Valaciclovir
Encyclopedia
Valaciclovir or valacyclovir (USAN
) is an antiviral drug
used in the management of herpes simplex
, herpes zoster
(shingles), and herpes B
. It is a prodrug
, being converted in vivo
to aciclovir
. It is marketed by GlaxoSmithKline
under the trade names Valtrex and Zelitrex. , valacyclovir is marketed in generic form in the United States by Ranbaxy Laboratories
.
L-valine
.
ified version of aciclovir
that has greater oral bioavailability (about 55%) than aciclovir (10–20%). It is converted by esterase
s to the active drug aciclovir, as well as the amino acid
valine
, via hepatic first-pass metabolism. Acyclovir is selectively converted into a monophosphate form by viral thymidine kinase
, which is far more effective (3000 times) in phosphorylation
than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into the active triphosphate form, aciclo-GTP, by cellular kinase
s. Aciclo-GTP is a very potent inhibitor of viral DNA polymerase
; it has approximately 100 times higher affinity to viral than cellular polymerase. Its monophosphate form also incorporates into the viral DNA, resulting in chain termination
. It has also been shown that the viral enzymes cannot remove aciclo-GMP from the chain, which results in inhibition of further activity of DNA polymerase. Aciclo-GTP is fairly rapidly metabolised within the cell, possibly by cellular phosphatase
s.
Activity is predominantly active against HSV, and to a lesser extent VZV. It is only of limited efficacy against EBV and CMV, however, valacyclovir has recently been shown to lower or eliminate the presence of the Epstein-Barr virus in subjects afflicted with acute mononucleosis, leading to a significant decrease in the severity of symptoms. It is inactive against latent viruses in nerve ganglia
.
To date, resistance to valaciclovir has not been clinically significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase; and mutations to viral thymidine kinase and/or DNA polymerase, altering substrate sensitivity.
, colloidal silicon dioxide, crospovidone, FD&C Blue No. 2 Lake, hypromellose
, magnesium stearate
, microcrystalline cellulose
, polyethylene glycol
, polysorbate 80
, povidone, and titanium dioxide
.
Valaciclovir is indicated for the treatment of HSV and VZV infections, including:
It has shown promise as a treatment for infectious mononucleosis
and is preventatively administered in suspected cases of Herpes B Virus
exposure.
s (≥1% of patients) associated with valaciclovir therapy are the same as for aciclovir
, its active metabolite, and include: nausea, vomiting, diarrhea and headache. Infrequent adverse effects (0.1–1% of patients) include: agitation, vertigo
, confusion, dizziness, edema
, arthralgia
, sore throat, constipation, abdominal pain, rash, weakness and/or renal impairment. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenia
, leukopenia
, tremor, ataxia
, encephalopathy
, psychotic symptoms, crystalluria
, anorexia
, fatigue, hepatitis
, Stevens–Johnson syndrome, toxic epidermal necrolysis
and/or anaphylaxis
.
United States Adopted Name
United States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association , the United States Pharmacopeial Convention , and the American Pharmacists...
) is an antiviral drug
Antiviral drug
Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses...
used in the management of herpes simplex
Herpes simplex
Herpes simplex is a viral disease caused by both Herpes simplex virus type 1 and type 2 . Infection with the herpes virus is categorized into one of several distinct disorders based on the site of infection. Oral herpes, the visible symptoms of which are colloquially called cold sores or fever...
, herpes zoster
Herpes zoster
Herpes zoster , commonly known as shingles and also known as zona, is a viral disease characterized by a painful skin rash with blisters in a limited area on one side of the body, often in a stripe...
(shingles), and herpes B
Herpes B Virus
Herpes Simian B virus is the endemic simplexvirus of macaque monkeys. B virus is an alphaherpesvirus, which consists of a subset of herpesviruses that travel within hosts using the peripheral nerves...
. It is a prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
, being converted in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
to aciclovir
Aciclovir
Aciclovir or acyclovir , chemical name acycloguanosine, abbreviated as ACV,is a guanosine analogue antiviral drug, marketed under trade names such as Cyclovir, Herpex, Acivir, Acivirax, Zovirax, and Zovir...
. It is marketed by GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
under the trade names Valtrex and Zelitrex. , valacyclovir is marketed in generic form in the United States by Ranbaxy Laboratories
Ranbaxy Laboratories
Ranbaxy Laboratories Limited is a pharmaceutical company that was incorporated in India in 1961. The company went public in 1973 and Japanese pharmaceutical company Daiichi Sankyo gained majority control in 2008...
.
Chemistry
Valaciclovir is prepared starting from the natural proteinogenic amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
L-valine
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
.
Mechanism of action
Valaciclovir is a prodrug, an esterEster
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
ified version of aciclovir
Aciclovir
Aciclovir or acyclovir , chemical name acycloguanosine, abbreviated as ACV,is a guanosine analogue antiviral drug, marketed under trade names such as Cyclovir, Herpex, Acivir, Acivirax, Zovirax, and Zovir...
that has greater oral bioavailability (about 55%) than aciclovir (10–20%). It is converted by esterase
Esterase
An esterase is a hydrolase enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis.A wide range of different esterases exist that differ in their substrate specificity, their protein structure, and their biological function.- EC classification/list...
s to the active drug aciclovir, as well as the amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
valine
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
, via hepatic first-pass metabolism. Acyclovir is selectively converted into a monophosphate form by viral thymidine kinase
Thymidine kinase
Thymidine kinase is an enzyme, a phosphotransferase : 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, . It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2...
, which is far more effective (3000 times) in phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into the active triphosphate form, aciclo-GTP, by cellular kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
s. Aciclo-GTP is a very potent inhibitor of viral DNA polymerase
DNA polymerase
A DNA polymerase is an enzyme that helps catalyze in the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best known for their feedback role in DNA replication, in which the polymerase "reads" an intact DNA strand as a template and uses it to synthesize the new strand....
; it has approximately 100 times higher affinity to viral than cellular polymerase. Its monophosphate form also incorporates into the viral DNA, resulting in chain termination
Protein biosynthesis
Protein biosynthesis is the process in which cells build or manufacture proteins. The term is sometimes used to refer only to protein translation but more often it refers to a multi-step process, beginning with amino acid synthesis and transcription of nuclear DNA into messenger RNA, which is then...
. It has also been shown that the viral enzymes cannot remove aciclo-GMP from the chain, which results in inhibition of further activity of DNA polymerase. Aciclo-GTP is fairly rapidly metabolised within the cell, possibly by cellular phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
s.
Microbiology
Aciclovir, the active metabolite of valaciclovir, is active against most species in the herpesvirus family. In descending order of activity:- Herpes simplex virusHerpes simplex virusHerpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious...
type I (HSV-1) - Herpes simplex virus type II (HSV-2)
- Varicella zoster virusVaricella zoster virusVaricella zoster virus is one of eight herpes viruses known to infect humans . It commonly causes chicken-pox in children and Herpes zoster in adults and rarely in children.-Nomenclature:...
(VZV) - Epstein-Barr virusEpstein-Barr virusThe Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis...
(EBV) - CytomegalovirusCytomegalovirusCytomegalovirus is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV or human herpesvirus-5 , and is the most studied of all cytomegaloviruses...
(CMV)
Activity is predominantly active against HSV, and to a lesser extent VZV. It is only of limited efficacy against EBV and CMV, however, valacyclovir has recently been shown to lower or eliminate the presence of the Epstein-Barr virus in subjects afflicted with acute mononucleosis, leading to a significant decrease in the severity of symptoms. It is inactive against latent viruses in nerve ganglia
Ganglion
In anatomy, a ganglion is a biological tissue mass, most commonly a mass of nerve cell bodies. Cells found in a ganglion are called ganglion cells, though this term is also sometimes used to refer specifically to retinal ganglion cells....
.
To date, resistance to valaciclovir has not been clinically significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase; and mutations to viral thymidine kinase and/or DNA polymerase, altering substrate sensitivity.
- Also used for Herpes B virusHerpes B VirusHerpes Simian B virus is the endemic simplexvirus of macaque monkeys. B virus is an alphaherpesvirus, which consists of a subset of herpesviruses that travel within hosts using the peripheral nerves...
post-exposure prophylaxis.
Ingredients
Valtrex is offered in 500 mg and 1 gram tablets, the active ingredient being valacyclovir hydrochloride, with the inactive ingredients carnauba waxCarnauba wax
Carnauba , also called Brazil wax and palm wax, is a wax of the leaves of the palm Copernicia prunifera, a plant native to and grown only in the northeastern Brazilian states of Piauí, Ceará, and Rio Grande do Norte. It is known as "queen of waxes" and usually comes in the form of hard yellow-brown...
, colloidal silicon dioxide, crospovidone, FD&C Blue No. 2 Lake, hypromellose
Hypromellose
Hypromellose , short for hydroxypropyl methylcellulose , is a semisynthetic, inert, viscoelastic polymer used as an ophthalmic lubricant, as well as an excipient and controlled-delivery component in oral medicaments, found in a variety of commercial products.As a food additive, hypromellose is an...
, magnesium stearate
Magnesium stearate
Magnesium stearate, also called octadecanoic acid, magnesium salt, is a white substance which is solid at room temperature. It has the chemical formula . It is a salt containing two equivalents of stearate and one magnesium cation...
, microcrystalline cellulose
Microcrystalline cellulose
Microcrystalline cellulose is a term for refined wood pulp and is used as a texturizer, an anti-caking agent, a fat substitute, an emulsifier, an extender, and a bulking agent in food production. The most common form is used in vitamin supplements or tablets...
, polyethylene glycol
Polyethylene glycol
Polyethylene glycol is a polyether compound with many applications from industrial manufacturing to medicine. It has also been known as polyethylene oxide or polyoxyethylene , depending on its molecular weight, and under the tradename Carbowax.-Available forms:PEG, PEO, or POE refers to an...
, polysorbate 80
Polysorbate 80
Polysorbate 80 is a nonionic surfactant and emulsifier derived from polyethoxylated sorbitan and oleic acid, and is often used in foods. Polysorbate 80 is a viscous, water-soluble yellow liquid...
, povidone, and titanium dioxide
Titanium dioxide
Titanium dioxide, also known as titanium oxide or titania, is the naturally occurring oxide of titanium, chemical formula . When used as a pigment, it is called titanium white, Pigment White 6, or CI 77891. Generally it comes in two different forms, rutile and anatase. It has a wide range of...
.
Indications
- Oral and Genital herpes simplexHerpes simplexHerpes simplex is a viral disease caused by both Herpes simplex virus type 1 and type 2 . Infection with the herpes virus is categorized into one of several distinct disorders based on the site of infection. Oral herpes, the visible symptoms of which are colloquially called cold sores or fever...
(treatment and prophylaxis) - Reduction of HSV transmission from people with recurrent infection to uninfected individuals
- Herpes zosterHerpes zosterHerpes zoster , commonly known as shingles and also known as zona, is a viral disease characterized by a painful skin rash with blisters in a limited area on one side of the body, often in a stripe...
(shingles) - Prevention of CMVCytomegalovirusCytomegalovirus is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV or human herpesvirus-5 , and is the most studied of all cytomegaloviruses...
disease following organ transplantation - Prophylaxis against herpesvirus' in immunocompromised patients (such as patients undergoing cancer chemotherapy)
It has shown promise as a treatment for infectious mononucleosis
Infectious mononucleosis
Infectious mononucleosis is an infectious, widespread viral...
and is preventatively administered in suspected cases of Herpes B Virus
Herpes B Virus
Herpes Simian B virus is the endemic simplexvirus of macaque monkeys. B virus is an alphaherpesvirus, which consists of a subset of herpesviruses that travel within hosts using the peripheral nerves...
exposure.
Adverse effects
Common adverse drug reactionAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s (≥1% of patients) associated with valaciclovir therapy are the same as for aciclovir
Aciclovir
Aciclovir or acyclovir , chemical name acycloguanosine, abbreviated as ACV,is a guanosine analogue antiviral drug, marketed under trade names such as Cyclovir, Herpex, Acivir, Acivirax, Zovirax, and Zovir...
, its active metabolite, and include: nausea, vomiting, diarrhea and headache. Infrequent adverse effects (0.1–1% of patients) include: agitation, vertigo
Vertigo (medical)
Vertigo is a type of dizziness, where there is a feeling of motion when one is stationary. The symptoms are due to a dysfunction of the vestibular system in the inner ear...
, confusion, dizziness, edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
, arthralgia
Arthralgia
Arthralgia literally means joint pain; it is a symptom of injury, infection, illnesses or an allergic reaction to medication....
, sore throat, constipation, abdominal pain, rash, weakness and/or renal impairment. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
, leukopenia
Leukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
, tremor, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, encephalopathy
Encephalopathy
Encephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...
, psychotic symptoms, crystalluria
Crystalluria
Crystalluria refers to crystals found in the urine when performing a urine test. Crystalluria is considered as one of the side effects of sulphonamides.-Clinical significance:It can be an indication of urolithiasis.It can be associated with cysteinuria....
, anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
, fatigue, hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
, Stevens–Johnson syndrome, toxic epidermal necrolysis
Toxic epidermal necrolysis
Toxic epidermal necrolysis is a rare, life-threatening dermatological condition that is usually induced by a reaction to medications...
and/or anaphylaxis
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
.