Absorption, Distribution and Excretion
A 50 mg oral film coated tablet reaches a Cmax of 72.6 ng/mL with a Tmax of 2.7 hours. A 100 mg suppository reaches a Cmax of 112.2 ng/mL with a Tmax of 5.3 hours.
Dimenhydrinate is predominantly eliminated in the urine. 1-3% of the dissociated diphenhydramine is eliminated in the urine unchanged, while 64% of diphenhydramine is eliminated in the urine as metabolites. The elimination of dimenhydrinate has not been fully studied.
The volume of distribution of dimenhydrinate is 3-4 L/kg.
DIMENHYDRINATE (ETHANOLAMINES): DURATION OF ACTION (HR) 4-6. /FROM TABLE/
H1 ANTAGONISTS ARE READILY ABSORBED FROM GI TRACT & PARENTERAL SITES OF ADMIN. FOLLOWING ORAL ADMIN, EFFECTS START WITHIN 15 TO 30 MIN, ARE FULLY DEVELOPED WITHIN 1 HR, & LAST ABOUT 3 TO 6 HR, ALTHOUGH SOME...ACT LONGER. /ANTIHISTAMINES/

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Metabolism / Metabolites
Dimenhydrinate is a theoclate salt that separates into [diphenhydramine] and [8-chlorotheophylline]. diphenhydramine can either be N-glucuronidated by UGTs to diphenhydramine N-glucuronide or N-demethylated by CYP2D6, CYP1A2, CYP2C9, and CYP2C19 to N-desmethyldiphenhydramine. N-desmethyldiphenhydramine can be N-demethylated again by the same enzymes to N,N-didesmethyldiphenhydramine, which undergoes oxidative deamination to form diphenylmethoxyacetic acid.
EXTENSIVE STUDIES OF METABOLIC FATE OF ANTIHISTAMINES HAVE BEEN LIMITED TO A FEW COMPD. ... MAIN SITE OF METABOLIC TRANSFORMATION IS LIVER. /ANTIHISTAMINES/

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Biological Half-Life
The plasma elimination half life of dimenhydrinate is 5-8 hours.

Hepatotoxicity
Despite widespread use, dimenhydrinate has not been linked to liver test abnormalities or to clinically apparent liver injury. The reason for its safety may relate to its limited duration of use.
Likelihood score: E (unlikely to be a cause of clinically apparent liver injury).
References on the safety and potential hepatotoxicity of antihistamines are given together after the Overview section on Antihistamines.
Drug Class: Antihistamines

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Small, occasional doses of dimenhydrinate would not be expected to cause any adverse effects in breastfed infants. Larger doses or more prolonged use may cause effects in the infant or decrease the milk supply, particularly in combination with a sympathomimetic such as pseudoephedrine or before lactation is well established. Single bedtime doses after the last feeding of the day may be adequate for many women and will minimize any effects of the drug.
◉ Effects in Breastfed Infants
Relevant published information on dimenhydrinate was not found as of the revision date. In one telephone follow-up study, mothers reported irritability and colicky symptoms 10% of infants exposed to various antihistamines and drowsiness was reported in 1.6% of infants. None of the reactions required medical attention. In this study, irritability was reported in one infant of seven exposed to dimenhydrinate in breastmilk.
◉ Effects on Lactation and Breastmilk
Antihistamines in relatively high doses given by injection can decrease basal serum prolactin in nonlactating women and in early postpartum women. However, suckling-induced prolactin secretion is not affected by antihistamine pretreatment of postpartum mothers. Whether lower oral doses of antihistamines have the same effect on serum prolactin or whether the effects on prolactin have any consequences on breastfeeding success have not been studied. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
One woman became dependent on dimenhydrinate during her first pregnancy and continued to take it in a dose of 150 mg daily while she breastfed her infant for 3 months. The infant did well except for a febrile seizure at 2 years of age, which was probably unrelated to dimenhydrinate. During her second pregnancy, she took dimenhydrinate 300 mg daily during the pregnancy and while breastfeeding her infant for 2 years.

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Protein Binding
Dimenhydrinate is 70-85% protein bound in plasma.

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Interactions
CHLORPHENIRAMINE COULD THEORETICALLY PREVENT BETA-ADRENERGIC BLOCKING EFFECT OF PROPRANOLOL & ENHANCE ITS QUINIDINE-LIKE EFFECT. .../ANTIHISTAMINES/ ARE SIMILAR TO CHLORPHENIRAMINE IN THEIR ACTIONS. OTHER ANTIHISTAMINES INCL...DIMENHYDRINATE...
PATIENTS RECEIVING ANTIHISTAMINES SHOULD BE WARNED AGAINST THE CONCOMITANT USE OF ALCOHOLIC BEVERAGES OR OTHER DRUGS THAT DEPRESS CNS... /ANTIHISTAMINES/

[1]. Assessment of the rewarding effects of dimenhydrinate using the conditioned place preference paradigm in mice. Neurosci Lett. 2010 Feb 26;471(1):38-42.

Dimenhydrinate is a crystalline white powder. (NTP, 1992)
8-chloro-1,3-dimethyl-7H-purine-2,6-dione 2-(diphenylmethyl)oxy-N,N-dimethylethanamine is a diarylmethane.
Dimehydrinate was first described in the literature in 1949, and patented in 1950. Early research into dimenhydrinate focused on its role as an antihistamine for urticaria; the treatment of motion sickness was an accidental discovery. Dimenhydrinate, also known as B-dimethylaminoethyl benzohydrol ether 8-chlorotheophyllinate, is indicated to prevent nausea, vomiting, and dizziness caused by motion sickness. Dimenhydrinate is a combination of [Diphenhydramine] and [8-chlorotheophylline] in a salt form, with 53%-55.5% dried diphenhydramine, and 44%-47% died 8-chlorotheophylline. The antiemetic properties of dimenhydrinate are primarily thought to be produced by diphenhydramine's antagonism of H1 histamine receptors in the vestibular system while the excitatory effects are thought to be produced by 8-chlorotheophylline's adenosine receptor blockade. When used in large doses, dimenhydrinate has been shown to cause a "high" characterized by hallucinations, excitement, incoordination, and disorientation. Dimenhydrinate was granted FDA approval on 31 May 1972.
Dimenhydrinate is a first generation antihistamine that is used for treatment or prevention of motion sickness or symptoms of nausea and dizziness. Dimenhydrinate has not been linked to instances of clinically apparent acute liver injury.
Dimenhydrinate is an ethanolamine and first-generation histamine antagonist with anti-allergic activity. Dimenhydrinate competitively blocks H1 receptors, thereby preventing the actions of histamine on bronchial smooth muscle, capillaries and gastrointestinal (GI) smooth muscle. This prevents histamine-induced bronchoconstriction, vasodilation, increased capillary permeability, GI smooth muscle spasm.
A drug combination that contains diphenhydramine and theophylline. It is used for treating VERTIGO, MOTION SICKNESS, and NAUSEA associated with PREGNANCY.
See also: Diphenhydramine (has active moiety); 8-Chlorotheophylline (has active moiety).

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Drug Indication
Dimenhydrinate is indicated for the prevention and treatment of nausea, vomiting, or vertigo of motion sickness.

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Mechanism of Action
Dimenhydrinate is a theoclate salt that separates into [diphenhydramine] and [8-chlorotheophylline]. While the exact mechanism of action is unknown, diphenhydramine is theorized to reduce disturbances to equilibrium through antimuscarinic effects or histamine H1 antagonism. 8-chlorotheophylline may produce excitation through blocking adenosine receptors, reducing the drowsiness produced by diphenhydramine.
IT IS ESSENTIAL TO NOTE THAT NEITHER H1...BLOCKERS INHIBIT HISTAMINE RELEASE. ...EFFECTS OF HISTAMINE ANTAGONISTS...FACILITATE RELEASE. BENEFICIAL EFFECTS OF HISTAMINE ANTAGONISTS ARE THUS CONFINED TO ANTAGONISM OF RESPONSES TO HISTAMINE THAT IS RELEASED. /ANTIHISTAMINES/
DRUGS USED TO BLOCK HISTAMINE RECEPTORS FALL INTO THAT LARGE GROUP OF PHARMACOLOGICAL ANTAGONISTS THAT APPEAR TO ACT BY OCCUPYING "RECEPTIVE SITES" ON EFFECTOR CELL, TO EXCLUSION OF AGONIST MOLECULES, WITHOUT THEMSELVES INITIATING RESPONSE. TYPICALLY...COMPETITIVE & REVERSIBLE. /ANTIHISTAMINES/
...ANTIHISTAMINES EFFECTIVE IN MOTION SICKNESS ACT BY VIRTUE OF CENTRAL ANTAGONISM OF ACH... ACT BY BLOCKING EXCITATORY LABYRINTHINE IMPULSES @ CHOLINERGIC SYNAPSES IN REGION OF VESTIBULAR NUCLEI. /ANTIHISTAMINES/
...MOTION SICKNESS. ...STIMULATION OF VESTIBULAR APPARATUS...& THAT VESTIBULAR CEREBELLAR MIDBRAIN "INTEGRATIVE VOMITING CENTER" & MEDULLARY CHEMORECEPTIVE TRIGGER ZONE ARE SOMEHOW INVOLVED. /ANTIHISTAMINES/

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Therapeutic Uses
Antiemetics; Histamine H1 Antagonists
ABILITY TO INHIBIT EFFECTS OF HISTAMINE ON CAPILLARY PERMEABILITY & ON VASCULAR, BRONCHIAL, & MANY OTHER TYPES OF SMOOTH MUSCLE IS PROPERTY THAT CHARACTERIZES H1 ANTAGONISTS & THAT PROVIDES BASIS FOR THEIR PREVALENT CLINICAL USE... /ANTIHISTAMINES/
"FLARE" COMPONENT OF TRIPLE RESPONSE & ITCHING CAUSED BY INTRADERMAL INJECTION OF HISTAMINE... H1-BLOCKING DRUGS SUPPRESS BOTH. ...HAVE LOCAL ANESTHETIC PROPERTIES... H1-BLOCKING DRUGS SELECTIVELY SUPPRESS STIMULANT EFFECT OF HISTAMINE ON ADRENAL CHROMAFFIN CELLS.../&/ AUTONOMIC GANGLION CELLS. /ANTIHISTAMINES/
...EFFICACY...IN COUNTERING HYPERSENSITIVITY REACTIONS WILL VARY, DEPENDING ON DEG TO WHICH SYMPTOMS ARE DUE TO HISTAMINE. ...IN MAN...SOME PHENOMENA, INCL EDEMA FORMATION & ITCH, ARE FAIRLY WELL CONTROLLED; OTHERS, SUCH AS HYPOTENSION ARE LESS SO; & BRONCHOCONSTRICTION...LITTLE IF AT ALL. /ANTIHISTAMINES/
For more Therapeutic Uses (Complete) data for DIMENHYDRINATE (12 total), please visit the HSDB record page.

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Drug Warnings
SEE ANTIHISTAMINICS. CONSIDERABLE MARGIN OF SAFETY SEPARATES THERAPEUTIC DOSE FROM USUAL LETHAL ONE. HOWEVER, BECAUSE CONVULSANT DOSE LIES NEAR LETHAL DOSE, CONVULSIONS INDICATE POOR PROGNOSIS. ADULTS HAVE SURVIVED SINGLE DOSES OF 2.5-5.0 G. CHILDREN...30-60 MG/KG HAS PRODUCED...POISONINGS. /ANTIHISTAMINICS/
IN THERAPEUTIC DOSES, ALL H1 ANTAGONISTS ELICIT SIDE EFFECTS. ...RARELY SERIOUS & OFTEN DISAPPEAR...SOMETIMES...DRUG MUST BE WITHDRAWN. SOME DIFFERENCE...WITH DIFFERENT PREPN IS DISCERNIBLE...MARKED VARIATION IN RESPONSES OF INDIVIDUAL SUBJECTS... /ANTIHISTAMINES/
...ANTICHOLINERGIC ACTIVITY, WHICH ACCOUNTS FOR DRYNESS OF MOUTH...&... DIFFICULTY IN MICTURATION & IMPOTENCE. SOME INTENSIFY RESPONSES TO NOREPINEPHRINE OR STIMULATION OF ADRENERGIC NERVES & INHIBIT RESPONSES TO TYRAMINE... RAPID IV INJECTION OF H1 ANTAGONISTS CAUSES TRANSIENT FALL IN BLOOD PRESSURE... /ANTIHISTAMINES/
H1 ANTAGONISTS CAN BOTH STIMULATE & DEPRESS CNS. ...CENTRAL EXCITATION IS STRIKING FEATURE OF POISONING WITH ANTIHISTAMINES & CAN RESULT IN CONVULSIONS, PARTICULARLY IN INFANTS. CENTRAL DEPRESSION...IS USUAL ACCOMPANIMENT OF THERAPEUTIC DOSES. /ANTIHISTAMINES/
PERSONS TAKING ANTIHISTAMINES SHOULD BE ALERTED TO THEIR SEDATIVE EFFECTS & SHOULD BE CAUTIONED NOT TO DRIVE AN AUTOMOBILE, FLY AN AIRPLANE, OR OPERATE HAZARDOUS MACHINERY... /ANTIHISTAMINES/

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Pharmacodynamics
Dimenhydrinate is indicated for the prevention and treatment of nausea, vomiting, or vertigo of motion sickness. It has a short duration of action of 4-8 hours. Patients should be counselled regarding pronounced drowsiness, avoiding alcohol and other sedatives, and exercising caution when operating a motor vehicle or heavy machinery.

C24H28CLN5O3

469.9638

469.188

523-87-5

76005-58-8 (HCl);523-87-5;

10660

White to off-white solid powder

343.7ºC at 760 mmHg

102-107ºC

101.5ºC

2.967

1

5

6

33

509

0

O=C(N1C)N(C)C2=C(NC(Cl)=N2)C1=O.CN(C)CCOC(C3=CC=CC=C3)C4=CC=CC=C4

NFLLKCVHYJRNRH-UHFFFAOYSA-N

InChI=1S/C17H21NO.C7H7ClN4O2/c1-18(2)13-14-19-17(15-9-5-3-6-10-15)16-11-7-4-8-12-16;1-11-4-3(9-6(8)10-4)5(13)12(2)7(11)14/h3-12,17H,13-14H2,1-2H3;1-2H3,(H,9,10)

2-benzhydryloxy-N,N-dimethylethanamine;8-chloro-1,3-dimethyl-7H-purine-2,6-dione

NSC-117855 NSC117855 NSC 117855 DramalenDimenhydrinate Dramamin

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 37 mg/mL (~78.73 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.43 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.43 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.43 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)