ファムシクロビル

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

0.6

0.32

Solubility in water (25 °C): > 25% w/v initially; rapidly precipitates as sparingly soluble monohydrate (2-3% w/v)

Freely soluble in acetone, methanol; sparingly soluble in ethanol, isopropanol

1.32e+00 g/L

Breast Feeding; Lactation; Milk, Human; Anti-Infective Agents; Antiviral Agents

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

102-104 °C

102-104 °C

102 - 104 °C

167.77 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

168.4 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Danger

H319 (50%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

P203, P264+P265, P280, P305+P351+P338, P318, P337+P317, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 4 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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

If breathed in, move person into fresh air. If not breathing, give artificial respiration.

In case of skin contact, wash off with soap and plenty of water.

In case of eye contact, flush eyes with water as a precaution.

If swallowed, never give anything by mouth to an unconscious person. Rinse mouth with water.

Water spray, dry chemical, carbon dioxide or foam as appropriate for surrounding fire and materials.

As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing.

Store Famvir at room temperature between 59 deg and 86 °F (15 deg to 30 °C).

Store in tight container as defined in the USP-NF. This material should be handled and stored per label instructions to ensure product integrity.

Recommended storage temperature: 2 - 8 °C

Wear approved respiratory protection, chemically compatible gloves, and protective clothing. Wipe up spillage or collect spillage using a high-efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately labeled container for disposal. Wash spill site.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Dispose of waste in accordance with all applicable Federal, State and local laws.

Avoid exposure to heat and moisture.

As a general rule, when handling USP Reference Standards, avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Clean equipment and work surfaces with suitable detergent or solvent after use. After removing gloves, wash hands and other exposed skin thoroughly.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

As with all dry powders it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity.

Airborne exposure should be controlled primarily by engineering controls such as general dilution ventilation, local exhaust ventilation, or process enclosure. Local exhaust ventilation is generally preferred to general exhaust because it can control the contaminant at its source, preventing dispersion into the work area. An industrial hygiene survey involving air monitoring may be used to determine the effectiveness of engineering controls. Effectiveness of engineering controls intended for use with highly potent materials should be assessed by use of nontoxic surrogate materials. Local exhaust ventilation such as a laboratory fume hood or other vented enclosure is recommended, particularly for grinding, crushing, weighing, or other dust-generating procedures.

Respiratory Protection: Where respirators are deemed necessary to reduce or control occupational exposures, use NIOSH-approved respiratory protection and have an effective respirator program in place. Gloves: Chemically compatible. For handling solutions, ensure that the glove material is protective against the solvent being used. Use handling practices that minimize direct hand contact. Employees who are sensitive to natural rubber (latex) should use nitrile or other synthetic nonlatex gloves. Use of powdered latex gloves should be avoided due to the risk of latex allergy. Eye Protection: Safety glasses with sideshields are recommended. Face shields or goggles may be required if splash potential exists or if corrosive materials are present. Approved eye protection (e.g., bearing the ANSI Z87 or CSA stamp) is preferred. Maintain eyewash facilities in the work area. Protective Clothing: For handling of laboratory scale quantities, a cloth lab coat is recommended. Where significant quantities are handled, work clothing may be necessary to prevent take-home contamination.

Handle with gloves. Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. Interactions with other drugs metabolized by this enzyme and/or inhibiting this enzyme could potentially occur. Clinical interaction studies of famciclovir with cimetidine and promethazine, in vitro inhibitors of aldehyde oxidase, did not show relevant effects on the formation of penciclovir. Raloxifene, a potent aldehyde oxidase inhibitor in vitro, could decrease the formation of penciclovir. However, a clinical drug-drug interaction study to determine the magnitude of interaction between penciclovir and raloxifene has not been conducted.

Potential pharmacokinetic interaction with other drugs metabolized by aldehyde oxidase.

Potential increased plasma penciclovir concentrations when used concomitantly with other drugs eliminated by active renal tubular secretion (e.g., probenecid).

Famciclovir has been associated with a low rate of serum aminotransferase elevations during oral therapy. In pooled analyses of patients on long term suppressive therapy, 3.2% of famciclovir vs 1.5% of placebo recipients had ALT elevations above twice normal. The elevations were transient and asymptomatic and resolved even without dose modification. Since approval, cases of cholestatic jaundice have been reported to the sponsor, but there have been no published cases. Thus, clinically apparent liver disease due to famciclovir must be rare if it occurs at all.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 330(SRC), determined from a structure estimation method(2), indicates that famciclovir is expected to have moderate mobility in soil(SRC). Volatilization of famciclovir from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 9.4X10-14 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Famciclovir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.1X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2013).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 330(SRC), determined from a structure estimation method(2), indicates that famciclovir is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 9.4X10-14 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from an estimated log Kow of 0.64(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2013).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), famciclovir, which has an estimated vapor pressure of 1.1X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase famciclovir may be removed from the air by wet and dry deposition(SRC). Famciclovir contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

The most common adverse events reported by patients taking famciclovir include headaches, nausea, and diarrhea. More severe adverse effects following famciclovir treatment are rare. Among the most reported and studied severe adverse effects of famciclovir include hepatotoxicity and Steven Johnsons-syndrome. However, hepatotoxicity is rare and is more strongly associated with long-term use of famciclovir. There is no evidence indicating it is necessary to alter the dose of famciclovir in patients "with well-compensated hepatic impairment." A correlation exists with elevated alkaline phosphatase (ALT) levels in patients taking famciclovir compared to patients taking a placebo.

There is no information on whether penciclovir is excreted in human milk after topical administration. However, following oral administration of famciclovir (the oral prodrug of penciclovir) to lactating rats, penciclovir was excreted in breast milk at concentrations higher than those seen in the plasma.

There are no significant toxic side effects associated with famciclovir treatment, and thus there is no antidote. If a patient taking famciclovir experiences any side effects or suspects toxic effects, they should consult with their doctor as early as possible.

Antiviral drugs have been recently recognized as one of the emerging contaminants in the environment. These are discharged after therapeutic use through human excretion. Effluent containing high concentration of antiviral drugs discharged from production facilities is also a cause of concern to nearby aquatic bodies. There is an increased interest in their removal because they are highly bioactive. Some antiviral drugs are resistant to conventional methods of degradation, and there is a risk of development of antiviral resistance in humans and animals if exposed repeatedly for long periods. To date, the potential human, animal, and ecological risks associated with the discharge of these antiviral compounds to the environment are not well documented. This study presents a brief summary on occurrence, ecotoxicological risks, and physicochemical properties of antiviral drugs in the environment. The needs regarding removal, disposal, and treatment of antiviral drugs are also addressed(1). /Antiviral drugs/

Using a structure estimation method based on molecular connectivity indices(1), the Koc of famciclovir can be estimated to be 330(SRC). According to a classification scheme(2), this estimated Koc value suggests that famciclovir is expected to have moderate mobility in soil.

/HUMAN EXPOSURE STUDIES/ There was no evidence of any clinically significant effects on sperm count, motility or morphology in 2 placebo-controlled clinical trials of Famvir (famciclovir [the oral prodrug of penciclovir], 250 mg b.i.d.; n=66) in immunocompetent men with recurrent genital herpes, when dosing and follow-up were maintained for 18 and 8 weeks, respectively (approximately 2 and 1 spermatogenic cycles in the human).

/CASE REPORTS/ The development of confusion and bradykinesia during famciclovir therapy for herpes zoster is reported in an 80-yr-old woman who received 500 mg of oral famciclovir 2 times/day for 7 days. The patient's pain and lesions improved markedly within 48 hr of the start of famciclovir therapy, but confusion, urinary incontinence, and periods of immobility developed. She was hospitalized and famciclovir was discontinued. By day 3 her mental status had improved but she experienced more pain and famciclovir was resumed at a dose of 250 mg 3 times/day. The neurologist diagnosed famciclovir related encephalopathy and dementia. ...

/CASE REPORTS/ A 67-year-old white female presented to the hospital for evaluation of large, bilateral palpable purpura; coalescing ulcers with central eschars; and small, red violaceous papules on her legs and groin. Approximately 2 months prior to this hospitalization, the woman was diagnosed with shingles of her left T1-T2 nerve distribution and was treated with famciclovir 500 mg 3 times daily, which was her first exposure to this medication. Her shingles resolved; however, on day 4 of treatment, she began to notice red spots on both of her legs that began to progressively blister and increase in size. She discontinued famciclovir at that time. The rash persisted and spread to her abdomen, groin, legs, feet, and toes. She underwent punch biopsy that revealed leukocytoclastic vasculitis (LCV). Workup was negative for antinuclear antibody, rheumatoid factor, hepatitis B and C virus, perinuclear-staining antineutrophil cytoplasmic antibodies, cytoplasmic-staining antineutrophil cytoplasmic antibodies, antibodies to extractable nuclear antigens, proteinase 3, and myeloperoxidase. The patient improved with daily oral steroids and local wound care. ... The most common cause of LCV is medication use, but it is a diagnosis of exclusion. It is hypothesized that drugs act as haptens, which cause an immune response. An objective causality assessment using the Naranjo probability scale suggested that famciclovir was the probable cause of LCV in this patient.

/GENOTOXICITY/ Famciclovir caused increases in polyploidy in human lymphocytes in vitro in the absence of chromosomal damage at a concentration of 1200 ug/mL.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Famciclovir

Ambiguous-DILI-concern

3

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

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

S - Sensory organs

J - Antiinfectives for systemic use

QS - Sensory organs

QJ - Antiinfectives for systemic use

Famciclovir is a prodrug that undergoes rapid biotransformation to the active antiviral compound penciclovir. Penciclovir is an anti-viral drug which has inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV). Therefore, herpes viral DNA synthesis and replication are selectively inhibited.

Famciclovir undergoes rapid biotransformation to the active antiviral compound penciclovir, which has inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV). In cells infected with HSV-1, HSV-2 or VZV, viral thymidine kinase phosphorylates penciclovir to a monophosphate form that, in turn, is converted to penciclovir triphosphate by cellular kinases. In vitro studies demonstrate that penciclovir triphosphate inhibits HSV-2 DNA polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes viral DNA synthesis and, therefore, replication are selectively inhibited.

Famciclovir is a prodrug of penciclovir, which has demonstrated inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV). In cells infected with HSV-1, HSV-2 or VZV, the viral thymidine kinase phosphorylates penciclovir to a monophosphate form that, in turn, is converted by cellular kinases to the active form penciclovir triphosphate. Biochemical studies demonstrate that penciclovir triphosphate inhibits HSV-2 DNA polymerase competitively with deoxyguanosine triphosphate. Consequently, herpes viral DNA synthesis and, therefore, replication are selectively inhibited. Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-1-, 20 hours in HSV-2- and 7 hours in VZV-infected cells grown in culture. However, the clinical significance of the intracellular half-life is unknown.

10 hours

Elimination half-life of penciclovir after oral administration of famciclovir 1.6-3 hours. Intracellular half-life of penciclovir triphosphate in cells infected with herpes simplex virus (HSV)-1 or HSV-2 is 10 and 20 hours, respectively; intracellular half-life in varicella zoster virus (VZV)-infected cells is 7-14 hours.

The plasma elimination half-life of penciclovir was 2.0 + or - 0.3 hours after intravenous administration of penciclovir to 48 healthy male volunteers and 2.3 + or - 0.4 hours after oral administration of 500 mg famciclovir to 124 healthy male volunteers. The half-life in 17 patients with herpes zoster was 2.8 + or - 1.0 hours and 2.7 + or - 1.0 hours after single and repeated doses, respectively.

Hepatic

Famciclovir is deacetylated and oxidized to penciclovir. Penciclovir is phosphorylated to penciclovir triphosphate (the active metabolite) in cells infected with HSV-1, HSV-2, or VZV. The inactive metabolite 6-deoxy penciclovir is converted to penciclovir by aldehyde oxidase. Famciclovir not metabolized by CYP enzymes.

Following oral administration, famciclovir is deacetylated and oxidized to form penciclovir. Metabolites that are inactive include 6-deoxy penciclovir, monoacetylated penciclovir, and 6-deoxy monoacetylated penciclovir (5%, <0.5% and <0.5% of the dose in the urine, respectively). Little or no famciclovir is detected in plasma or urine. An in vitro study using human liver microsomes demonstrated that cytochrome P450 does not play an important role in famciclovir metabolism. The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase.

QIC03ANI02

FAMCICLOVIR

Mechanisms of Action [MoA] - DNA Polymerase Inhibitors

Mechanisms of Action [MoA] - DNA Polymerase Inhibitors

Established Pharmacologic Class [EPC] - Herpes Simplex Virus Nucleoside Analog DNA Polymerase Inhibitor

Nucleoside Analog [EXT]

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.

77 %

Active tubular secretion contributes to the renal elimination of penciclovir.

1.08±0.17 L/kg [healthy male subjects following a single intravenous dose of penciclovir at 400 mg administered as a 1-hour intravenous infusion]

36.6 +/- 6.3 L/hr [healthy male]

Following oral administration of famciclovir to lactating rats, penciclovir was distributed into breast milk at concentrations higher than those observed in plasma.

Not known whether penciclovir crosses the placenta or is distributed into human milk.

Used in the treatment of herpes simplex virus (HSV), varcilla zoster virus (VZV), and cytomegalovirus (CMV)

MEDICATION

MEDICATION (VET)

Antiviral Agents

Use (kg; approx.) in Germany (2009): >50

One method involves first the formation of 5-(2-hydroxy-ethyl)-2,2-dimethyl-1,3-dioxolane (I) by the reaction of triethylethane-1,1,2-tricarboxylate with THF and lithium aluminum hydride to form an oil which reacts with 2,2-dimethoxypropane in the presence of p-toluenesulfonic acid to yield I. The OH group is replaced by bromine using CBr4 and trimethyl phosphine. The bromo derivative is combined with 2-amino-6-chloropurine to alkylate in the 7-position. The dioxalane ring is opened by warming with dilute HCl and the resulting diol esterified with acetic anhydride using 4-(dimethylamino)pyridine as the acid scavenger.

Table: Famciclovir Preparations [Table#8089]

Oravir