Hyoscine

Endpoint summary

Description of key information

 

The following is related to CSR section skin sensitization 5.5.1.2 Human information:

For the articles that met the relevance criteria, an assessment of the outcome and reliability of the study was carried out. A review of the published literature for scopolamine concludes that the active causes allergic contact dermatitis (type IV delayed hypersensitivity) in humans using well established clinical criteria.

Additional information

There are seven published (see table below) unique clinical reports with information to scopolamine and skin sensitization. The publication were selected and sorted in two categories:

1. Publications which meet the relevance criteria are assessed to be reliable and where the endpoint
will have an impact on the risk assessment
2. Publications not meeting the relevance criteria
The reliability assessment for relevant studies was done according to Klimisch et al.

Trozak:
Transdermal devices are marketed for the delivery of systemic medications through the skin. In a 53 year old female who suffered from persistent vertigo and dizziness, was given Transderm Scop containing the active ingredient scopolamine. Prompt relief of her symptoms resulted, with the transdermal device used daily. Three months post the initial treatment, erythema and pruritus were noted beneath the transdermal device at the site of application. Standardized patch testing was undertaken which confirmed that the patient demonstrated a delayed hypersensitivity reaction to scopolamine.
During the developmental testing of Transderm-Scop, there were no reports of irritant or contact allergy. The reason may be the low antigenicity of scopolamine or the short-term applications and limited repeat exposures employed. The patient in this case report had a constant challenge over a 3-month period, which enhanced the opportunity for delayed hypersensitivity to develop.

van der Willigen et al.:
In a case report, Scopolamine-TTS (transdermal therapeutic system) was applied dermally to glabrous skin behind the ear of a 10 year old male who had severe chronic ptyalism (excessive salivation). The transdermal device was used continuously for 2 weeks prior to the onset of reaction at the application site.
Patch testing was performed with the routine European standard (ICDRG)-test battery. Scopolamine-
TTS and scopolamine in several concentrations (0.25%, 0.5, 1%) was applied in standardized patch
tests applied to the back. Dermal readings were taken at 48 and 72 h.
Positive reactions were obtained for Scopolamine-TTS and scopolamine in all concentrations tested.
The ICDRG test battery was negative.

Gordon et al.
A total of 164 patients were treated for seasickness with transdermal hyoscine (scopolamine) applied as a patch to glabrous skin behind the ear. Hyoscine containing dermal patches were applied 1 – 2 times/week for several months (1.5 – 15 months). None of the patients involved had previously handled or had contact with hyoscine. Of the 164 patients treated, allergic contact dermatitis caused by the drug was diagnosed in 16 patients. Of these patients, all had pruritus and erythema at the site of the patch. The pruritus started after several hours and lasted for a few days, whereas erythema was clearly evident within 24 to 48 hours after the patch was applied.
The study showed a high rate (10%) of allergic contract dermatitis to transdermal hyoscine in healthy
men treated for several months. Allergic contact dermatitis (type IV delayed hypersensitivity) was
diagnosed by well-established clinical criteria and was further confirmed by the absence of any reaction to a placebo patch.
The results were in contrast with those conducted by the manufacturer (Alza Corporation, California,
USA) in which no delayed contract sensitisation occurred in 203 subjects examined. The treatment
regimen involved consecutive application of hyoscine patches daily for nine days, with a tenth application applied after a 2 week rest. The failure of such a treatment regimen does not leave sufficient time for the immune system to respond (i.e. development of activated and memory T cells as opposed to antibody production), and consequently does not rule out the possibility of delayed type IV hypersensitivity occurring.

Non-relevant publications:
Three available papers evaluated the efficacy of scopolamine, absorbed through intact skin, in
preventing motion sickness. In all three papers a single dermal patch containing scopolamine was
applied to glabrous skin behind the ear. The duration of the application was only confirmed in one of
the papers (7-8 hours). Whilst all three papers confirmed that scopolamine provided protection against
motion sickness, no dermal assessment at the site of application was made. Furthermore, a single
application of scopolamine with an acute assessment post application is an insufficient methodology to determine a delayed hypersensitivity type reaction. These papers are therefore considered inadequate to conclude on dermal hypersensitivity potential of scopolamine.
Of the side effects reported to the US FDA from the current sample period of October 2011 until
September 2012 [DrugLib Portal] 600,000 reports were made concern drug side effects. Of these,
scopolamine was suspected to be the cause in a 104 cases. It is important to understand that while
this information is potentially useful when analysed properly (e.g. for post-marketing analysis of drug
side effects), it can be easily over interpreted or misinterpreted. Of the 104 cases, scopolamine was
administered dermally in 5 cases, with no associated dermal reactions reported. Of the other cases
reported, the route of administration was not report (86 cases), orally (11 cases) or intravenously (2
cases) administered. It is also important to understand that the causative relation between a drug and its FDA-reported side effects is only suspected, not proven. In many of the cases, the patient was on
multiple drugs, all of which may get reported as a suspected side-effect cause even though only one
(or none) may actually be responsible. For the cases where scopolamine was applied dermally, the data are considered inadequate to conclude on dermal hypersensitivity potential of scopolamine.

 

 

 

Table 1: Data for Skin sensitization for scopolamine (CAS 51-34-3)

Route	Effect	Reference	Result and Justification	Evaluation according to Table 3.2, 3.3 and 3.4 of the CLP Guidance (Guidance on Application of the CLP Criteria (2017))
Application of transdermal patch, human	Allergic contact dermatitis occurred in 16 out of 164 men being treated for seasickness with transdermal hyoscine for 6 weeks to 15 months. All 16 men showed pruritus after several hours and erythema after 24-48 hours after exposure. All reactions resolved upon patch removal and reappeared when patches were reapplied. Allergic contact dermatitis (type IV hypersensitivity) was diagnosed by well-established clinical criteria.	Gordon CR, et al.Allergic contact dermatitis caused by transdermal hyoscine.   BMJ 1989;298: 1220–1	Positive Did not rule out prior induction of sensitization by cross-reactive molecules.  Klimisch 2   Results have not been duplicated despite ongoing use of transdermal hyoscine. FDA surveillance reports do not support the conclusions of this study.	Occurrence: high frequency Concentration/dose: 0.5 mg/day and 1.5 cm² (= score 0) Repeated exposure: permanent (score 2) Number of exposure: up to 15 months (score 2)   Ø  According to Table 3.4 of the CLP guidance a Category 1A is described.
Application of transdermal patch, human	One case of delayed hypersensitivity to transdermal hyoscine has been reported during standardized patch testing, carried out following daily use of the patch for 3 months. Reactions to other components of the device were all negative apart from a transient erythema (irritation) to mineral oil at 72 hours.	Trozak DJ, Modesto MD. Delayed hypersensitivity to scopolamine delivered by a transdermal device. IAm Acad Dermatol 1985;13:247-51.	Positive Limited data on the study are available and only 1 case study was reported. Cross reactivity from prior induction of sensitization to another material was not ruled out. This study cannot be used to make a determination of the dermal sensitization potential of scopolamine   Klimisch 2	Occurrence: single case Concentration/dose: 0.3 mg/day assuming the patch is about 1 cm² (= score 0) Repeated exposure: permanent (score 2) Number of exposure: at least 90 days (score 0)   Ø  According to Table 3.4 of the CLP guidance a Category 1 or case by case evaluation is described.
Application of transdermal patch, human	Positive reactions were reported in one 10 year old child following continuous treatment for 2 weeks with scopoloamine patches. Standardized patch testing was consequently carried out with different concentrations of scopolamine and again showed positive reactions. No reaction was seen with the test battery. Reactions were considered extremely positive (erythema, induration, papules, vesicles exceeding the border of the test area).	Van der Willigen AH, Oranje AP, Stolz E, Van Joost T. Delayed hypersensitivity to scopolamine in transdermal therapeutic systems. J Am Acad Dermatol 1988;18:146-7.	Positive Limited data on the study are available and only 1 case study was reported.   Klimisch 2	Occurrence: single case Concentration/dose: 0.5 mg/day and 1.5 cm² (= score 0) Repeated exposure: permanent (score 2) Number of exposure: 2 weeks (score 0)   Ø  According to Table 3.4 of the CLP guidance a Category 1 or case by case evaluation is described.
Application of transdermal patch, human	No delayed contact sensitization occurred in studies conducted by manufacturer of transdermal patches (Alza Corporation, Calafornia). 203 subjects were subjected to consecutive application of 9 hyoscine patches followed by application of the tenth patch 2 weeks later. The design of the studies does not rule out the possibility of delayed type IV sensitivity occurring due to a more prolonged use of the patches.	Alza Corporation, California, United States	Negative No sufficient data on the study are available   Klimisch 4	n/a
Application of transdermal patch, human	No irritation or contact allergy were reported in 36 healthy men and women with either the scopoloamine Transderm Scop or placebo patch used for 3 days. This may be due to low antigenicity of scopolamine, the short-term applications and limited repeat exposures employed, or the lack or reporting of such effects as participants were only asked about any symptoms of drowsiness, dry mouth and blurred vision.	Price N, Schmitt RN, Shaw JE: Transdermal delivery of scopolamine for prevention of motion-induced nausea in rough seas. Clin Ther 2:258-262, 1979.	Negative Limited study as sensitization effects may not have been recorded   Klimisch 4	n/a
Application of transdermal patch, human	No irritation or contact allergy were reported in 35 healthy men and women with either the scopoloamine Transderm Scop or placebo patch was used for 12-24 hours, three times at least a week apart. This may be due to low antigenicity of scopolamine, the short-term applications and limited repeat exposures employed or the lack or reporting of such effects as participants were not asked to report any side effects.	McCauley ME, Royal JW, Shaw JE, Schmitt LG: Effect of transdermally administered scopolamine in preventing motion sickness. Aviat Space Environ Med 50: 11081111, 1979.	Negative Limited study as sensitization effects may not have been recorded   Klimisch 4	n/a
Application of transdermal patch, human	No irritation or contact allergy were reported in 163 healthy men and women with either the scopoloamine or placebo patch Transderm Scop used for 14-16 hours. This may be due to the short-term applications and limited repeat exposures employed or reporting of such effects as participants were not asked to report any side effects.	Price N, Schmitt L, McGuire J, et al: Transdermal scopolamine jn the prevention of motion sickness at sea. Clin Pharmacol Ther 29:414-419, 1981.	Negative Limited study as sensitization effects may not have been recorded and due to the short exposure period   Klimisch 4	n/a