Penciclovir

1.7mg/ml

Occurs as monohydrate, stable crystalline solid. Solubility in water (20deg C): >200 mg/mL, 30 mg/mL solution has pH 11/Penciclovir sodium salt/

Solubility in water at 20 °C: 1.7 mg/mL, pH 7

7.45e+00 g/L

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

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

275-277 °C

275-277 °C ... /also reported as/ 272-275 °C

275 - 277 °C

Warning

H319 (100%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

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

Aggregated GHS information provided per 40 reports by companies from 2 notifications to the ECHA C&L Inventory.

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

Hazardous decomposition products formed under fire conditions. - Carbon oxides, nitrogen oxides (NOx)

Emits toxic fumes under fire conditions. /Famciclovir/

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

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

Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Store at controlled room temperature, 20-25 °C (68 -77 °F).

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

Keep container tightly closed in a dry and well-ventilated place.

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. /Famciclovir/

Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

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. /Famciclovir/

Avoid exposure to heat and moisture. /Famciclovir/

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. /Famciclovir/

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. /Famciclovir/

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. /Famciclovir/

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. /Famciclovir/

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that penciclovir is expected to have very high mobility in soil(SRC). Volatilization of penciclovir from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 9.5X10-32 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Penciclovir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.0X10-17 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). A biodegradation half-life of 3.4 hours using activated sludge(4) indicates that biodegradation may be an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a structure estimation method(2), indicates that penciclovir is not 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 9.5X10-32 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 -1.14(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). A biodegradation half-life of 3.4 hours using activated sludge(7) indicates that biodegradation may be an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), penciclovir, which has an estimated vapor pressure of 3.0X10-17 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 penciclovir may be removed from the air by wet and dry deposition(SRC). Penciclovir contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be suscetible to direct photolysis by sunlight(SRC).

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.

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

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/

Penciclovir was tested for in raw and treated wastewater from two conventional German waste water treatment plants. Plant 1 activated sludge hydraulic retention time and sludge retention time of 12 hrs and 10-12 days respectively; treating 330,000 population equivalents, daily flow rate of 60,000 cu m. Penciclovir was present at 42.8 ng/L in the effluent and below the limit of quantification (5 ng/L) in the effluent, a >94% elimination (grab samples). Plant 2 treats 200,000 cu m daily serving 1,350,000 population equivalents and incorporates primary aerobic, secondary anaerobic treatments. Penciclovir was present at 19,5 ng/L in the influent and below the limit of quantification (5 ng/L) in the effluent, a >87% elimination (24hr composite samples). (1)

Using a structure estimation method based on molecular connectivity indices(1), the Koc of penciclovir can be estimated to be 10(SRC). According to a classification scheme(2), this estimated Koc value suggests that penciclovir is expected to have very high 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).

/SIGNS AND SYMPTOMS/ Since penciclovir is poorly absorbed following oral administration, adverse reactions related to penciclovir ingestion are unlikely. There is no information on overdose.

/GENOTOXICITY/ ...Penciclovir did not cause an increase in unscheduled DNA repair in mammalian HeLa S3 cells (at up to 5,000 ug/mL).

/GENOTOXICITY/ An increase in clastogenic responses was seen with penciclovir in human lymphocytes incubated in vitro at doses >/=250 ug/mL.

/GENOTOXICITY/ In human lymphocytes, penciclovir caused chromosomal aberrations in the absence of metabolic activation at a concentration of 250 ug/mL.

Penciclovir's production and administration as an antiviral(1) may result in its release to the environment through various waste streams(SRC). The administration of famciclovir is also a source of penciclovir, since pensisclovir is a human metabolite of famciclovir(2).

AEROBIC: Penciclovir was biodegraded in activated sludge, with a half-life 3.4 hrs and first-order rate constants in relation to the amount of suspended solids of 7.6/day. The main transformation pathway was the oxidation of one of the primary hydroxyl groups to the respective carboxylic moiety(1). There are eight unspecified products, one of which was shown to result in inactivation of enzymes and mutagensis in the human body(2).

An estimated BCF of 3 was calculated in fish for penciclovir(SRC), using an estimated log Kow of -1.14(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for penciclovir is estimated as 9.5X10-32 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that penciclovir is expected to be essentially nonvolatile from water and moist soil surfaces(2). Penciclovir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.0X10-17 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Two-year carcinogenicity studies were conducted with famciclovir (the oral prodrug of penciclovir) in rats and mice. An increase in the incidence of mammary adenocarcinoma (a common tumor in female rats of the strain used) was seen in female rats receiving 600 mg/kg/day (approximately 395 times the maximum theoretical human exposure to penciclovir following application of the topical product, based on area under the plasma concentration curve comparisons [24 hr. AUC]). No increases in tumor incidence were seen among male rats treated at doses up to 240 mg/kg/day (approximately 190 times the maximum theoretical human AUC for penciclovir), or in male and female mice at doses up to 600 mg/kg/day (approximately 100 times the maximum theoretical human AUC for penciclovir).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Testicular toxicity was observed in multiple animal species (rats and dogs) following repeated intravenous administration of penciclovir (160 mg/kg/day and 100 mg/kg/day, respectively, approximately 1155 and 3255 times the maximum theoretical human AUC). Testicular changes seen in both species included atrophy of the seminiferous tubules and reductions in epididymal sperm counts and/or an increased incidence of sperm with abnormal morphology or reduced motility. Adverse testicular effects were related to an increasing dose or duration of exposure to penciclovir... No adverse testicular or reproductive effects (fertility and reproductive function) were observed in rats after 10 to 13 weeks dosing at 80 mg/kg/day, or testicular effects in dogs after 13 weeks dosing at 30 mg/kg/day (575 and 845 times the maximum theoretical human AUC, respectively).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Intravenously administered penciclovir had no effect on fertility or reproductive performance in female rats at doses of up to 80 mg/kg/day (260 times the maximum human dose [BSA]).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No adverse effects on the course and outcome of pregnancy or on fetal development were noted in rats and rabbits following the intravenous administration of penciclovir at doses of 80 and 60 mg/kg/day, respectively (estimated human equivalent doses of 13 and 18 mg/kg/day for the rat and rabbit, respectively, based on body surface area conversion; the body surface area doses being 260 and 35 times the maximum recommended dose following topical application of the penciclovir cream).

For more Non-Human Toxicity Excerpts (Complete) data for Penciclovir (13 total), please visit the HSDB record page.

Penciclovir is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Penciclovir contains chromophores that absorb at wavelengths >290 nm(1) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Occupational exposure to penciclovir may occur through inhalation and dermal contact with this compound at workplaces where penciclovir is produced or used. Exposure to penciclovir among the general population may be limited to those administered the drug. (SRC)

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

D06BB06

J - Antiinfectives for systemic use

D - Dermatologicals

QJ - Antiinfectives for systemic use

QD - Dermatologicals

Penciclovir is the active metabolite of the oral product famciclovir. The more favorable results observed with topical penciclovir versus topical acyclovir for the treatment of herpes labialis may be due to the longer intracellular half-life of penciclovir in HSV-infected cells. The activated drug inhibits the viral DNA polymerase. This impairs the ability of the virus to replicate within the cell.

Penciclovir has <i>in vitro</i> activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). In cells infected with HSV-1 or HSV-2, viral thymidine kinase phosphorylates penciclovir to a monophosphate form. The monophosphate form of the drug is then converted to penciclovir triphosphate by cellular kinases. The intracellular triphosphate of penciclovir is retained <i>in vitro</i> inside HSV-infected cells for 10-20 hours, compared with 0.7-1 hour for acyclovir. <i>in vitro</i> studies show that penciclovir triphosphate selectively inhibits viral DNA polymerase by competing with deoxyguanosine triphosphate. Inhibition of DNA synthesis of virus-infected cells inhibits viral replication. In cells not infected with HSV, DNA synthesis is unaltered. Resistant mutants of HSV can occur from qualitative changes in viral thymidine kinase or DNA polymerase. The most commonly encountered acyclovir-resistant mutants that are deficient in viral thymidine kinase are also resistant to penciclovir.

Penciclovir is converted to the pharmacologically active triphosphate metabolite, which has in vitro and in vivo inhibitory activity against various Herpes viridae, including herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), and Epstein-Barr virus (EBV). The drug exhibits only limited activity in vitro against cytomegalovirus (CMV). ... Penciclovir triphosphate exerts its antiviral effect on HSV and VZV by interfering with DNA synthesis and inhibiting viral replication. The inhibitory activity of penciclovir triphosphate is highly selective because of its affinity for the enzyme thymidine kinase encoded by HSV and VZV. Virus-encoded thymidine kinase converts penciclovir into penciclovir monophosphate, a nucleotide analog. The monophosphate is further converted to the diphosphate via cellular kinase and then to the triphosphate via other cellular enzymes.

In vitro, penciclovir triphosphate stops replication of herpes viral DNA by competing with deoxyguanosine triphosphate for viral DNA polymerase and inhibiting viral DNA chain elongation.

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.

2 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 ... pharmacokinetics of intravenously administered penciclovir (BRL 39,123A), a novel anti-herpes agent, were investigated in 15 healthy male subjects. A mean terminal-phase half-life of 2.0 hr /was reported/.

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

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.

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.

359HUE8FJC

PENCICLOVIR

Mechanisms of Action [MoA] - DNA Polymerase Inhibitors

Established Pharmacologic Class [EPC] - Herpesvirus Nucleoside Analog DNA Polymerase Inhibitor

Nucleoside Analog [EXT]

Penciclovir is a Herpesvirus Nucleoside Analog DNA Polymerase Inhibitor. The mechanism of action of penciclovir is as a DNA Polymerase Inhibitor.

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.

Measurable penciclovir concentrations were not detected in plasma or urine of healthy male volunteers (n= 12) following single or repeat application of the 1% cream at a dose of 180 mg penciclovir daily.

Measurable penciclovir concentrations were not detected in plasma or urine of healthy male volunteers (n=12) following single or repeat application of the 1% cream at a dose of 180 mg penciclovir daily (approximately 67 times the estimated usual clinical dose).

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.

The ... pharmacokinetics of intravenously administered penciclovir (BRL 39,123A), a novel anti-herpes agent, were investigated in 15 healthy male subjects. The volunteers were divided into three groups, receiving either 10, 15 or 20 mg/kg penciclovir by a 60 min constant-rate infusion. Blood samples were taken sequentially up to 48 hr after the start of the infusion and urine collections made at appropriate intervals up to 72 hr. After a simple solid phase extraction, concentrations of penciclovir in plasma and urine were determined using HPLC with U.V. detection. Mean values of Cmax, corresponding usually with the end of infusion, and of AUC appeared to increase proportionately with dose. Furthermore, there was no evidence that dose significantly affected any individual pharmacokinetic parameter. Penciclovir was distributed into tissues with an overall mean volume of distribution of approximately 1.5 L.kg-1, i.e. approximately double that of body water. It was rapidly eliminated, with a mean total plasma clearance of 39.3 L.hr-1, and a mean terminal-phase half-life of 2.0 hr. The majority of the dose, approximately 70%, was excreted unchanged in the urine. Mean renal clearance of BRL 39,123 was 28.1 L.hr-1, which exceeds normal glomerular filtration rate and approaches renal plasma flow.

Following the oral administration of a single 500 mg dose of radiolabeled famciclovir to three healthy male volunteers, 73% and 27% of administered radioactivity were recovered in urine and feces over 72 hours, respectively. Penciclovir accounted for 82% and 6-deoxy penciclovir accounted for 7% of the radioactivity excreted in the urine. Approximately 60% of the administered radiolabeled dose was collected in urine in the first 6 hours.

For more Absorption, Distribution and Excretion (Complete) data for Penciclovir (15 total), please visit the HSDB record page.

Viral DNA polymerase inhibitor

MEDICATION

THERAPEUTIC CATEGORY: Antiviral

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

Denavir (penciclovir) cream 1% contains penciclovir, an antiviral agent active against herpes viruses. Denavir is available for topical administration as a 1% white cream. Each gram of Denavir contains 10 mg of penciclovir and the following inactive ingredients: cetomacrogol 1000 BP, cetostearyl alcohol, mineral oil, propylene glycol, purified water and white petrolatum.

Vectavir