AHFS Class:

• Antimuscarinics/Antispasmodics 12:08.08

Generic Name(s):

• Scopolamine

• Scopolamine Hydrobromide

Scopolamine is a naturally occurring tertiary amine antimuscarinic.

Scopolamine is used principally for the prevention of nausea and vomiting induced by motion or recovery from anesthesia and surgery. The drug is also used as an adjunct to anesthesia. Scopolamine's usefulness in chronic forms of therapy (e.g., in the adjunctive treatment of peptic ulcer disease) is generally limited by its adverse effects, especially CNS effects.

Nausea and Vomiting

Motion Sickness

Of currently available drugs (e.g., chlorpromazine, dextroamphetamine, dimenhydrinate, ephedrine, meclizine, prochlorperazine, promethazine, trimethobenzamide), scopolamine is considered the single most effective drug in preventing nausea and vomiting induced by motion. Since oral or IM scopolamine has a short duration of effect and a high incidence of adverse effects, oral or IM therapy usually has been reserved for prophylactic treatment of patients exposed to short periods of intense motion or those who are highly susceptible to motion. Because of the adverse effects associated with oral scopolamine therapy, antihistamines (e.g., dimenhydrinate) or other drugs (e.g., combination therapy with promethazine and ephedrine) have generally been preferred for the prevention of motion sickness in patients with prolonged exposure to mild to moderate motion. Transdermal scopolamine is effective in the prevention of motion sickness. Although transdermal scopolamine is associated with fewer adverse effects and increased duration of therapeutic effect compared with oral scopolamine, transdermal scopolamine's place in the prophylactic treatment of exposure to mild to severe motion, including that associated with prolonged periods of motion exposure, has not been fully determined. IM administration of scopolamine may be effective in some patients who have already developed symptoms of motion sickness.

Although the manufacturer states that transdermally administered scopolamine is more effective than oral dimenhydrinate in the prevention of motion sickness, the comparative efficacy of these drugs has not been fully determined. In a report summarizing four, double-blind, controlled studies conducted in adults with a history of motion sickness who were exposed to various sea conditions, the pooled data indicated that transdermal administration of scopolamine (Transderm Scop^®) or oral administration of dimenhydrinate 4-16 or 1.5 hours before exposure to motion, respectively, was more effective than placebo in protecting against symptoms of motion sickness; however, transdermal scopolamine was not shown to be more effective than oral dimenhydrinate. In another placebo-controlled study in adults with a history of motion sickness who were exposed to motion in a controlled-motion simulator, transdermal administration of scopolamine or oral administration of dimenhydrinate 12-24 hours or 30-45 minutes before exposure to motion, respectively, was more effective than placebo in preventing symptoms of motion sickness; however, transdermal scopolamine was not shown to be more effective than oral dimenhydrinate. In another placebo-controlled study in healthy adults who were exposed to motion in a controlled-motion simulator, transdermal administration of scopolamine or oral administration of meclizine at least 12 or 2 hours before exposure to motion, respectively, showed that scopolamine was more effective than placebo or meclizine in preventing symptoms of motion sickness.100

Postoperative Nausea and Vomiting

The transdermal scopolamine system is used for the prevention of nausea and vomiting associated with recovery from anesthesia and surgery. Although results of some clinical studies have indicated that the transdermal scopolamine system was more effective than placebo in preventing postoperative nausea and vomiting, results of other clinical studies have not demonstrated such benefit.112,114,115,116,117,118 Reports on the efficacy of the transdermal scopolamine system in the prevention of postoperative nausea and vomiting are equivocal. In 2 clinical studies in women undergoing cesarean section or gynecologic surgery with epidural or general anesthesia and opiate-agonist analgesia, the transdermal scopolamine system was more effective than placebo in preventing nausea and vomiting.112,114

Combined results of these studies indicate that 66 or 46% of those receiving the transdermal scopolamine system or placebo, respectively, reported no retching or vomiting within the 24-hour period following administration of anesthesia and opiate analgesia. Additional antiemetic therapy was not required during that period in 76 or 59% of patients receiving the transdermal scopolamine system or placebo, respectively. However, in another study in women undergoing various types of surgery, the transdermal scopolamine system was no more effective than placebo in preventing postoperative nausea and vomiting.115 Some clinicians believe that the transdermal scopolamine system is somewhat effective in the prevention of postoperative nausea and vomiting, especially when the drug is applied several hours prior to surgery.117,118

Cancer Chemotherapy-induced Nausea and Vomiting

Transdermal scopolamine has shown minimal antiemetic activity against chemotherapy-induced vomiting†. In one study in patients receiving cisplatin alone or in combination with other antineoplastic agents, application of transdermal scopolamine 12 hours before IV administration of cisplatin and removal 48 hours later (72 hours total) was no more effective than placebo in preventing vomiting. In another study in patients receiving cisplatin, transdermal scopolamine did not augment the antiemetic effect of metoclopramide.

Surgery

Scopolamine hydrobromide injection has been used as a preoperative medication to inhibit salivation and excessive secretions of the respiratory tract; however, the current practice of using thiopental (no longer commercially available in the US), halothane, or similar general anesthetics that do not stimulate the production of salivary and tracheobronchial secretions has reduced the need to control excessive respiratory secretions during surgery. Scopolamine may be used to prevent cholinergic effects during surgery, such as cardiac arrhythmias, hypotension, and bradycardia, which may result from traction on viscera (with resultant vagal stimulation), stimulation of the carotid sinus, or administration of drugs (e.g., succinylcholine); however, scopolamine is less effective than atropine in preventing cholinergic cardiovascular effects. Although scopolamine hydrobromide injection has been administered concurrently with anticholinesterase agents (e.g., neostigmine) to block adverse muscarinic effects of these latter agents when they are used after surgery to terminate curarization, scopolamine may not be effective for this purpose and other antimuscarinics (e.g., atropine, glycopyrrolate) are preferred. Scopolamine has greater sedative, antisecretory (e.g., on respiratory tract secretions), and antiemetic effects than atropine and may be preferred as a preoperative medication in some patients when these effects are desirable.

Scopolamine hydrobromide also is used preoperatively and in obstetrics in conjunction with analgesics or sedatives to produce tranquilization and amnesia. Benzodiazepines appear to produce a more rapid onset of and possibly more marked amnesia than does scopolamine, and benzodiazepines may be preferred by some clinicians as preoperative amnestic agents. Scopolamine, alone or in combination with an opiate (e.g., morphine), is more effective than atropine, alone or in combination with an opiate (e.g., morphine), in producing amnesia and sedation and reducing anxiety in surgical patients. Since scopolamine may cause behavioral changes in patients with pain or anxiety, the drug should be administered concomitantly with an analgesic and/or sedative when it is used as a preoperative medication in these patients.

Transdermal scopolamine also has been used as a preoperative medication†. In one study, transdermal scopolamine applied 12 hours before and removed 48 hours after surgery was more effective than placebo as a sedative, antisialagogue, and antiemetic and was more effective than scopolamine administered IM 90 minutes before surgery as an antiemetic in the postoperative period.

Other Uses

Although transdermal scopolamine has been shown to decrease basal acid output and inhibit betazole-, pentagastrin-, and peptone-stimulated gastric acid secretion in healthy individuals, it has not been determined whether transdermal scopolamine is effective in the adjunctive treatment of peptic ulcer disease†.

Although preparations containing scopolamine hydrobromide and other salts were previously available for self-medication as nighttime sedatives, a dose of 0.25 mg was not considered effective for this use and higher, possibly more effective doses, were not considered safe for self-medication.

Scopolamine has been used in the symptomatic treatment of parkinsonian syndrome, including postencephalitic parkinsonian syndrome, and other spastic states and as an anticholinergic CNS depressant.119 The drug inhibits excessive motility and hypertonus of the GI tract in some conditions (e.g., irritable bowel syndrome, mild dysentery, diverticulitis, pylorospasm, cardiospasm).119 For additional information on the use of antimuscarinics (e.g., scopolamine) in these and other conditions, see Uses in the Antimuscarinics/Antispasmodics General Statement 12:08.08.

For ophthalmic uses of scopolamine hydrobromide, see 52:24.

Administration

Scopolamine hydrobromide is administered orally or by IM, direct IV, or subcutaneous injection. Scopolamine is administered percutaneously by topical application of a transdermal system (Transderm Scop^®).

For direct IV administration, scopolamine hydrobromide injection should be diluted with sterile water for injection prior to administration. When given as a preoperative medication, scopolamine hydrobromide injection is given 30-60 minutes prior to the anticipated time of induction of anesthesia or at the time other preanesthetic medications (e.g., opiates, sedatives) are administered. When scopolamine hydrobromide is administered orally or IM for the prevention of motion sickness, the drug should generally be administered 1 hour (range: 0.5-1.5 hours) before anticipated exposure to motion.

When scopolamine is administered percutaneously as the transdermal system for the prevention of motion sickness, the system should be applied topically at least 4 hours (e.g., 4-24 hours) before anticipated exposure to motion.

For prevention of postoperative nausea and vomiting, transdermal scopolamine should be applied the evening before scheduled surgery. If transdermal scopolamine is used prophylactically in patients undergoing cesarean section, the drug should be applied one hour prior to surgery to minimize exposure of the fetus to the drug. Patients should be carefully instructed in the use of transdermal scopolamine. To obtain optimum results, patients also should be given a copy of the patient instructions provided by the manufacturer. The scopolamine transdermal system should not be cut, and only one transdermal system should be worn at any time.

Prior to administration of the transdermal system, the area behind the ear should be wiped with a clean, dry tissue to ensure that the area is dry. To expose the adhesive surface of the system, the clear plastic protective strip should be peeled and discarded prior to administration; finger contact with the exposed adhesive layer should be avoided to prevent contamination of the fingers with scopolamine. The transdermal system is applied topically to a dry, hairless area of skin behind the ear (postauricular) by firmly pressing the system with the adhesive side touching the skin. Patients should be warned to thoroughly wash their hands after handling (e.g., initial application, removal) the scopolamine transdermal system, since contamination of fingers and subsequent contact with the eyes may result in cycloplegia (i.e., mydriasis and blurred vision). Individuals who assist the patient in the application or removal of the transdermal system also should thoroughly wash their hands with soap and water afterwards.101 If the system becomes dislodged during the intended period of use (up to 72 hours), it should be removed and replaced with another system at a different postauricular site. The system is generally not affected by limited exposure to water (e.g., during bathing or swimming). Following removal of the transdermal system, the application site should be thoroughly washed with soap and water to remove any traces of scopolamine that might remain on the skin.

Dosage

Scopolamine Hydrobromide Parenteral Dosage

The usual adult IM, IV, or subcutaneous dose of scopolamine hydrobromide is 0.3-0.65 mg; if necessary, these doses may be repeated 3 or 4 times daily. The usual pediatric IM, IV, or subcutaneous dose of scopolamine hydrobromide is 0.006 mg/kg (6 mcg/kg) or 0.2 mg/m². Alternatively, adult parenteral doses of scopolamine hydrobromide of 0.2-1 mg have been suggested for antiemetic effect, 0.2-0.6 mg for inhibition of salivation, 0.32-0.65 mg for amnestic effect, or 0.6 mg for sedation or tranquilization.

Scopolamine Transdermal Dosage

For the prevention of motion sickness, the usual adult dose of scopolamine transdermal system is one system programmed to deliver approximately 1 mg of scopolamine over 72 hours. The system is applied at least 4 hours prior to anticipated exposure to motion and may be used for up to 72 hours if necessary; the transdermal system may be removed during the 72-hour period when an antiemetic effect is no longer required. When continued therapy is necessary beyond 72 hours, the initial system should be removed and another system placed behind the ear at a different site.

For prevention of postoperative nausea and vomiting, the transdermal scopolamine system should be applied the evening before scheduled surgery. If the transdermal scopolamine system is used prophylactically in patients undergoing cesarean section, the system should be applied one hour prior to surgery to minimize exposure of the infant to the drug. The transdermal system should remain in place for 24 hours following surgery, then removed and discarded.

Scopolamine Hydrobromide Oral Dosage

The usual oral dose range of scopolamine hydrobromide soluble tablets is 0.4-0.8 mg.119 For the prevention of motion sickness, 0.25-0.8 mg of the drug may be administered 1 hour before exposure to motion; subsequent doses of 0.25-0.8 mg may be given 3 times daily as needed and as tolerated.120

Scopolamine shares the toxic potentials of antimuscarinics, and the usual cautions, precautions, and contraindications of antimuscarinic therapy should be observed. For a complete discussion of the adverse effects, precautions, and contraindications associated with scopolamine, see the Antimuscarinics/Antispasmodics General Statement 12:08.08.

Adverse Effects

Although transdermal scopolamine has been associated with fewer adverse effects than orally administered scopolamine hydrobromide, adverse systemic effects have occurred following application to the skin of the transdermal system. The most frequent adverse effect of transdermally administered scopolamine is dry mouth, occurring in about 67 or 29% of patients receiving the drug for prevention of motion sickness or postoperative nausea and vomiting, respectively. Drowsiness was reported in about 17% of patients in clinical studies using the transdermal system for prevention of motion sickness. Dizziness was reported by about 12% of patients in clinical studies receiving the scopolamine transdermal system perioperatively for prevention of nausea and vomiting.

Ocular Effects

Transient impairment of ocular accommodation, including blurred vision and mydriasis, has also occurred following transdermal application of scopolamine. Scopolamine-induced cycloplegia manifested as fixed, dilated pupils has occurred following transdermal application of the drug; cycloplegia may be bilateral or unilateral and has persisted for 48 hours or longer in some patients. It has been suggested that unilateral cycloplegia probably results from touching the eye or contact lens with scopolamine-contaminated fingers after handling the transdermal system. Since neurogenic mydriasis (e.g., caused by head injury, tumor) responds (pupillary constriction) to local instillation of a parasympathomimetic, failure of the pupillary sphincter to constrict within 30 minutes after instillation of several drops of a 0.5 or 1% ophthalmic solution of pilocarpine, in the absence of local ocular injury (traumatic iridoplegia) or increased intraocular pressure (angle-closure glaucoma), usually indicates chemically induced (e.g., scopolamine) blockade of the sphincter. Transdermal application of scopolamine also has precipitated angle-closure glaucoma in several patients; at least one patient has required surgery. Ocular dryness or pruritus or conjunctival injection of eyes has occasionally occurred following transdermal administration of the drug.

CNS Effects

Less frequently, adverse CNS effects, including disorientation, memory disturbances, dizziness, restlessness, giddiness, hallucinations, delirium, and confusion, have occurred following transdermal administration of scopolamine. Signs and symptoms of acute toxic psychosis, including confusion, agitation, rambling and pressured speech, visual hallucinations, paranoid behavior, and delusions, have occurred in a few patients receiving transdermal scopolamine; psychotic signs and symptoms resolved within 3 hours after IM administration of physostigmine in one patient and within 24-36 hours after removal of the transdermal system in several others.

Drug withdrawal symptoms, including nausea, vomiting, headache, dizziness, and disturbances of equilibrium, have been reported in some patients following discontinuance of the transdermal system. Such symptoms usually do not appear until 24 hours or more after the transdermal system has been removed. Some of these symptoms may be related to adaptation to a motion-free environment from an environment in motion. More serious symptoms, including muscle weakness, bradycardia, and hypotension, also may occur following discontinuance of the transdermal system. It is necessary to distinguish the signs and symptoms of withdrawal following discontinuance of the transdermal scopolamine system from scopolamine overdosage. (See Acute Toxicity: Manifestations in the Antimuscarinics General Statement 12:08.08.) Although mental confusion and dizziness may be observed with both acute toxicity and withdrawal, patients with withdrawal symptoms typically exhibit signs and symptoms of bradycardia, headache, nausea, abdominal cramps, and sweating, while tachyarrhythmias, dry skin, and decreased bowel sounds are suggestive of anticholinergic toxicity.

Dermatologic and Sensitivity Reactions

Delayed allergic contact dermatitis, manifested as pruritus and erythema at the site of application, has occurred with transdermal administration of scopolamine.103 The reaction developed 1.5-15 months after initiation of long-term transdermal therapy, subsided within 2 weeks after removal of the transdermal system, and was attributed to scopolamine rather than to components of the transdermal system.103 Rash and erythema also have occurred occasionally following transdermal administration of the drug.

Other Effects

Difficulty in urinating and transient changes in heart rate have occurred occasionally following transdermal administration of scopolamine. However, a causal relationship to transdermal scopolamine has not been established.

Precautions and Contraindications

Some patients may exhibit excessive susceptibility to the effects of scopolamine and toxic symptoms may occur with therapeutic doses. Marked CNS disturbances, ranging from complete disorientation to an active delirium resembling that encountered in atropine overdosage, may occur in these patients. Some patients may exhibit marked somnolence. Other manifestations may include dilated pupils, accelerated pulse rate, and dryness of the mouth with a husky quality of the voice apparently caused by laryngeal paralysis. This idiosyncratic reaction can usually be reversed by administering physostigmine. Transdermal scopolamine should be used with caution in patients with a history of seizures or psychosis, since the drug potentially can aggravate these conditions. Several cases of scopolamine overdosage associated with use of illicit drugs (e.g., heroin) that apparently were mixed (“cut”) with scopolamine have been reported to date.106 (See Acute Toxicity: Treatment in the Antimuscarinics/Antispasmodics General Statement 12:08.08.)

When scopolamine is administered as a preoperative medication to patients with pain or severe anxiety, an analgesic and/or sedative should be administered concomitantly to avoid scopolamine-induced behavioral changes. Scopolamine should be used with extreme caution in geriatric patients since scopolamine-induced mental confusion and other adverse CNS effects occur more commonly in this age group. One manufacturer states that scopolamine should be used with extreme caution in patients with hepatic or renal dysfunction, since adverse CNS effects occur more commonly in these patients. In addition, scopolamine hydrobromide soluble tablets should be used with caution in patients with cardiac disease.119

Patients should be warned that scopolamine may impair their ability to perform activities requiring mental alertness, physical coordination, or visual acuity (e.g., operating machinery, driving a motor vehicle). In addition, patients who intend to participate in underwater sports should be warned that scopolamine may produce disorientation. Patients also should be warned to thoroughly wash their hands with soap and water after handling (e.g., initial application, removal) the scopolamine transdermal system and to wash the application site thoroughly after removing the system, since contamination of the fingers and subsequent contact with the eyes may result in cycloplegia (i.e., mydriasis and blurred vision). Individuals who assist the patient in the application or removal of the transdermal system should also thoroughly wash their hands with soap and water afterwards.101 In addition, patients receiving transdermal scopolamine therapy should be advised regarding proper disposal of this preparation and cautioned to keep the transdermal system out of the reach of children or pets. Patients receiving transdermal scopolamine should be advised to remove the transdermal system and contact their clinician if symptoms of angle-closure (obstructive, narrow-angle) glaucoma (e.g., pain and reddening of eyes accompanied by dilated pupils) occur. Patients also should be advised to remove the transdermal system if they experience difficulty in urinating.

Scopolamine generally is contraindicated in patients with glaucoma (i.e., angle-closure), pyloric obstruction, or urinary bladder neck obstruction. Scopolamine generally also is contraindicated in patients with tachycardia secondary to cardiac insufficiency or thyrotoxicosis and in those with paralytic ileus. The manufacturer states that scopolamine hydrobromide soluble tablets are contraindicated in patients with prostatic hypertrophy or impaired renal or hepatic function.119 Scopolamine is contraindicated in patients who are hypersensitive to the drug, to any other belladonna alkaloid, or to any ingredient or component in the formulation or administration system.

Pediatric Precautions

Safety and efficacy of scopolamine hydrobromide soluble tablets or the scopolamine transdermal system in children have not been established. The manufacturer states that scopolamine transdermal system should not be used in children since it is not known whether the system might release an amount of drug that could cause serious adverse effects in the child. In addition, the manufacturer warns that children are particularly susceptible to adverse effects of scopolamine. For further discussion of the pediatric precautions associated with antimuscarinics, see Cautions: Pediatric Precautions, in the Antimuscarinics/Antispasmodics General Statement 12:08.08.

Mutagenicity and Carcinogenicity

Studies have not been performed to date to evaluate the mutagenic potential of scopolamine. Studies to evaluate the carcinogenic potential of scopolamine in animals are ongoing.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and rabbits using IV scopolamine hydrobromide at dosages producing plasma concentrations of the drug 100 times greater than those achievable after application of the transdermal system in humans have shown a marginal embryotoxic effect in rabbits; no teratogenic effects were observed in rats. Scopolamine does not increase the duration of labor or affect uterine contractions during labor following parenteral administration; however, the drug crosses the placenta. Although one manufacturer states that adverse fetal effects have not been reported to date when scopolamine was used during labor and delivery, fetal toxicity, including tachycardia, fever, and lethargy, which responded to treatment with physostigmine, were reported in one infant following maternal administration of a total dosage of 1.8 mg of scopolamine during labor and delivery.110,111 Decreased heart rate variability and decreased heart rate deceleration also have been reported in infants of mothers who received scopolamine during labor and delivery.110,111 However, in one clinical study in women undergoing cesarean sections, adverse effects, including CNS depression, were not observed in neonates when transdermal scopolamine was used concomitantly with epidural anesthesia and opiate analgesics.112 There are no adequate and controlled studies to date using scopolamine in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Fertility

Although it is not known whether scopolamine affects fertility in humans, antimuscarinics may cause impotence in males. Reproduction studies in female rats using scopolamine hydrobromide have not revealed evidence of impaired fertility.

Lactation

Scopolamine is distributed into milk.110,113 Although some manufacturers recommend that scopolamine be used with caution in nursing women, no observable change in infants associated with such exposure has been reported to date, and the American Academy of Pediatrics (AAP) considers scopolamine to be usually compatible with breast-feeding.110,113

Acute Toxicity

The manufacturer of transdermal scopolamine states that if symptoms of overdosage occur, an adequate airway should be established and cardiac and respiratory support should be instituted, followed by rapid removal of all transdermal systems from the skin and/or mouth. If there is evidence of ingestion of the transdermal system, gastric lavage, endoscopic removal of swallowed patches, or administration of activated charcoal should be considered depending on the clinical situation. In addition, appropriate symptomatic treatment should be initiated. For a more complete discussion of the management of overdosage with antimuscarinics (e.g., scopolamine), see Acute Toxicity: Treatment, in the Antimuscarinics/Antispasmodics General Statement 12:08.08.

Pharmacology

Scopolamine generally exhibits the pharmacologic actions associated with other antimuscarinics. In general, scopolamine is more potent than atropine in its antimuscarinic action on the iris, ciliary body, and certain secretory (salivary, bronchial, sweat) glands, and less potent than atropine in its antimuscarinic action on the heart and on bronchial and intestinal smooth muscle. Although scopolamine is extensively metabolized, its pharmacologic activity results principally from the parent drug.

Unlike atropine and most other antimuscarinics, scopolamine, at usual dosages, produces CNS depression manifested as drowsiness, euphoria, amnesia, fatigue, and dreamless sleep (with a reduction in rapid eye movement [REM] sleep). However, excitement, restlessness, hallucinations, or delirium may paradoxically occur, especially when scopolamine is used in the presence of severe pain. High doses of scopolamine produce CNS effects (e.g., restlessness, disorientation, irritability, hallucinations) similar to those produced by toxic doses of other antimuscarinics.

Although other antimuscarinics have been used in the prevention of motion sickness, it appears that scopolamine is most effective. Scopolamine apparently corrects some central imbalance of acetylcholine and norepinephrine that may occur in patients with motion sickness. It has been suggested that antimuscarinics may block the transmission of cholinergic impulses from the vestibular nuclei to higher centers in the CNS and from the reticular formation to the vomiting center; these effects result in prevention of motion-induced nausea and vomiting.

For a complete discussion of the pharmacologic effects of scopolamine, see Pharmacology in the general statement on Antimuscarinics/Antispasmodics 12:08.08.

Pharmacokinetics

Absorption

Scopolamine hydrobromide is rapidly absorbed following IM or subcutaneous injection. The drug is well absorbed from the GI tract, principally from the upper small intestine. Scopolamine also is well absorbed percutaneously. Following topical application behind the ear of a transdermal system (Transderm Scop^®), scopolamine is detected in plasma within 4 hours, with peak concentrations occurring within an average of 24 hours. In one study in healthy individuals, mean free and total (free plus conjugated) plasma scopolamine concentrations of 87 and 354 pg/mL, respectively, have been reported within 24 hours following topical application of a single transdermal scopolamine system that delivered approximately 1 mg/72 hours.

Following oral administration of a 0.906-mg dose of scopolamine in one individual, a peak concentration of about 2 ng/mL was reached within 1 hour. Although the commercially available transdermal system contains 1.5 mg of scopolamine, the membrane-controlled diffusion system is designed to deliver approximately 1 mg of the drug to systemic circulation at an approximately constant rate over a 72-hour period. An initial priming dose of 0.14 mg of scopolamine is released from the adhesive layer of the system at a controlled, asymptotically declining rate over 6 hours; then, the remainder of the dose is released at an approximate rate of 5 mcg/hour for the remaining 66-hour functional lifetime of the system. The manufacturer states that the initial priming dose saturates binding sites on the skin and rapidly brings the plasma concentration to steady-state. In a crossover study comparing urinary excretion rates of scopolamine during multiple 12-hour collection intervals in healthy individuals, there was no difference between the rates of excretion of drug during steady-state (24-72 hours) for constant-rate IV infusion (3.7-6 mcg/hour) and transdermal administration. The transdermal system appeared to deliver the drug to systemic circulation at the same rate as the constant-rate IV infusion; however, relatively long collection intervals (12 hours) make it difficult to interpret the data precisely. During the 12- to 24-hour period of administration and after 72 hours, the rate of excretion of scopolamine was higher with the transdermal system than with the constant-rate IV infusion.

Scopolamine-induced inhibition of salivation occurs within 30 minutes or within 30 minutes to 1 hour and peaks within 1 or 1-2 hours after IM or oral administration, respectively; inhibition of salivation persists for up to 4-6 hours. Following IV administration of a 0.6-mg dose in one study, amnesia occurred within 10 minutes, peaked between 50-80 minutes, and persisted for at least 120 minutes after administration. Following IM administration of a 0.2-mg dose of scopolamine in one study, antiemetic effect occurred within 15-30 minutes and persisted for about 4 hours. Following IM administration of a 0.1- or 0.2-mg dose in another study, mydriasis persisted for up to 8 hours. The transdermal system is designed to provide an antiemetic effect with an onset of about 4 hours and with a duration of up to 72 hours after application.

Distribution

The distribution of scopolamine has not been fully characterized. The drug appears to be reversibly bound to plasma proteins. Scopolamine apparently crosses the blood-brain barrier since the drug causes CNS effects. The drug also reportedly crosses the placenta and is distributed into milk.

Elimination

Following application of a single transdermal scopolamine system that delivered approximately 1 mg/72 hours, the average elimination half-life of the drug was 9.5 hours. Although the metabolic and excretory fate of scopolamine has not been fully determined, the drug is thought to be almost completely metabolized (principally by conjugation) in the liver and excreted in urine. Following oral administration of a single dose of scopolamine in one study, only small amounts of the dose (about 4-5%) were excreted unchanged in urine within 50 hours; urinary clearance of unchanged drug was about 120 mL/minute. In another study, 3.4% or less than 1% of a single dose was excreted unchanged in urine within 72 hours following subcutaneous injection or oral administration of the drug, respectively. Following application of a single transdermal scopolamine system that delivered approximately 1 mg/72 hours in healthy individuals, the urinary excretion rate of free and total (free plus conjugated) scopolamine was about 0.7 and 3.8 mcg/hour, respectively. Following removal of the transdermal system of scopolamine, depletion of scopolamine bound to skin receptors at the site of the application of the transdermal system results in a log-linear decrease in plasma scopolamine concentrations. Less than 10% of the total dose is excreted in urine as unchanged drug and its metabolites over 108 hours.

Chemistry and Stability

Chemistry

Scopolamine is a naturally occurring tertiary amine antimuscarinic. Scopolamine is one of the principal antimuscarinic components of the belladonna alkaloids. The drug may be prepared synthetically but is usually obtained by extraction from various members of the Solanaceae genus of plants including Datura metel (datura herb), D. stramonium (Jimson weed), Duboisia myoporoides, Hyoscyamus niger (henbane), and Scopolia carniolica.

Scopolamine is an aminoalcohol ester formed by combining scopine and tropic acid. Scopolamine differs structurally from atropine by the addition of an oxygen bridge between C16 and C17 on the atropine molecule resulting in conversion of tropine to scopine. Scopolamine occurs as a viscous liquid that is slightly soluble in water and very soluble in alcohol, chloroform, or ether. Scopolamine is unstable as a free base; for the commercially available transdermal preparation (Transderm Scop^®), scopolamine is prepared via chloroform extraction from a buffered solution of scopolamine hydrobromide. The drug has a pK_a of 7.55 (23°C)-7.81 (25°C).

The commercially available transdermal system of scopolamine (Transderm Scop^®) consists of an outer layer of aluminized polyester; a drug reservoir of scopolamine, light mineral oil, and polyisobutylene; a microporous polypropylene membrane that controls the rate of diffusion of the drug; and a final adhesive layer that provides a rapid initial release of drug (priming dose) and contains those ingredients found in the reservoir. The adhesive layer is covered by a protective strip which is removed prior to application. Light mineral oil and polyisobutylene are inactive ingredients and are not released from the system.

Scopolamine hydrobromide is the trihydrate hydrobromide salt of scopolamine. Scopolamine and scopolamine hydrobromide occur as the l -isomer ( l -hyoscine); atroscine ( dl -hyoscine) is the racemic mixture. Scopolamine hydrobromide occurs as colorless or white, odorless crystals or as a white, granular powder which is slightly efflorescent in dry air. Scopolamine hydrobromide has solubilities of approximately 0.67 g/mL in water and 0.05 g/mL in alcohol at 25°C. Scopolamine hydrobromide injection is a sterile solution of the drug in water for injection; the injection has a pH of 3.5-6.5. The commercially available injections in multiple-dose containers may contain methylparaben as a preservative.

Stability

Scopolamine is readily racemized in the presence of dilute alkali. Scopolamine hydrobromide solutions are incompatible with alkalies.

When admixed in the same syringe, scopolamine hydrobromide injection is reported to be physically compatible for at least 15 minutes with the following injections: atropine sulfate, butorphanol tartrate, chlorpromazine hydrochloride, dimenhydrinate, diphenhydramine hydrochloride, droperidol, fentanyl citrate, glycopyrrolate, hydromorphone hydrochloride, hydroxyzine hydrochloride, meperidine hydrochloride, metoclopramide, morphine sulfate, concentrated opium alkaloids hydrochlorides, pentazocine lactate, pentobarbital sodium, perphenazine, prochlorperazine edisylate, promazine hydrochloride, promethazine hydrochloride, or thiopental sodium (no longer commercially available in the US). Since the compatibility of these and other admixtures with scopolamine hydrobromide injection depends on several factors (e.g., concentration of the drugs, resulting pH, temperature), specialized references should be consulted for specific compatibility information. A haze may form within 1 hour when scopolamine hydrobromide injection is mixed with methohexital sodium solutions.

The commercially available transdermal system of scopolamine (Transderm Scop^®) should be stored at controlled room temperature between 20-25°C. Scopolamine hydrobromide should be stored in tight, light-resistant containers. Scopolamine hydrobromide injections should be stored in light-resistant, single-dose or multiple-dose containers, preferably of USP Type I glass, at 15-30°C; freezing of the injections should be avoided. Commercially available scopolamine hydrobromide soluble tablets should be stored at controlled room temperature (15-30°C).119

Additional Information

For further information on the chemistry, pharmacology, pharmacokinetics, uses, cautions, acute toxicity, drug interactions, and dosage and administration of scopolamine and scopolamine hydrobromide, see the Antimuscarinics/Antispasmodics General Statement 12:08.08. The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

100. Dahl E, Offer-Ohlsen D, Lillevold PE et al. Transdermal scopolamine, oral meclizine, and placebo in motion sickness. Clin Pharmacol Ther . 1984; 36:116-20. [PubMed 6734040]

101. Bienia RA, Smith M, Pellegrino T. Scopolamine skin-disks and anisocoria. Ann Intern Med . 1983; 99:572-3. [PubMed 6625403]

102. Rozzini R, Inzoli M, Trabucchi M. Delirium from transdermal scopolamine in an elderly woman. JAMA . 1988; 260:478. [PubMed 3385907]

103. Gordon CR, Shupak A, Doweck I et al. Allergic contact dermatitis caused by transdermal hyoscine. BMJ . 1989; 298:1220-1. [PubMed 2526675]

104. Sennhauser FH, Schwarz HP. Toxic psychosis from transdermal scopolamine in a child. Lancet . 1986; 2:1033. [PubMed 2877187]

105. Ciba, Woodbridge, NJ: Personal communication.

106. Centers for Disease Control and Prevention. Scopolamine poisoning among heroin users—New York City, Newark, Philadelphia, and Baltimore, 1995 and 1996. MMWR Morb Mortal Wkly Rep . 1996; 45:457-60. [PubMed 8622615]

107. Anon. Novartis Transderm Scop^® re-launch will begin with direct mail campaign to health-care professionals in September. FDC Rep . 1997(Sep 1):T&G4.

108. Novartis, Summit, NJ: Personal communication.

109. Novartis Consumer Health, Inc. Dear healthcare professional letter regarding availability of transdermal scopolamine (Transderm Scop^®). Woodbridge, NJ: Ciba; 1997 Oct.

110. Briggs GG, Freeman RK, Sumner JY. Scopolamine. In: Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 7th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2005:1448-9.

111. Evens RP, Leopold JC. Scopolamine toxicity in a newborn. Pediatrics . 1980; 66:329-30. [PubMed 7402826]

112. Kotelko DM, Rottman RL, Wright WC et al. Transdermal scopolamine decreases nausea and vomiting following cesarean section in patients receiving epidural morphine. (IDIS 260122)

113. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics . 2001; 108:776-89. [PubMed 11533352]

114. Bailey PL, Streisand JB, Pace NL et al. Transdermal scopolamine reduces nausea and vomiting after outpatient laparoscopy. Anesthesiology . 1990; 72:977-80. [PubMed 2140929]

115. Koski EMJ, Mattila MAK, Knapik D et al. Double blind comparison of transdermal hyoscine and placebo for the prevention of postoperative nausea. Br J Anesth . 1990; 64:16-20.

116. Haynes GR, Bailey MK. Postoperative nausea and vomiting: review and clinical approaches. South Med J . 1996; 89:940-9. [PubMed 8865784]

117. Sung YF. Risks and benefits of drugs used in the management of postoperative nausea and vomiting. Drug Saf . 1996; 14:181-97. [PubMed 8934580]

118. Rowbotham DJ. Current management of postoperative nausea and vomiting. Br J Anesth . 1992; 69:46S-59S.

119. Hope Pharmaceuticals. Scopace (scopolamine hydrobromide) USP soluble tablets prescribing information. Scottsdale, AZ; 1998 Oct.

120. Remington: the science and practice of pharmacy. 19th ed. Gennaro AR, Chairman, Chase GD, Der Marderosian A et al, eds. Easton, PA: Mack Publishing Company; 1995:1024-5.