Idoxuridin

log Kow = -0.96

-0.5

-0.95

Solubility at 25 °C in mg/ml: 2.0 in 0.2N HCl; 74.0 in 0.2N NaOH; 4.4 in methanol; 2.6 in alcohol; 0.014 in ether; 0.003 in chloroform; 1.6 in acetone; 1.8 in ethyl acetate; 5.7 in dioxane.

In water, 2.0X10+3 mg/L at 25 °C

Solubility at 25 °C in mg/mL: 2.0 in 0.2N HCl; 74.0 in 0.2N NaOH; 4.4 in methanol; 2.6 in alcohol; 0.014 in ether; 0.003 in chloroform; 1.6 in acetone; 1.8 in ethyl acetate; 5.7 in dioxane.

2.34e+01 g/L

0.1 N NaOH 30 (mg/mL)

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Decomposes at 160 °C

164 - 166 °C

Idoxuridine is rapidly inactivated by deaminases or nucleotidases. To ensure stability, the ophthalmic solution should not be mixed with other medications. Burning after application or failure to respond to treatment may suggest deterioration of the ophthalmic solution; replace with fresh solution. /Ophthalmic Solution USP/

Bulk: No changes were found in material stored at room temperature and at 60 ° C for 28 days. Solution: An aqueous solution (2 mg/mL) shows no decomposition after 24 hours at room temperature (UV and paper chromatography).

Warning

H315 (89.6%): Causes skin irritation [Warning Skin corrosion/irritation]

P203, P261, P264, P264+P265, P271, P280, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 48 reports by companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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

Store between 2 and 8 °C (36 and 46 °F). Store in a tight, light-resistant container. /Ophthalmic Solution USP/

Store between 8 and 15 °C (46 and 59 °F). Store in a collapsible ophthalmic ointment tube. Note: Some manufacturers indicate that the ointment does not require refrigeration. /Ophthalmic Ointment USP/

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.

Concurrent use of boric acid with idoxuridine formulations is not recommended; boric acid may interact with inactive ingredients in some idoxuridine formulations, resulting in precipitate formation; in addition, boric acid may interact with preservatives, especially higher concentrations of thimerosal, in other idoxuridine formulations, resulting in increased ocular toxicity.

/HUMAN EXPOSURE STUDIES/ A total of 45 of 60 patients with herpes zoster previously treated with topical idoxuridine 5-40% in dimethylsulfoxide were patch tested 2 years later with idoxuridine 0.5% and 5% in petrolatum. Three (7%) showed positive reactions. Idoxuridine is considered a weak sensitizer, but in strong concentrations and in active solvents, which increases absorption, there seems to be a risk of sensitization.

/CASE REPORTS/ Four patients had idoxuridine-induced conjunctival cicatrization similar to ocular cicatricial pemphigoid develop, but in the treated eye only. Three of the four patients had chronic, recurrent herpes simplex epithelial and stromal keratitis. The fourth patient had Sjogren's syndrome. All received idoxuridine (0.1% drops and/or 0.5% ointment) and topical corticosteroids from one to 3 1/2 years. Substantial morbidity resulted that included visual loss, stromal ulceration, corneal scarring, and keratinization. Conjunctival biopsy specimens showed cicatrization with a mixed inflammatory cell reaction and absence of goblet cells. Results of direct immunofluorescent microscopy of the conjunctiva were either negative or nonspecific for autoantibody. No circulating autoantibody was detected in any of the four patients.

/CASE REPORTS/ A case of herpes encephalitis diagnosed by brain biopsy and treated with 5-iodo-2-deoxyuridine (IDU) is presented. The infection occurred in a previously well 19-year-old female patient. Plasma and cerebrospinal fluid (CSF) uptake of the substance was determined using 125I labelled IDU. Top CSF levels of IUD and metabolites of less than 4 microgram/mL, about 1/10 of the corresponding plasma level, were obtained after 6 hours of continuous infusion. The result is discussed and compared with a similar study made on 5 healthy beagle dogs where in addition the levels obtained in various parts of the brain were determined. In the animal experiment a mean value of 2.5 microgram/ml of IDU and metabolites was obtained in the CSF after 8 hours, less than 1/20 of the plasma level. The levels in brain tissue were only slightly higher than in the CSF.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

idoxuridine

DILI Positive

Opthalmic, Topical

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Fetal malformations in rabbits (including exophthalmos and clubbing of forelegs).[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006.]

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Nonradioactive idoxuridine (IDU,5-iodo-2'-deoxyuridine), while not teratogenic to rats, does produce fetal maliformations in rabbits when administered topically to the eye in doses similar to those used clinically, 0.1% four times a day for 12 days. These maliformations include exophthalmos and clubbing of the forelegs. By contrast, trifluorothymidine (F3TdR), another highly effective antiherpetic agent currently under investigation but not available for general use, was found not to be teratogenic to rabbits, even when given in concentrations tenfold greater than the doses used to produce idoxuridine teratogenicity.[Itoi M et al; Arch Ophthalmol 93 (1): 46-51 (1975)]

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Pregnant mice and rats were treated daily with 5-iododeoxyuridine (IUDR) or cytosine arabinoside (CA) on 3 consecutive days, beginning on day 16 and 18 of pregnancy, respectively. Offspring were killed at 10 and 20 days of age and the cerebellum, eye, and kidney examined histologically. All offspring of mice treated with 400 mg/kg IUDR were stillborn or died within the first 48 h of life, and deaths occurred at other dosages in both species. In IUDR-exposed mice and rats there was persistence of granule cells in the external granular layer, and scattered foci of microcystic tubular change in the renal cortices. ...The teratogenic effects of IUDR were minimal and were induced by dosages much higher than normally used in human medicine.[Percy DH; Teratology 11 (1): 103-17 (1975)]

/GENOTOXICITY/ ...Chromosomal aberrations in mice have been reported.[Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006.]

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

Rat(ip): LD50: 4000 mg/kg

Mouse(ip): LD50: 1000 mg/kg

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

S - Sensory organs

D - Dermatologicals

J - Antiinfectives for systemic use

QJ - Antiinfectives for systemic use

QD - Dermatologicals

QS - Sensory organs

In chemical structure idoxuridine closely approximates the configuration of thymidine, one of the four building blocks of DNA (the genetic material of the Herpes virus). As a result, idoxuridine is able to replace thymidine in the enzymatic step of viral replication or "growth". The consequent production of faulty DNA results in a pseudostructure which cannot infect or destroy tissue. In short, by pre-empting a vital building block in the genetic material of the Herpes simplex virus, Herplex-D topical solution destroys the infective and destructive capacity of the viral material. The virus infected cell may only be attacked during the period of active synthesis of DNA. This occurs early in the development of the Herpes simplex lesion, but at different times in different cells. Therefore, ideally, the affected area should remain saturated with the antiviral agent.

Idoxuridine acts as an antiviral agent by inhibiting viral replication by substituting itself for thymidine in viral DNA. This in turn inhibits thymidylate phosphorylase and viral DNA polymerases from properly functioning. The effect of Idoxuridine results in the inability of the virus to reproduce or to infect/destroy tissue.

Idoxuridine, which closely resembles thymidine, inhibits thymidylic phosphorylase and specific DNA polymerases, which are necessary for the incorporation of thymidine into viral DNA. Idoxuridine is incorporated in place of thymidine into viral DNA, resulting in faulty DNA and the inability to infect or destroy tissue or to reproduce. Idoxuridine is incorporated into mammalian DNA as well.

Idoxuridine is rapidly inactivated by deaminases or nucleotidases.

Idoxuridine is rapidly inactivated by deaminases or nucleotidases.

LGP81V5245

IDOXURIDINE

Nucleoside Analog [EXT]

Established Pharmacologic Class [EPC] - Nucleoside Analog Antiviral

Idoxuridine is a Nucleoside Analog Antiviral.

Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly.

Compounds that inhibit cell production of DNA or RNA.

Systemic absorption is unlikely following ocular administration even when nasolacrimal secretions are swallowed, since vidarabine is rapidly deaminated in the gastrointestinal tract.

Idoxuridine penetrates the cornea poorly and therefore is ineffective in the treatment of iritis or deep stromal infections.

Idoxuridine crosses the placenta. Studies in humans have not been done.

It is not known whether idoxuridine is distributed into breast milk. However, problems in humans have not been documented.

A reproducible microbiologic assay of microgram quantities of idoxuridine (IDU) in serum, urine, or cerebrospinal fluid is presented. The antiviral assay is not interfered with by type-specific antibody or interferon. During slow intravenous infusions of idox-uridine (4 mg/min) in patients with suspected diagnoses of Herpesvirus hominis encephalitis, the rate of inactivation and/or removal of drug exceeded its administration. During several rapid infusions of idoxuridine (50 mg/min) significant quantities of the drug were found in serum, urine, and cerebrospinal fluid. Idoxuridine is not significantly bound to serum proteins and is not deiodinated in fresh serum or urine in vitro to inactive products (iodouracil, uracil, iodide). It is rapidly excreted into the urine. Inactivation of IDU occurs in tissues. This antiviral assay of IDU in body fluids should be applicable to other viruses and potential antiviral agents.

U.S., 0.1% (Rx) [Herplex Liquifilm (polyvinyl alcohol 1.4%, benzalkonium chloride); Stoxil (thimerosal 1:50,000)]; Canada, 0.1% (Rx) [Herplex Liquifilm (polyvinyl alcohol 1.4%, benzalkonium chloride 0.004%); Stoxil (thimerosal 1:50,000)]. /Ophthalmic Solution USP/

U.S., 0.5% (Rx) [Stoxil]; Canada, 0.5% (Rx) [Stoxil]. /Ophthalmic Ointment USP/