Transderm Scop (Page 3 of 4)

8.2 Labor and Delivery

During a clinical study among women undergoing cesarean section treated with Transderm Scōp in conjunction with

epidural anesthesia and opiate analgesia, no evidence of CNS depression was found in newborns. [see Clinical Studies (14.2)]Scopolamine administered parenterally to rats and rabbits at doses higher than the dose delivered by

Transderm Scōp did not affect uterine contractions or increase the duration of labor. Scopolamine does cross the

placenta.

8.3 Nursing Mothers

Scopolamine is excreted in human milk. Caution should be exercised when Transderm Scōp is administered to a

nursing woman.

8.4 Pediatric Use

A safe and effective dose has not been established in the pediatric population. [ see Warnings and Precautions (5.6)]

8.5 Geriatric Use

Transderm Scōp should be used with caution in the elderly because of the increased likelihood of CNS effects, such

as hallucinations, confusion and dizziness. Clinical trials of Transderm Scop did not include sufficient number of

subjects aged 65 years and older to determine if they respond differently from younger subjects. [ see Warnings and Precautions (5.6)]

8.6 Renal or Hepatic Impairment

Transderm Scōp should be used with caution in individuals with impaired renal or hepatic functions because of the increased likelihood of CNS effects. [ see Warnings and Precautions (5.6)]

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance Class

Scopolamine is not a controlled substance.

9.2 Abuse

Scopolamine is an antagonist at muscarinic receptors in the cholinergic system. Drugs in this class are not known to

have significant abuse potential in humans.

9.3 Dependence

Abrupt termination of Transderm Scōp may result in withdrawal symptoms such as dizziness, nausea, vomiting,

abdominal cramps, sweating, headache, mental confusion, muscle weakness, bradycardia and hypotension. [ see Adverse Reaction (6.3) and Overdosage (10)] These withdrawal symptoms indicate that anticholinergic drugs, like

scopolamine may produce physical dependence. These symptoms can be severe and may require medical

intervention.

10 OVERDOSAGE

Because strategies for the management of drug overdose continually evolve, it is strongly recommended that a

poison control center be contacted to obtain up-to-date information regarding the management of Transderm Scōp®

patch overdose. The prescriber should be mindful that antidotes used routinely in the past may no longer be

considered optimal treatment. For example, physostigmine, used more or less routinely in the past, is seldom

recommended for the routine management of anticholinergic syndromes.

Until up-to-date authoritative advice is obtained, routine supportive measures should be directed to maintaining

adequate respiratory and cardiac function.

The signs and symptoms of anticholinergic toxicity include: lethargy, somnolence, coma, confusion, agitation,

hallucinations, convulsion, visual disturbance, dry flushed skin, dry mouth, decreased bowel sounds, urinary

retention, tachycardia, hypertension, and supraventricular arrhythmias. These symptoms can be severe and may

require medical intervention.

In cases of toxicity remove the patch. Serious symptomatic cases of overdosage involving multiple patch

applications and/or ingestion may be managed by initially ensuring the patient has an adequate airway, and

supporting respiration and circulation. This should be rapidly followed by removal of all patches from the skin and

the mouth. If there is evidence of patch ingestion, gastric lavage, endoscopic removal of swallowed patches, or

administration of activated charcoal should be considered, as indicated by the clinical situation. In any case where

there is serious overdosage or signs of evolving acute toxicity, continuous monitoring of vital signs and ECG,

establishment of intravenous access, and administration of oxygen are all recommended.

The symptoms of overdose/toxicity due to scopolamine should be carefully distinguished from the occasionally

observed syndrome of withdrawal. [ see Adverse Reactions (6.3)] Although mental confusion and dizziness may be

observed with both acute toxicity and withdrawal, other characteristic findings differ: tachyarrhythmias, dry skin,

and decreased bowel sounds suggest anticholinergic toxicity, while bradycardia, headache, nausea and abdominal

cramps, and sweating suggest post-removal withdrawal. Obtaining a careful history is crucial to making the correct

diagnosis.

11 DESCRIPTION

The Transderm Scōp® (scopolamine) transdermal system is a circular flat patch designed for continuous release of

scopolamine following application to an area of intact skin on the head, behind the ear. Each system contains 1.5 mg

of scopolamine base. Scopolamine is α -(hydroxymethyl) benzeneacetic acid 9-methyl-3-oxa-9-azatricyclo

[3.3.1.0 2 ,4 ] non-7-yl ester. The empirical formula is C17H21NO4 and its structural formula is:

Chemical Structure

Scopolamine is a viscous liquid that has a molecular weight of 303.35 and a pKa of 7.55-7.81. The Transderm Scōp

system is a film 0.2 mm thick and 2.5 cm2 , with four layers. Proceeding from the visible surface towards the surface

attached to the skin, these layers are: (1) a backing layer of tan-colored, aluminized, polyester film; (2) a drug

reservoir of scopolamine, light mineral oil, and polyisobutylene; (3) a microporous polypropylene membrane that

controls the rate of delivery of scopolamine from the system to the skin surface; and (4) an adhesive formulation of

mineral oil, polyisobutylene, and scopolamine. A protective peel strip of siliconized polyester, which covers the

adhesive layer, is removed before the system is used. The inactive components, light mineral oil (12.4 mg) and

polyisobutylene (11.4 mg), are not released from the system.

Cross section of the system:

Patch Cross Section
(click image for full-size original)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Scopolamine, a belladonna alkaloid, is an anticholinergic agent. Scopolamine acts: i) as a competitive inhibitor at

postganglionic muscarinic receptor sites of the parasympathetic nervous system, and ii) on smooth muscles that

respond to acetylcholine but lack cholinergic innervation. It has been suggested that scopolamine acts in the central

nervous system (CNS) by blocking cholinergic transmission from the vestibular nuclei to higher centers in the CNS

and from the reticular formation to the vomiting center. Scopolamine can inhibit the secretion of saliva and sweat,

decrease gastrointestinal secretions and motility, cause drowsiness, dilate the pupils, increase heart rate, and depress

motor function.

12.3 Pharmacokinetics

The pharmacokinetics of scopolamine delivered via the system are due to the characteristics of both the drug and

dosage form. The system is formulated to deliver in-vivo approximately 1 mg of scopolamine at an approximately

constant rate to the systemic circulation over 3 days. Upon application to the postauricular skin, an initial priming

dose of scopolamine is released from the adhesive layer to saturate skin-binding sites. The subsequent delivery of

scopolamine to the blood is determined by the rate controlling membrane and is designed to produce stable plasma

levels in a therapeutic range. Following removal of the used system, there is some degree of continued systemic

absorption of scopolamine bound in the skin layers.

Absorption
Scopolamine is well absorbed percutaneously. Following application to the skin behind the ear, circulating plasma

levels are detected within 4 hours with peak levels being obtained, on average, within 24 hours. The average plasma

concentration produced is 87 pg/mL (0.28 nM) for free scopolamine and 354 pg/mL for total scopolamine (free +

conjugates).

Distribution
The distribution of scopolamine is not well characterized. It crosses the placenta and the blood brain barrier and may be reversibly bound to plasma proteins.

Metabolism and Excretion
The exact elimination pattern of scopolamine has not been determined. Following patch removal, plasma levels of scopolamine decline in a log linear fashion with an observed half-life of 9.5 hours. Less than 10% of the total dose is excreted in the urine as the parent drug and metabolites over 108 hours. Scopolamine is extensively metabolized and conjugated with less than 5% of the total dose appearing unchanged in the urine. The enzymes responsible for metabolizing scopolamine are unknown.

Drug Interaction

An in vitro study using human hepatocytes examined the induction of CYP1A2 and CYP3A4 by scopolamine.

Scopolamine did not induce CYP1A2 and CYP3A4 isoenzymes at the concentrations up to 10 nM.

In an in vitro study using human liver microsomes which evaluated the inhibition of CYP1A2, 2C8, 2C9, 2C19, 2D6

and 3A4, scopolamine did not inhibit these cytochrome P450 isoenzymes at the concentrations up to 1 mcM.

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