Background

 

Q1. Side effects and hirsutism?

As of yet, a significant amount of data regarding the long-term safety effects of sublingually administered testosterone in women is not available. Via this route, a fast absorption of testosterone results in an early peak plasma level and after approximately 90 minutes the level is back to baseline values.

Information is available, however, on the long-term use of transdermal testosterone, which results in continuous absorption and a continuous increase of testosterone plasma levels over the baseline values. Braunstein and colleagues (1) reported on the safety of a testosterone patch in surgically menopausal women. In this study women were dosed for 24 weeks with a placebo or testosterone patch and several safety parameters were assessed. Every group consisted of at least 100 women (N= 107-119) and continuously received placebo, testosterone 0.15 mg/day, 0.30 mg/day or 0.45 mg/day. No differences in safety evaluations, including various sensitive measurements for the occurrence of hirsutism, were observed. This illustrates that continuous dosing of testosterone for 24 weeks at a level 0.45 mg/day is safe without signs of hirsutism and does not differ from placebo.

Continuously elevated testosterone levels are generally expected to result in more pronounced side effects due to the continuous change in hormonal levels. A short peak in testosterone and a subsequent rapid decline to baseline levels is anticipated to have even fewer side effects. This was also indicated by the regulators that were consulted by Emotional Brain during the discussions before the start of the clinical studies in the USA. In Lybrido and Lybridos, 0.5 mg of testosterone is prescribed for on demand use and during our larger scale clinical studies in the USA, on average 1 tablet was taken per week. In earlier, small scale clinical studies in Europe, no side effects different from placebo treatment were observed. Similarly, during the larger scale clinical studies in the USA (N=400 patients and treatment for 16 weeks), no testosterone-related side effects were observed, compared to placebo. It goes without saying that Emotional Brain will generate additional safety data in larger patient groups and treatment for at least one year before the product will be submitted for marketing approval.

(1) Safety and Efficacy of a Testosterone Patch for the Treatment of Hypoactive Sexual Desire Disorder in Surgically Menopausal Women. : A Randomized, Placebo-Controlled Trial. Glenn D. Braunstein, MD; Dale A. Sundwall, MD; Molly Katz, MD; Jan L. Shifren, MD; John E. Buster, MD; James A. Simon, MD; Gloria Bachman, MD; Oscar A. Aguirre, MD; Johna D. Lucas, MD; Cynthia Rodenberg, PhD; Akshay Buch, PhD; Nelson B. Watts, MD Arch Intern Med. 2005;165(14):1582-1589.

 

Q2. Misuse?

The mechanism of action for Lybrido and Lybridos is based on an immediate peak plasma level of testosterone followed by a delayed release of the second component. This first immediate testosterone peak can only be obtained by intravenous, pulmonal or sublingual testosterone administration. When Lybrido(s) is not taken with full consent and the instruction to keep the tablet under the tongue for at least one minute, but is instead swallowed, testosterone will not be absorbed via the buccal membrane. After swallowing testosterone, the compound is orally available via the gastrointestinal route. Oral administration of testosterone results in a very low bioavailability due to presystemic clearance by the liver and not in a peak plasma level profile. Studies indicate that the extensive metabolism of testosterone in the liver is the reason that orally administered testosterone appears in the systemic circulation only in small amounts, even though testosterone was completely absorbed from the gastrointestinal tract (2).

To circumvent this first-pass effect in the liver, testosterone and testosterone esters are sometimes administered in patches, gels, injections, or implants. Another option is Andriol, the only oral testosterone formulation, designed to deliver testosterone to the systemic circulation via the intestinal lymphatic route, thereby circumventing first-pass inactivation in the liver. Andriol contains testosterone undecanoate dissolved in oleic acid inside a soft gelatin capsule. The esterification of testosterone to a lipophilic ester enables absorption with lipids into the lymphatic system and pass to the peripheral circulation thus bypassing the liver (3). Andriol or the testosterone administration via patches, gels, implants or injectable esters will always lead to sustained increased plasma levels and never to transient peak levels.

Only patient controlled sublingual absorption of testosterone enables the pharmacological effect of the essential testosterone component in the combination drug products Lybrido and Lybridos.

If Lybrido and Lybridos are taken as prescribed, the patient will not lose control over her actions. Drugs like Rohypnol (flunitrazepam), GHB (Gamma hydroxybutyric acid) or ketamine, which are known to be used in drug-facilitated sexual assault (date rape drugs or "roofies"), have in common that they have a sedative and/or anesthetic and often amnestic effect. Neither Lybrido nor Lybridos (or any of their components) have sedative, anesthetic or amnestic effects.

(2) Absorption, metabolism, and excretion of oral testosterone in humans by mass fragmentography.

Shinohara Y, Baba S, Kasuya Y. J Clin Endocrinol Metab. 1980 Dec;51(6):1459-62.

 

(3) Lymphatic absorption and metabolism of orally administered testosterone undecanoate in man

H. -J. Horst, W. J. Höltje, M. Dennis, A. Coert, J. Geelen, K. D. Voigt. Klin. Wochenschrift 1976, vol 54,18, 875-879.

 

Q3. Diagnosis

The Diagnostic and Statistical Manual for Mental Disorders (or DSM) is the gold standard for mental health diagnostic criteria. The DSM-IV-TR (4th edition, text revision) (4) diagnosis Hypoactive Sexual Desire Disorder (HSDD) is characterized as a lack or absence of sexual fantasies and desire for sexual activity, as judged by a clinician. For this to be regarded as a disorder, it must cause marked distress or interpersonal difficulties and not be better accounted for by another mental disorder, a drug (legal or illegal), or some other medical condition. This largely corresponds to the new DSM-5 (5th edition, 2013) (5) diagnosis Female Sexual Interest/Arousal Disorder (FSIAD), which merges the DSM-IV-TR diagnoses HSDD and Female Sexual Arousal Disorder into one. The diagnosis HSDD or FSIAD cannot be made if sexual problems are caused by relationship problems, or if there is a discrepancy in intensity or frequency of experienced sexual desire between two sexual partners, nor can the diagnosis be made if decreases in desire are the result of stress, fatigue or an inattentive partner.

Lybrido and Lybridos are meant solely for women who suffer from HSDD/FSIAD, and will only be available upon medical prescription.

(4) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. Text Revision. Washington, DC: American Psychiatric Publishing; 2000.

(5) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Health Disorders, 5th Ed. Washington, DC: American Psychiatric Publishing; 2013.

 

Q4. Behavioral effects

The behavioral effects of Lybrido and Lybridos are partly realized by the single sublingual administration of 0.5mg testosterone. Testosterone is mostly known as a sex hormone, but it has broader effects on social behavior (of which sexual behavior is also a part). For example, this exact same administration method and dosing of testosterone induces increases in fair bargaining behavior in women (6). See Bloemers et al. (7) for a review on testosterone’s influence on social behavior, and of social stimuli’s influence on endogenous testosterone levels.

Lybrido

The Lybrido tablet combines sublingual (under the tongue) administration of 0.5 mg testosterone and oral administration of 50 mg sildenafil. The sildenafil is released into the body approximately two and a half hours after it has been swallowed. This ensures Lybrido’s window of effect approximately 3 to 6 hours after the sublingual administration of testosterone. Lybrido has been developed for women with the DSM-IV-TR diagnosis Hypoactive Sexual Desire Disorder (HSDD) which corresponds to the new DSM-5 diagnosis Female Sexual Interest/Arousal Disorder (FSIAD), and is specifically aimed to those women who have HSDD/FSIAD due to low sensitivity to sexual cues. The cause of low sensitivity to sexual cues is dependent on the androgen system and the brain’s ability to detect stimulus salience and to perceive bodily responses (interoception). Thus, a dual treatment approach targeting both central and local components—to increase the brain’s sensitivity for sexual cues by testosterone and to enhance peripheral mechanisms of sexual responding by sildenafil—has been shown to be associated with significant increases in genital arousal as well as the frequency of satisfying sexual events and the quality of sexual encounters. Thus, Lybrido ‘normalizes’ the brain’s ability to process sexual cues and the body’s response to these but does not induce an insatiable sexual appetite. When taking Lybrido, a woman does not lose control.

Lybridos

The Lybridos tablet combines sublingual administration of 0.5 mg testosterone and oral administration of 10 mg buspirone. Buspirone is released into the body approximately two and a half hours after it has been swallowed. This ensures Lybridos’ window of effect approximately 3 to 6 hours after the sublingual administration of testosterone. Lybridos has been developed for women with HSDD/FSIAD as the result of maladaptive activation of sexual inhibitory mechanisms. The cause of this maladaptive inhibition lies in a propensity for enhanced (re)activity of inhibitory physiological systems (possibly in response to negative sexual experiences). This dual-treatment approach targeting two central components—to increase the brain’s sensitivity for sexual cues by testosterone and to repress inhibitory mechanisms in the prefrontal cortex by buspirone—has been shown to be associated with significant increases in genital arousal and in the frequency of satisfying sexual events and the quality of sexual encounters. Thus, Lybridos increases the brain’s ability to process sexual cues (which have in part been under chronic inhibition) and decreases the inhibitory response to welcomed and safe sexual stimuli. It does not induce an insatiable sexual appetite. When taking Lybridos, a woman does not lose control.

(6) Prejudice and truth about the effect of testosterone on human bargaining behaviour. Eisenegger C, Naef M, Snozzi R, Heinrichs M, Fehr E. Nature 2010; 463:356-9.

(7) Toward Personalized Sexual Medicine (Part 1): Integrating the "Dual Control Model" into Differential Drug Treatments for HSDD and FSAD. Bloemers J, van Rooij K, Poels S, Goldstein I, Everaerd W, Koppeschaar H, Chivers M, Gerritsen J, van Ham D, Olivier B, Tuiten A. JSM 2013;10 (3):791-809.