level when indicated."
New ADHD Formulations: Adzenys ER, Cotempla XE-ODT, Mydayis
Adzenys ER (amphetamine)
• Formulation: extended-release liquid amphetamine medication, it does not require refrigeration or reconstitution at the pharmacy level

• Indication

o Treatment of ADHD in patients 6 years and older
• Manufacturer: Neos Therapeutics

• Comments

o This formulation provides a once-daily ready-to-use dosing option [6] Cotempla XE-ODT (methylphenidate)
• Formulation: methylphenidate-based extended-release orally disintegrating tablet

• Indication

o Treatment ADHD in pediatric patients 6 to 17 years of age
• Manufacturer: Neos Therapeutics

• Comments

o This is another alternative for children with ADHD who cannot swallow a capsule or a tablet [7]
o For those who are willing to swallow capsule contents sprinkled on applesauce, generic Ritalin LA would
be a less expensive option [7]
Mydayis (mixed salts of a single-entity amphetamine product)
• Formulation: long-acting, triple-bead, mixed amphetamine salts

• Indication

o ADHD in patients 13 years and older, not for children 12 years and younger
• Manufacturer: Shire

• Comments

o Published trial data demonstrate a longer duration of action than other preparations of MAS-based
formulations
o Because of its long duration of action, this preparation may be associated with more insomnia and appetite suppression than other mixed amphetamine salts formulations [8]

New Clinical Guidelines Published in 2017
Use of psychotropic medication in pregnancy and postpartum

British Association for Psychopharmacology consensus guidance on the use of psychotropic medication preconception, in pregnancy and postpartum 2017
General management issues across all childbearing stages
• Using a drug of known efficacy in a particular woman may be preferable to using one of unknown efficacy but possible lower pregnancy risk

• Subtherapeutic doses of medication should be avoided The preconception period

• Valproate is the only psychotropic contraindicated in women of childbearing potential when used for psychiatric indications, although even here there can be very rare exceptions
During pregnancy
• Generally avoid stopping medication suddenly on discovery of pregnancy, since this does not necessarily remove risks of malformations and sudden discontinuation of medication may pose risks to the mother’s health

• Although there may be some potential advantages of changing medications early in pregnancy, by mid-trimester there might be fewer, if any, advantages in changing (with the exception of valproate)
Postnatally and during breastfeeding

• A guide to the possible risk of breastfeeding while taking a particular drug is the relative infant dose (RID) – the daily amount of drug ingested by the infant during exclusive breastfeeding per kg body weight divided by the maternal daily dose per kg body weight. Information regarding this can be found in the Drugs and Lactation Database, 2016
Antidepressants
• Antidepressants, when studied as a group, may have a small effect on some pregnancy outcomes (gestational age, Apgar score) but these may be due to residual confounding issues and in addition may not be clinically significant

• Antidepressants that block serotonin uptake may be associated with an increased risk of postpartum hemorrhage, but the magnitude and clinical significance of this risk is uncertain

• There have been concerns about antidepressant (mainly SSRIs and possibly particularly paroxetine) exposure in utero being associated with cardiac malformations

o This may not be the case once all confounders are taken into account
• Although the risk of PPHN in babies exposed in utero to SSRIs is increased, the absolute risk is low
o There is some evidence of neonatal effects following late pregnancy exposure to SSRIs, particularly respiratory distress and neonatal behavioral syndrome
• Babies born to mothers with depression and treated with antidepressants during pregnancy may have better long- term emotional and behavioral development compared to babies born to mothers with depression that was untreated

• Sertraline has a low rate of reported adverse effects on breastfed babies and for new episodes of depression may be appropriate

o Choice of antidepressant should be guided by the same principles as choice during pregnancy, for example taking into account a woman’s previous response to medication
  

Download the guidelines here
Bipolar disorder: mixed depression and mixed states
The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders: Acute and long-term treatment of mixed states in bipolar disorder
Selected key points
• Manic symptoms in bipolar mixed states appeared responsive to treatment with several atypical antipsychotics, the best evidence resting with olanzapine

• For depressive symptoms, the addition of ziprasidone to treatment as usual may be beneficial

o the evidence base is much more limited than for the treatment of manic symptoms
• Besides olanzapine and quetiapine, valproate and lithium should also be considered for recurrence prevention Download the guidelines here
Guidelines for the recognition and management of mixed depression – CNS Spectrums
Selected key points
• All patients who receive antidepressants for a major depressive episode should be monitored for signs of abnormal behavioral activation or psychomotor acceleration

• The use of antidepressants in major depressive episode patients with mixed features may not alleviate depressive symptoms and may pose a potential hazard for exacerbating subthreshold mania symptoms that accompany depression

• For an individual presenting with a depressive episode with mixed features, in addition to antidepressant medication, alternative psychotropic agents (e.g., lithium, anticonvulsant mood stabilizers, atypical antipsychotics) with demonstrated efficacy in treating depressive symptoms as part of major depressive episode may be considered
Download the guidelines here
References

1. Müller, T. (2017). Valbenazine for the treatment of tardive dyskinesia. Expert review of neurotherapeutics, 17(12), 1135-1144

2. Ingrezza (valbenazine) [Prescribing information] San Diego, CA : Neurocrine Biosciences, Inc.; 2017

3. Austedo (deutetrabenazine) [Prescribing information] North Wales, PA: Teva Pharmaceuticals USA, Inc:; 2017

4. Sublocade (buprenorphine extended release) [Prescribing information] North Chesterfield, VA: Indivior Inc; 2017

5. Masand, P., Han, C., & Pae, C. U. (2017). Will the Proteus sensor enhance adherence to aripiprazole or other antipsychotics?.Expert Rev Neurother. 2017 Apr;17(4):319-321.

6. Mattingly, G. W., Wilson, J., & Rostain, A. L. (2017). A clinician’s guide to ADHD treatment options. Postgraduate medicine, 129(7), 657-666.

7. [No authors listed] (2017) Cotempla XR-ODT–another long-acting methylphenidate for ADHD. Med Lett Drugs Ther. 2017 Nov 6;59(1533):183-185

8. Strawn, J, Picard, L (2017) Triple-bead mixed amphetamine salt for ADHD Current Psychiatry. August;16(8):33- 37

          

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