2.1 Important Application and Removal Instructions

• Each scopolamine transdermal system is formulated to deliver in vivo approximately 1 mg of scopolamine over 3 days.
• Only wear one transdermal system at any time.
• Donot cut the transdermal system.
• Apply the transdermal system to the skin in the postauricular area (hairless area behind one ear).
• After the transdermal system is applied on the dry skin behind the ear, wash hands thoroughly with soap and water and dry hands [see Warnings and Precautions (5.6)].
• If the transdermal system becomes displaced, discard the transdermal system and apply a new transdermal system on the hairless area behind the other ear.
• Once the transdermal system has been affixed, avoid touching or applying pressure to the transdermal system while it is being worn, since pressure exerted on it may cause scopolamine to ooze out at the edge.
• Upon removal, fold the used transdermal system in half with the sticky side together and discard in household trash in a manner that prevents accidental contact or ingestion by children, pets or others.
• Wash the hands and application site with soap and water after transdermal system removal [see Warnings and Precautions (5.6)].

2.2 Recommended Adult Dosage

Motion Sickness

Apply one scopolamine transdermal system to the hairless area behind one ear at least 4 hours before the antiemetic effect is required – for use up to 3 days. If therapy is required for longer than 3 days, remove the first transdermal system and apply a new scopolamine transdermal system behind the other ear.

PONV

For surgeries other than cesarean section

Apply one scopolamine transdermal system the evening before scheduled surgery. Remove the transdermal system 24 hours following surgery.

5.1 Acute Angle Closure Glaucoma

The mydriatic effect of scopolamine may cause an increase in intraocular pressure resulting in acute angle closure glaucoma. Monitor intraocular pressure in patients with open angle glaucoma and adjust glaucoma therapy during scopolamine transdermal system use, as needed. Advise patients to immediately remove the transdermal system and contact their healthcare provider if they experience symptoms of acute angle closure glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema).

5.2 Neuropsychiatric Adverse Reactions

Psychiatric Adverse Reactions

Scopolamine has been reported to exacerbate psychosis. Other psychiatric reactions have also been reported, including acute toxic psychosis, agitation, speech disorder, hallucinations, paranoia and delusions [see Adverse Reactions (6.2)]. Monitor patients for new or worsening psychiatric symptoms during treatment with scopolamine transdermal system. Also, monitor patients for new or worsening psychiatric symptoms during concomitant treatment with other drugs that are associated with similar psychiatric effects [see Drug Interactions (7.1)]. In cases of psychiatric reactions occurring scopolamine transdermal system should be removed at once. If, despite this, the symptoms persist in a severe form, instruct patients to seek medical attention.

Seizures

Seizures and seizure-like activity have been reported in patients receiving scopolamine. Weigh this potential risk against the benefits before prescribing scopolamine transdermal system to patients with a history of seizures, including those receiving anti-epileptic medication or who have risk factors that can lower the seizure threshold.

Cognitive Adverse Reactions

Scopolamine can cause drowsiness, disorientation and confusion. Discontinue scopolamine transdermal system if signs or symptoms of cognitive impairment develop. If, despite this, the symptoms persist in a severe form, instruct patients to seek medical attention. Elderly and pediatric patients may be more sensitive to the neurological and psychiatric effects of scopolamine transdermal system. Consider more frequent monitoring during treatment with scopolamine transdermal system in elderly patients [see Use in Specific Populations (8.5)]. Scopolamine transdermal system is not approved for use in pediatric patients [see Use in Specific Populations (8.4)].

Hazardous Activities

Scopolamine transdermal system may impair the mental and/or physical abilities required for the performance of hazardous tasks such as driving a motor vehicle, operating machinery or participating in underwater sports. Concomitant use of other drugs that cause central nervous system (CNS) adverse reactions (e.g., alcohol, sedatives, hypnotics, opiates and anxiolytics) or have anticholinergic properties (e.g., other belladonna alkaloids, sedating antihistamines, meclizine, tricyclic antidepressants and muscle relaxants) may increase this effect [see Drug Interactions (7.1)]. Inform patients not to operate motor vehicles or other dangerous machinery or participate in underwater sports until they are reasonably certain that scopolamine transdermal system does not affect them adversely.

5.3 Eclamptic Seizures in Pregnant Women

Eclamptic seizures have been reported in pregnant women with severe preeclampsia soon after injection of intravenous and intramuscular scopolamine [see  Use in Specific Populations (8.1)]. Avoid use of scopolamine transdermal system in patients with severe preeclampsia.

5.4 Gastrointestinal and Urinary Disorders

Scopolamine, due to its anticholinergic properties, can decrease gastrointestinal motility and cause urinary retention. Consider more frequent monitoring during treatment with scopolamine transdermal system in patients suspected of having intestinal obstruction, patients with pyloric obstruction or patients with impeded flow of urine (e.g., in diseases of the prostate or urinary bladder neck obstruction and patients receiving other anticholinergic drugs [see Drug Interactions (7.2)]. Discontinue scopolamine transdermal system in patients who develop difficulty in urination.

5.5 Drug Withdrawal/Post-Removal Symptoms

Discontinuation of scopolamine transdermal system, usually after several days of use, may result in withdrawal symptoms, such as disturbances of equilibrium, dizziness, nausea, vomiting, abdominal cramps, sweating, headache, mental confusion, muscle weakness, bradycardia and hypotension. The onset of these symptoms is generally 24 hours or more after the transdermal system has been removed. Instruct patients to seek medical attention if they experience severe symptoms.

5.6 Blurred Vision

Scopolamine can cause temporary dilation of the pupils resulting in blurred vision if it comes in contact with the eyes.

Advise patients to wash their hands thoroughly with soap and water and dry their hands immediately after handling the transdermal system, do not touch the system while wearing it, and wash hands and the application site with soap and water after transdermal system removal [see Dosage and Administration (2.1)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Motion Sickness

The most common adverse reaction (approximately two thirds) was dry mouth. Less common adverse reactions, included drowsiness (less than one sixth), blurred vision and dilation of the pupils.

PONV

Common adverse reactions, occurring in at least 3% of patients in PONV clinical trials are shown in Table 1.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of scopolamine transdermal system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Psychiatric disorders:  acute psychosis including: hallucinations, disorientation and paranoia

Nervous system disorders: headache, amnesia, coordination abnormalities, speech disorder, disturbance in attention, restlessness

General disorders and administration site conditions: application site reactions including burning, rash, pruritus and blistering

Eye disorders: dry eyes, eye pruritus, angle closure glaucoma, amblyopia, eyelid irritation

Skin and subcutaneous tissue disorders: rash generalized, skin irritation, erythema

Renal and urinary disorders: dysuria

Ear and labyrinth disorders: vertigo

7.1 Drugs Causing Central Nervous System (CNS) Adverse Reactions

The concurrent use of scopolamine transdermal system with other drugs that cause CNS adverse reactions of drowsiness, dizziness or disorientation (e.g., sedatives, hypnotics, opiates, anxiolytics and alcohol) or have anticholinergic properties (e.g., other belladonna alkaloids, sedating antihistamines, meclizine, tricyclic antidepressants and muscle relaxants) may potentiate the effects of scopolamine transdermal system [see Warnings and Precautions (5.2)]. Either scopolamine transdermal system or the interacting drug should be chosen, depending on the importance of the drug to the patient. If the interacting drug cannot be avoided, monitor patients for CNS adverse reactions.

7.2 Anticholinergic Drugs

Concomitant use of scopolamine with other drugs having anticholinergic properties may increase the risk of CNS adverse reactions [see Drug Interactions (7.1)], intestinal obstruction and/or urinary retention. Consider more frequent monitoring during treatment with scopolamine transdermal system in patients receiving anticholinergic drugs [see Warnings and Precautions (5.2, 5.4)].

7.3 Oral Drugs Absorbed in the Stomach

Scopolamine transdermal system, as an anticholinergic, may delay gastric and upper gastrointestinal motility and, therefore, the rate of absorption of other orally administered drugs. Monitor patients for modified therapeutic effect of concomitant orally administered drugs with a narrow therapeutic index.

7.4 Interaction with Gastric Secretion Test

Scopolamine will interfere with the gastric secretion test. Discontinue scopolamine transdermal system 10 days prior to testing.

8.1 Pregnancy

Risk Summary

Eclamptic seizures have been reported in pregnant women with severe preeclampsia soon after injection of intravenous or intramuscular scopolamine. Avoid use of scopolamine transdermal system in patients with severe preeclampsia [see Warnings and Precautions (5.3) and Data]. Available data from observational studies and postmarketing reports with scopolamine use in pregnant women have not identified a drug associated risk of major birth defects, miscarriage or adverse fetal outcomes.

In animal studies, there was no evidence of adverse developmental effects with intravenous administration of scopolamine hydrobromide revealed in rats. Embryotoxicity was observed in rabbits at intravenous doses producing plasma levels approximately 100 times the levels achieved in humans using a transdermal system.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

In published case reports, two pregnant patients with severe preeclampsia were administered intravenous and intramuscular scopolamine, respectively and developed eclamptic seizures soon after scopolamine administration [see Warnings and Precautions (5.3)].

Animal Data

In animal reproduction studies, when pregnant rats and rabbits received scopolamine hydrobromide by daily intravenous injection, no adverse effects were observed in rats. An embryotoxic effect was observed in rabbits at doses producing plasma levels approximately 100 times the levels achieved in humans using a transdermal system. Scopolamine administered parenterally to rats and rabbits at doses higher than the dose delivered by scopolamine transdermal system did not affect uterine contractions or increase the duration of labor.

8.2 Lactation

Risk Summary

Scopolamine is present in human milk. There are no available data on the effects of scopolamine on the breastfed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for scopolamine transdermal system and any potential adverse effects on the breastfed child from scopolamine or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Pediatric patients are particularly susceptible to the adverse reactions of scopolamine; including mydriasis, hallucinations, amblyopia and drug withdrawal syndrome. Neurologic and psychiatric adverse reactions, such as hallucinations, amblyopia and mydriasis have also been reported.

8.5 Geriatric Use

Clinical trials of scopolamine transdermal system did not include sufficient number of subjects aged 65 years and older to determine if they respond differently from younger subjects. In other clinical experience, elderly patients had an increased risk of neurologic and psychiatric adverse reactions, such as hallucinations, confusion, dizziness and drug withdrawal syndrome [see Warnings and Precautions (5.2, 5.5)]. Consider more frequent monitoring for CNS adverse reactions during treatment with scopolamine transdermal system in elderly patients [see Warnings and Precautions (5.2)].

8.6 Renal or Hepatic Impairment

Scopolamine transdermal system has not been studied in patients with renal or hepatic impairment. Consider more frequent monitoring during treatment with scopolamine transdermal system in patients with renal or hepatic impairment because of the increased risk of CNS adverse reactions [see Warnings and Precautions (5.2)].

9.1 Controlled Substance

Scopolamine transdermal system contains scopolamine, which is not a controlled substance.

9.3 Dependence

Termination of scopolamine transdermal system, usually after several days of use, may result in withdrawal symptoms such as disturbances of equilibrium, dizziness, nausea, vomiting, abdominal cramps, sweating, headache, mental confusion, muscle weakness, bradycardia and hypotension. These withdrawal symptoms indicate that scopolamine, like other anticholinergic drugs, may produce physical dependence. The onset of these symptoms, generally 24 hours or more after the transdermal system has been removed, can be severe and may require medical intervention [see Warnings and Precautions (5.5)].

12.1 Mechanism of Action

Scopolamine, a belladonna alkaloid, is an anticholinergic. 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 system is formulated to deliver approximately 1 mg of scopolamine to the systemic circulation over 3 days.

Absorption

Following application to the skin behind the ear, circulating plasma concentrations are detected within 4 hours with peak concentrations 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). Following removal of the used transdermal system, there is some degree of continued systemic absorption of scopolamine bound in the skin layers.

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.

Elimination

Metabolism and Excretion

Scopolamine is metabolized and conjugated with less than 5% of the total dose appearing unchanged in the urine. The enzymes responsible for metabolizing scopolamine are unknown. The exact elimination pattern of scopolamine has not been determined. Following transdermal system removal, plasma concentrations 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.

Drug Interaction Studies

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 micromolar. No in vivo drug-drug interaction studies have been conducted.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been conducted to evaluate the carcinogenic potential of scopolamine. The mutagenic potential of scopolamine has not been evaluated.

Fertility studies were performed in female rats and revealed no evidence of impaired fertility or harm to the fetus due to scopolamine hydrobromide administered by daily subcutaneous injection. Maternal body weights were reduced in the highest-dose group (plasma level approximately 500 times the level achieved in humans using a transdermal system). However, fertility studies in male animals were not performed.

14.1 Prevention of Motion Sickness

In 195 adult subjects of different racial origins who participated in clinical efficacy studies at sea or in a controlled motion environment, there was a 75% reduction in the incidence of motion-induced nausea and vomiting. Scopolamine transdermal system was applied from 4 to 16 hours prior to the onset of motion in these studies.

14.2 Prevention of Post-Operative Nausea and Vomiting

A clinical efficacy study evaluated 168 adult female patients undergoing gynecological surgery with anesthesia and opiate analgesia.  Patients received scopolamine transdermal system or placebo applied approximately 11 hours before anesthesia/opiate analgesia. No retching/vomiting during the 24-hour post-operative period was reported in 79% of those treated with scopolamine transdermal system compared to 72% of those receiving placebo. When the need for additional antiemetic medication was assessed during the same period, there was no need for medication in 89% of patients treated with scopolamine transdermal system as compared to 72% of placebo-treated patients.