Scopolamine (Page 4 of 6)

12 CLINICAL PHARMACOLOGY

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 NONCLINICAL TOXICOLOGY

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 CLINICAL STUDIES

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 50090-5349

NDC: 50090-5349-0 1 d in a POUCH / 4 in a CARTON

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Administration Instructions: Counsel patients on how to apply and remove the transdermal system [see Dosage and Administration (2.1)]:

Only wear one transdermal system at any time.
Do not cut the transdermal system.
Apply the transdermal system to the skin in the postauricular (hairless area behind one ear) area.
After the transdermal system is applied on the dry skin behind the ear, wash hands thoroughly with soap and water and dry hands.
If the transdermal system becomes displaced, discard the transdermal system, and apply a new transdermal system on the hairless area behind the other ear.
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.

Patients with Open-Angle Glaucoma: Advise patients with open-angle glaucoma to remove the scopolamine transdermal system immediately and contact their healthcare provider if they experience symptoms of acute angle closure glaucoma, including pain and reddening of the eyes, accompanied by dilated pupils, blurred vision and/or seeing halos around lights [see Warnings and Precautions (5.1)].

Neuropsychiatric Adverse Reactions:

Advise patients that psychiatric adverse reactions may occur, especially in patients with a past psychiatric history or in those receiving other drugs also associated with psychiatric effects, and to report to their healthcare provider any new or worsening psychiatric symptoms.
Advise patients to discontinue scopolamine transdermal system and contact a healthcare provider immediately if they experience a seizure.
Advise patients, especially elderly patients, that cognitive impairment may occur during treatment with scopolamine transdermal system, especially in those receiving other drugs also associated with CNS effects, and to report to their healthcare provider if they develop signs or symptoms of cognitive impairment such as hallucinations, confusion or dizziness.
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 [see Warnings and Precautions (5.2)].

Decreased Gastrointestinal Motility and Urinary Retention: Instruct patients to remove the transdermal system if they develop symptoms of intestinal obstruction (abdominal pain, nausea or vomiting) or any difficulties in urinating [see Warnings and Precautions (5.4)].

Drug Withdrawal/Post-Removal Symptoms: Inform patients that if they remove the scopolamine transdermal system before treatment is complete, withdrawal symptoms may occur and to seek immediate medical care if they develop severe symptoms after removing scopolamine transdermal system [see Warnings and Precautions (5.5)].

Blurred Vision: Inform patients that temporary dilation of the pupils and blurred vision may occur if scopolamine transdermal system comes in contact with the eyes. Instruct patients to wash their hands thoroughly with soap and water immediately after handling the transdermal system [see Dosage and Administration (2.1), Warnings and Precautions (5.6)].

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