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Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals

ODORLESS; WHITE TO NEARLY WHITE, FINE, CRYSTALLINE POWDER; SOL IN ALC

Mol wt 296.84. Crystals, dec 300-303 °C. Freely sol in water, alcohol. Practically insol in ether, chloroform, benzene /Hydrochloride/

Insoluble in diethyl ether, chloroform, and benzene

5.15e-02 g/L

Breast Feeding; Lactation; Milk, Human; Adrenergic alpha-Agonists; Sympathomimetics; Nasal Decongestants

FDA approved drugs -> Active ingredient

Pharmaceuticals

181-183 °C

182 °C

Danger

H300+H330 (96.6%): Fatal if swallowed or if inhaled [Danger Acute toxicity, oral; acute toxicity, inhalation]

P260, P264, P264+P265, P270, P271, P273, P280, P284, P301+P316, P304+P340, P305+P354+P338, P316, P317, P320, P321, P330, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 29 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Chemical: Phenol, 3-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-6-(1,1-dimethylethyl)-2,4-dimethyl-

Status: Active Update: 06-02-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/22185

Nasal decongestant active ingredients. The active ingredient of the product consists of any of the following when used within the dosage limits and in the dosage forms established for each ingredient: ... Topical nasal decongestants: Oxymetazoline hydrochloride. /Oxymetazoline hydrochloride/

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed over-the-counter drug products, incl oxymetazoline, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Gilstrap LC, Little BB; Drugs & Pregnancy 269-75 (1992). Antihistamines, decongestants, and expectorants during pregnancy.

Smith MB, Feldman W; JAMA 269: 2256-63 (1993). Over the counter cold medications: critical review of clinical trials between 1950 and 1991.

Oxymetazoline hydrochloride nasal solutions should be stored in tight containers at a temperature less than 40 °C, preferably at 2-30 °C; freezing should be avoided. Oxymetazoline hydrochloride ophthalmic solutions should be stored at 15-30 °C. Oxymetazoline is probably degraded in the presence of aluminum and, therefore, should not be stored in aluminum containers.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

If significant systemic absorption of nasal /or ophthalmic/ oxymetazoline occurs, concurrent use of maprotiline or tricyclic antidepressants may potentiate the pressor effect of oxymetazoline.

A case is described in which a 34 yr old man presented with severe hypertension, cardiomegaly, and congestive heart failure, presumably due to oxymetazoline hydrochloride, phenylephrine hydrochloride, and ephedrine hydrochloride, consumed in massive doses by an overuse of nasal decongestants and cough syrup. Coadamin chlorpromazine hydrochloride and trimeprazine tartrate may have contributed to the effects through anticholinergic and antihistamine properties. The patient was treated with furosemide and nifedipine. Signs and symptoms of heart failure quickly resolved and blood pressure dropped to 140/100 mm Hg. /Oxymetazoline hydrochloride/

Self-treatment of anaphylaxis due to a single 75 mg dose of ketoprofen is reported in a 39 yr old female patient who used 12 inhalations of an oxymetazoline nasal solution in each nostril to relieve the respiratory symptoms of the allergic reaction. Within min of using the nasal solution, the respiratory symptoms began to subside, and the patient slept through the night and consulted her doctor the next day.

Reported is a case of chronic hallucination in a 61-yr-old man associated with long term use of phenylephrine hydrochloride (Neo-Synephrine), and, more recently, oxymetazoline hydrochloride (Afrin) nasal preparations. Trifluoperazine hydrochloride (10 mg/day) was begun, nasal preparations were discontinued, and a combination of pseudoephedrine hydrochloride and tripolidine hydrochloride (Actifed) was given 2 times/day. The nasal obstruction gradually decreased and the symptoms of psychosis and anxiety were alleviated.

/SIGNS AND SYMPTOMS/ Excessive dosage and/or prolonged or too frequent intranasal use of oxymetazoline may irritate nasal mucosa and, especially in children, cause adverse systemic effects. Excessive dosage or inadvertent ingestion in children may cause profound CNS depression, possibly necessitating intensive supportive care. CNS depression, shock-like hypotension, and coma have occurred following overdosage of naphazoline and tetrahydrozoline; the possibility that this may occur with oxymetazoline should be considered.

/CASE REPORTS/ In this incident, oxymetazoline nasal spray 0.025% was administered to a 2-year-old patient during general anesthesia for nasal endoscopy. Severe hypertension with reflex bradycardia progressed to sinus arrest and was successfully treated with atropine and cardiopulmonary resuscitation.

/CASE REPORTS/ A patient prescribed oxymetazoline hydrochloride nasal drops presented with recurrent ventricular tachycardia of fascicular origin. Cardiac ultrasound showed a calcified lesion, presumably a fibroma arising from the interventricular septum. Fascicular tachycardia related to the lesion and provoked by the use of a sympathomimetic agent is postulated.

/CASE REPORTS/ Oxymetazoline is a sympathomimetic amine found in over-the-counter nasal decongestants. A case of chronic use of nasal oxymetazoline associated with thunderclap headache due to reversible segmental intracranial vasoconstriction /is reported/.

For more Human Toxicity Excerpts (Complete) data for OXYMETAZOLINE (11 total), please visit the HSDB record page.

/LABORATORY ANIMALS: Acute Exposure/ ... Oxymetazoline injected icvt /intracerebroventricular injection/ into the lateral ventricle of NZW rabbits induced bilateral ocular hypotension (> 7.0 mmHg) that peaked at 2 hr. Unilateral topical application of oxymetazoline induced maximal, bilateral hypotension (> 12 mm/Hg), at 3 hr, in both the contralateral and ipsilateral eyes, that persisted more than 12 hr. ...

/LABORATORY ANIMALS: Neurotoxicity/ To determine if intrathecal oxymetazoline induces histological evidence of spinal neurotoxicity, male, Sprague-Dawley rats (300-450 g; implanted with an intrathecal catheter) were treated with intrathecal saline or 100 nmol oxymetazoline twice daily for 3 days, or 200 or 300 nmol oxymetazoline once daily for 3 days. Spantide (D-Arg1, D-Try7,9, Leu11-substance P; 0.067 nmol = 0.1 ug, 0.167 nmol = 0.25 ug or 0.334 nmol = 0.5 ug) or capsaicin (0.164 mumol = 50 ug), given as a single intrathecal injection, were used as positive controls. Animals were killed 12 hr after the last injection of saline or oxymetazoline, and 72 hr after spantide or capsaicin. Spinal cord sections (L1 and adjacent segments) were examined by light microscopy for changes in gross morphology, substance P-like immunoreactivity (SP-IR) and calcitonin gene related peptide-like immunoreactivity (CGRP-IR). All doses of intrathecal oxymetazoline produced antinociception (tail-flick ED50 = 53.7 nmol, paw pressure withdrawal ED50 = 93.3 nmol). Rectal temperature decreased by 1.5-2.4 degrees C up to 12 hr after 100 nmol of intrathecal oxymetazoline. There were no signs of inflammation or necrosis, and no detectable loss or damage to either spinal afferents or motor neurons as judged by SP-IR and CGRP-IR structures in spinal cords of oxymetazoline-treated animals (all doses) as compared to intrathecal saline controls. Spantide (0.1 ug) had no antinociceptive or neurotoxic effect; 0.25 ug induced irreversible loss of the TF reflex and transient hind limb paralysis; 0.5 microgram induced irreversible loss of TF and PP responses, permanent hind limb paralysis, bladder and bowel dysfunction. The spinal cords from these animals showed signs of extensive necrosis, cavitation, and hemorrhage in the ventral horn accompanied by a loss of CGRP-IR motor neurons. Capsaicin-treated rats exhibited a permanent loss of the TF but not the PP response and a marked reduction of SP-IR spinal afferents in the dorsal horn. It is concluded that i.t. oxymetazoline produces antinociception in the rat with no detectable spinal neurotoxicity as assessed by parameters which are sensitive to the neurotoxins, spantide and capsaicin.

/OTHER TOXICITY INFORMATION/ In dogs, signs of intoxication may include vomiting, bradycardia, cardiac arrhythmias, poor capillary refill time, hypotension or hypertension, panting, increased upper respiratory sounds, depression, weakness, nervousness, hyperactivity, or shaking. These signs appear within 30 min to 4 hr postexposure. In general, imidazoline decongestant exposure may affect the GI, cardiopulmonary, and nervous systems. /Imidazoline decongestions/

/VET:/ Decontamination may not be practical due to the rapid absorption and onset of clinical signs. Heart rate and rhythm and blood pressure should be assessed, and an ECG obtained if needed. IV fluids should be given, along with atropine at 0.02 mg/kg, IV, if bradycardia is present. Diazepam (0.25-0.5 mg/kg, IV) can be given if CNS signs (eg, apprehension, shaking) are present. Serum electrolytes (ie, potassium, sodium, chloride) should be assessed and corrected as needed. Yohimbine, which is a specific a2-adrenergic antagonist, can also be used at 0.1 mg/kg, IV, and repeated in 2-3 hr if needed. /Imidazoline decongestants/

◉ Summary of Use during Lactation

◈ What is oxymetazoline?

LD50 Rat oral 800 ug/kg

LD50 Rat sc 1100 ug/kg

Nasal decongestant active ingredients. The active ingredient of the product consists of any of the following when used within the dosage limits and in the dosage forms established for each ingredient: ... Topical nasal decongestants: Oxymetazoline hydrochloride. /Oxymetazoline hydrochloride/

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed over-the-counter drug products, incl oxymetazoline, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

R01AA05

S - Sensory organs

R - Respiratory system

R - Respiratory system

D - Dermatologicals

QD - Dermatologicals

Oxymetazoline is an adrenergic α₁- and α₂-agonist and a direct-acting sympathomimetic drug. By stimulating adrenergic receptors, oxymetazoline causes vasoconstriction of dilated arterioles and reduces blood flow. In a radioligand competition study, oxymetazoline displayed higher affinity at α_1A-adrenoceptors compared to α_2B-adrenoceptors, but with higher potency at α_2B-adrenoceptors. When sprayed intranasally, oxymetazoline relieved relief nasal congestion and improved nasal airflow in patients with acute coryzal rhinitis for up to 12 hours following a single dose. An early _in vitro_ study demonstrated oxymetazoline to exert anti-oxidant actions, where it inhibited microsomal lipid peroxidation and mediated hydroxyl radical scavenging activity. This suggests that oxymetazoline has a beneficial effect against oxidants, which play a role in tissue damage in inflammation.

Oxymetazoline binds to α₁- and α₂-adrenoceptors, which are Gq- and Gi-protein-coupled receptors respectively. α₁-adrenoceptors agonism promotes vascular smooth muscle contraction by increasing intracellular calcium levels through activating phospholipase C, while α₂-adrenoceptors agonism, specifically the α_2B-adrenoceptors, can also elicit vasoconstriction through the inhibition of adenyl cyclase. Rosacea is a condition characterized by transient and persistent facial erythema. By stimulating α_1A-adrenoceptors and causing vasoconstriction, oxymetazoline is believed to diminish the symptoms of erythema. In blepharoptosis, it is hypothesized that oxymetazoline works by stimulating α-adrenergic receptors on the Müller muscle that elevates the upper eyelid, causing muscle contraction. Oxymetazoline is used in combination with tetracaine for local anesthesia in dentistry. Such combination use adds beneficial effects: the vasoconstrictor counteracts the local anesthetic agent's vasodilatory action, thereby constricting dilated arterioles and reducing blood flow to the application area. Oxymetazoline relieves nasal congestion by vasoconstricting the respiratory microvasculature, in both resistance and capacitance blood vessels on the human nasal mucosa, leading to decreased nasal mucosal blood flow, edema, and airflow resistance.

The mechanism of action of oxymetazoline has not been conclusively determined. Most pharmacologists believe that the drug directly stimulates a-adrenergic receptors of the sympathetic nervous system and exerts little or no effect on beta-adrenergic receptors. Intranasal application of oxymetazoline results in constriction of dilated arterioles and reduction in nasal blood flow and congestion. In addition, obstructed eustachian ostia may be opened. Nasal ventilation and aeration are improved temporarily; however, rebound vasodilation and congestion usually occur to some degree. Following topical application of oxymetazoline hydrochloride ophthalmic solution, conjunctival congestion is temporarily relieved, but overuse of the drug may produce rebound hyperemia.

Following ocular administration in healthy adults, the mean terminal half-life was 8.3 hours, ranging from 5.6 to 13.9 hours. The terminal half-life of oxymetazoline following nasal administration of the combination product containing tetracaine and oxymetazoline in adult subjects is approximately 5.2 hours.

_In vitro_, oxymetazoline was minimally metabolized by human liver enzymes to produce mono-oxygenated and dehydrogenated metabolites. About 95.9% of the total dose of oxymetazoline remained as an unchanged parent compound after a 120-minute incubation with human liver microsomes. When incubated in rat, rabbit, and human liver post-mitochondrial supernatant fraction from homogenized tissue (S9) fractions, oxymetazoline was more efficiently metabolized by rabbit liver S9 fractions (~65%) than by rat (~20%) or human (~10%) liver S9 fractions. At concentrations (50 μM) at least 130-fold greater than the usual therapeutic intranasal dose (400 nM), CYP2C19 was suggested to be involved in the oxidation of oxymetazoline following intranasal administration; however, metabolites in humans have not been fully characterized up to date and remain speculated based on _in vitro_ studies using rat and rabbit liver S9 fractions and microsomes. The O-glucuronide metabolite catalyzed by UGT1A9 has been identified _in vitro_.

8VLN5B44ZY

OXYMETAZOLINE

Established Pharmacologic Class [EPC] - Vasoconstrictor

Physiologic Effects [PE] - Vasoconstriction

Physiologic Effects [PE] - Increased Sympathetic Activity

Chemical Structure [CS] - Imidazolines

Drugs that selectively bind to and activate alpha adrenergic receptors.

Drugs that mimic the effects of stimulating postganglionic adrenergic sympathetic nerves. Included here are drugs that directly stimulate adrenergic receptors and drugs that act indirectly by provoking the release of adrenergic transmitters.

Drugs designed to treat inflammation of the nasal passages, generally the result of an infection (more often than not the common cold) or an allergy related condition, e.g., hay fever. The inflammation involves swelling of the mucous membrane that lines the nasal passages and results in inordinate mucus production. The primary class of nasal decongestants are vasoconstrictor agents. (From PharmAssist, The Family Guide to Health and Medicine, 1993)

Imidazole derivatives such as oxymetazoline are readily absorbed across mucosal membranes, especially in children. In adult subjects with erythema associated with rosacea, the mean ± standard deviation (SD) Cmax was 60.5 ± 53.9 pg/mL and the AUC from time 0 to 24 hours (AUC0-24hr) was 895 ±798 pg x hr/mL following topical administration of first-dose oxymetazoline. Following once-daily topical applications for 28 days, the mean ± SD Cmax was 66.4 ± 67.1 pg/mL and the AUC0-24hr was 1050 ± 992 pg x hr/mL. Following twice-daily applications for 28 days, the mean ± SD Cmax was 68.8 ± 61.1 pg/mL and the AUC0-24hr was 1530 ± 922 pg x hr/mL. Following single-drop ocular administration of oxymetazoline in healthy adult subjects, the mean ± SD Cmax was 30.5 ± 12.7 pg/mL and the area under the concentration-time curve (AUCinf) was 468 ± 214 pg x hr/mL. The median Tmax was 2 hours, ranging from 0.5 to 12 hours. Following nasal administration of an 0.6 mL combination product containing tetracaine and oxymetazoline in adult subjects, the maximum concentrations of oxymetazoline were reached within approximately 10 minutes. The mean Cmax was 1.78 ng/mL and the AUC0-inf value was 4.24 ng x h/mL, with a median Tmax of 5 minutes.

While the excretion of oxymetazoline following nasal, topical, or ophthalmic administration of oxymetazoline has not been fully characterized in humans, it is believed that the predominant route of elimination at clinically relevant concentrations of oxymetazoline is renal excretion.

There is limited information on the volume of distribution of oxymetazoline.

There is limited information on the clearance rate of oxymetazoline.

... Oxymetazoline /at an optimum strength of 0.025%/ was absorbed slowly into the eye: only 0.006% of the original drug concentration was found in the aqueous humors of rabbits 30 minutes after instillation; the balance remained primarily in external ocular tissues. Metabolic studies in rabbits indicated that excreted amounts of unmetabolized radioactive oxymetazoline in urine following drug administration were similar (23%) for the ocular and nasal routes of application. The proportions of oxymetazoline metabolite to unchanged oxymetazoline were constant for all administration routes tested.

Following intranasal application of oxymetazoline hydrochloride solutions, local vasoconstriction usually occurs within 5-10 minutes and persists for 5-6 hours with a gradual decline over the next 6 hours. Following topical application of oxymetazoline hydrochloride ophthalmic solution, local vasoconstriction usually occurs within minutes and may persist for up to 6 hours. Occasionally, enough oxymetazoline may be absorbed to produce systemic effects.

THERAP CAT: Adrenergic (vasoconstrictor); nasal decongestant

MEDICATION

Oxymetazoline nasal spray is a potent /alpha 2/-adrenergic agonist commonly used to vasoconstrict blood vessels in the nasal mucosa.

Use (kg; approx.) in Germany (2009): >10

From (4-tert-butyl-2,6-dimethyl-3-hydroxyphenyl)acetonitrile & ethylenediamine: FRUHSTORFER, MUELLER-CALGAN...CHEM ABST 57, 4674A (1962).

6-t-Butyl-2,4-dimethylphenol + formaldehyde + sodium cyanide + ethylenediamine (chloromethylation/cyanidation/condensation)

Nasal: Solution: 0.05%* Afrin ( with benzalkonium chloride, povidone, and propylene glycol; with or without menthol and regular drops and spray), (Schering-Plough), Afrin No Drip Extra Moisturizing 12 Hour Pump Mist ( with benzalkonium chloride, benzyl alcohol, glycerin, and povidone), (Schering-Plough) Afrin No Drip Original 12 Hour Pump Mist ( with benzalkonium chloride, benzyl alcohol, and povidone), (Schering-Plough), Afrin No Drip Severe Congestion 12 Hour Pump Mist ( with benzalkonium chloride, benzyl alcohol, povidone, and propylene glycol), (Schering-Plough) Afrin No Drip Sinus 12 Hour Pump Mist ( with benzalkonium chloride, benzyl alcohol, and propylene glycol), (Schering-Plough), Dristan 12 Hour Nasal Spray ( with benzalkonium chloride and benzyl alcohol), (Wyeth), Duramist Plus 12 Hour Nasal Decongestant Spray ( with benzalkonium chloride), (Pfeiffer), 4-Way 12 Hour Long Lasting Spray ( with benzalkonium chloride and phenylmercuric acetate), (Bristol-Myers Squibb), Nasal Decongestant Maximum Strength Spray ( with benzalkonium chloride, povidone, and propylene glycol), (Taro), Neo-Synephrine 12 Hour Extra Moisturizing Spray ( with benzalkonium chloride, glycerin, and phenylmercuric acetate), (Bayer), Neo-Synephrine 12 Hour Long Acting Spray ( with benzalkonium chloride and phenylmercuric acetate), (Bayer), Nostrilla12 Hour Nasal Decongestant ( with benzalkonium chloride; with metered pump spray), (Insight), Vicks Sinex 12 Hour Nasal Decongestant Spray ( with benzalkonium chloride and with regular or metered pump mist spray), (Procter & Gamble).

Ophthalmic: Solution: 0.025% Visine L.R. Eye Drops (with benzalkonium chloride), (Pfizer).

Trade names: Ocuclear Eye Drops (Schering), Visine L.R. Eye Drops (Pfizer) /Oxymetazoline hydrochloride/

PATENTS: GERMAN PATENT 1,117,588 (1961 TO E MERCK).

Available commercially as the free base or hydrochloride.