RiteMED Aciclovir

Aciclovir.

RiteMED Aciclovir 400 mg is a light green, round tablet, 7/16" in diameter, bisected on one side and plain on the other side.
RiteMED Aciclovir 800 mg is a light green, elliptical-shaped tablet, scored on one side and plain on the other side.
Each tablet contains: Aciclovir 400 mg or 800 mg.

Pharmacology: Pharmacodynamics: Mechanism of Action: Aciclovir is a synthetic purine nucleoside analog with a highly selective antiviral activity, dependent upon intracellular activation of the drug to aciclovir triphosphate. Aciclovir is converted to aciclovir monophosphate principally via virus-coded thymidine kinase (TK). The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes (e.g., phosphoglycerate kinase, pyruvate kinase, phosphoenolpyruvate carboxykinase).
Aciclovir also is apparently converted to aciclovir triphosphate by other mechanisms since the drug has some activity against some viruses that do not code for viral TK (e.g., Epstein-Barr virus and cytomegalovirus). Aciclovir triphosphate is formed in virally infected cells in amounts of 40 to 100 times greater than in normal uninfected cells. Aciclovir triphosphate functions as a substrate for and preferential inhibitor of herpesvirus DNA polymerases to a much greater extent than cellular DNA polymerase and thus inhibits viral DNA replication much more effectively than cellular DNA replication. Aciclovir triphosphate is incorporated into the growing viral DNA primer template, inactivates the polymerase, and terminates biosynthesis of the DNA chain.
Antimicrobial Spectrum of Activity: After intracellular conversion of aciclovir to a pharmacologically active triphosphate metabolite, aciclovir is active in vitro against various Herpesviridae including: Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2); Varicella-zoster virus (VSV); Epstein-Barr virus; Herpesvirus simiae (B virus); Cytomegalovirus (CMV).
Aciclovir is much less active against CMV than against many other Herpesviridae, This may occur because CMV does not produce TK and therefore is less able than other viruses to phosphorylate aciclovir to its triphosphate derivative.
Aciclovir is inactive against vaccinia virus, adenovirus type 5, and several RNA viruses.
Pharmacokinetics: Absorption of aciclovir from the gastrointestinal tract is variable and incomplete. Aciclovir is only partially absorbed from the gastrointestinal (GI) tract. It is estimated that 10% to 30% of an oral dose of the drug is absorbed. Some data suggest that GI absorption of aciclovir may be saturable; in a crossover study in which oral aciclovir was administered to healthy adults as 200 mg capsules, 400 mg tablets, or 800 mg tablets 6 times daily, the extent of absorption decreased with increasing dose, resulting in bioavailabilities of 20, 15, or 10%, respectively. In addition, steady-state peak and trough plasma aciclovir levels were not dose proportional over the oral dosage range of 200 to 800 mg 6 times daily, averaging 0.83 and 0.46, 1.21 and 0.63, or 1.61 and 0.83 μg/mL for the 200-, 400-, or 800-mg dosing regimens, respectively.
After oral administration, the peak plasma concentrations of aciclovir usually occur within 1.5 to 2.5 hours.
The mean steady-state peak and trough plasma concentrations of aciclovir in immunocompromised patients were 0.49-0.56 and 0.29-0.31 μg/mL, respectively, after oral administration of aciclovir 200 mg every 4 hours, 1.2 and 0.62 μg/mL, respectively, after oral administration of aciclovir 400 mg every 4 hours, and 2.8 and 1.8 μg/mL, respectively, after oral administration of aciclovir 800 mg (as capsules) every 4 hours.
Food does not appear to affect aciclovir absorption.
Aciclovir is widely distributed into body tissues and fluids including the brain, kidney, saliva, lung, liver, muscle, spleen, uterus, vaginal mucosa and secretions, CSF, and herpetic vesicular fluid. The drug is also distributed into semen, achieving concentrations about 1.4 and 4 times those in plasma during chronic oral therapy at dosages of 400 mg and 1 g daily, respectively.
The apparent volume of distribution of aciclovir is 32.4-61.8 L/1.73 m² in adults and 28.8, 31.6, 42, or 51.2-53.6 L/1.73 m² in neonates up to 3 months of age, children 1 to 2 years, 2 to 7 years or 7 to 12 years of age, respectively.
About 9% to 33% of aciclovir is bound to plasma proteins in vitro at plasma concentrations of 0.41 to 5.2 μg/mL. Drug interactions involving binding site displacement is not anticipated.
Aciclovir crosses the placenta. Limited data indicate that the drug is distributed into milk, generally in concentrations greater than concurrent maternal plasma concentrations, possibly via an active transport mechanism.
Aciclovir is metabolized partially to 9-carboxymethoxymethylguanine (CMMG) and minimally to 8-hydroxy-9-(2-hydroxyethoxymethyl)guanine.
Plasma concentrations of aciclovir appear to decline in a biphasic manner. In adults with normal renal function, the mean terminal plasma half life is 2.1 to 3.5 hours.
In patients with chronic renal impairment the mean terminal half life was 19.5 hours. The mean aciclovir half-life during hemodialysis was 5.4 to 5.7 hours, Plasma aciclovir levels dropped at about 60% during dialysis.
In neonates, the half life of aciclovir depends principally on the maturity of renal mechanisms for excretion as determined by gestational age, chronologic age, and weight. In children older than 1 year of age, half life of the drug appears to be similar to that of adults. The mean terminal half life was 3.8 to 4.1,1.9, 2.2 to 2.8, or 3.6 hours in neonates up to 3 months of age, children 1 to 2 years, 2 to 12 years, or 12 to 17 years of age, respectively.
Aciclovir undergoes urinary excretion via glomerular filtration and tubular secretion.
Total body clearance of aciclovir is reported to be 327, 248, 190, or 29 mL/minute per 1.73 m² in patients with creatinine clearances of greater than 80, 50 to 80, 15 to 50, or 0 mL/minute per 1.73 m², respectively.
Aciclovir is removed by hemodialysis.

For the treatment of herpes simplex virus infections of the skin and mucous membranes including initial and recurrent genital herpes.
For the suppression (prevention of recurrences) of recurrent herpes simplex infections in immune-competent patients.
For the prophylaxis of herpes simplex infections in immune-compromised patients.
For the treatment of varicella infections (chickenpox) and acute herpes zoster (shingles); for the reduction of duration and severity of acute symptoms and rash, for the reduction of all zoster-associated pain (post-herpetic neuralgia).
For the management of certain severely immunocompromised patients, namely those with advanced HIV disease (CD4+ counts <200/mm³, including patients with AIDS or severe ARC) or following bone marrow transplantation.

The dose and treatment duration depends on the type and severity of the infection.
The dosage of aciclovir should be reduced in patients with impaired renal function.
Adequate fluid intake is recommended to prevent acute renal failure or precipitation of aciclovir crystals in the renal tubules.
Therapy should be initiated as soon as possible after a diagnosis of chickenpox or herpes zoster, or at the first sign or symptom of an outbreak of genital herpes.
Usual Adult Dose: See Table 1.

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Usual Dose in Children: See Table 2.

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Dosing may be more accurately calculated as 20 mg/kg body weight (not to exceed 800 mg) aciclovir every 6 hours.
Recommended Oral Dose in Patients with Impaired Renal Function: See Table 3.

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Overdoses involving ingestion of up to 20 g have been reported. Clinical features of aciclovir overdose include agitation, coma, seizures, and lethargy. Precipitation of acyclovir crystals in the renal tubules which may cause renal dysfunction leading to renal failure and anuria have been observed when renal concentrations of aciclovir exceed 2.5 mg/mL.
Management: Patients should be observed closely for signs of toxicity. Hemodialysis significantly enhances the removal of aciclovir from the blood and may, therefore, be considered a management option in the event of symptomatic overdose.

Known hypersensitivity to aciclovir or valaciclovir, or to any component of the product.

Use with caution in patients with renal impairment and elderly patients [see Use in Patients with Renal Impairment and Use in the Elderly as follows].
Caution should be exercised when administering aciclovir to patients receiving potentially nephrotoxic agents since this may increase the risk of renal dysfunction and/or the risk of reversible central nervous system symptoms such as those that have been reported in patients treated with intravenous aciclovir [see Adverse Reactions].
Patients with genital herpes receiving aciclovir therapy should be advised that the drug is not a cure for genital herpes and therefore, should avoid sexual contact while visible lesions are present since there is a risk of transmitting the infection to their sexual partner.
Care should be taken to maintain adequate hydration in patients receiving high doses of aciclovir.
Effects on Ability to Drive and Use Machines: None reported.
Use in Patients with Renal Impairment: Aciclovir is eliminated by renal clearance; therefore the dose must be reduced in patients with renal impairment. Both elderly patients and patients with renal impairment are at increased risk of developing neurological side effects and should be closely monitored for evidence of these effects.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Mutagenic changes and chromosomal damage have occurred in vitro in human lymphocytes and mouse lymphoma cells at aciclovir concentrations at least 25 times greater than plasma concentrations achievable with usual dosage in humans. In other in vitro microbial and mammalian cell assays, no evidence of mutagenicity or inconclusive results were observed. Aciclovir was tested in 16 in vitro and in vivo genetic toxicity assays and was positive in 5 of these assays.
Evidence of mutagenicity or carcinogenicity in humans have not been reported.
Aciclovir did not impair fertility or reproduction in mice given 450 mg/kg/day orally or in rats 25 mg/kg/day subcutaneously (SC). However, at higher doses (50 mg/kg/day SC), implantation efficacy, but not litter size, was decreased. In peri- and post-natal studies in rats, higher doses also resulted in significant decrease in group mean numbers of corpora lutea, total implantation sites, and live fetuses.
No testicular abnormalities were seen in dogs given aciclovir 50 mg/kg/day IV for one month or aciclovir 60 mg/kg/day orally for one year. Testicular atrophy and aspermatogenesis were observed in rats and dogs at higher dose levels.
Use in Children: Safety and efficacy of oral aciclovir in children younger than 2 years old have not been established.
Use in the Elderly: Elderly patients are likely to have reduced renal function and therefore the need for dose reduction must be considered in this group of patients.

Pregnancy: (Pregnancy Category B) There are no adequate and well-controlled studies in pregnant women. The use of the drug during pregnancy should justify potential benefits to the women against potential risk to the fetus.
Lactation: Aciclovir has been detected in breast milk at concentrations ranging from 0.6 to 4.1 times the corresponding plasma levels. These levels would potentially expose infants to aciclovir dosages of up to 0.3 mg/kg/day. The drug should be used in caution in breastfeeding women.

General: fatigue, fever, headache, pain, peripheral edema.
Nervous System: Aggressive behavior, agitation, ataxia, coma, confusion, decreased consciousness, delirium, dizziness, dysarthria, encephalopathy, hallucinations, convulsions, malaise, obtundation, paresthesia, psychosis, seizures, somnolence, tremors.
Digestive System: Abdominal pain, diarrhea, gastrointestinal distress, nausea, vomiting.
Hematologic and Lymphatic: Anemia, leukocytoclastic vasculitis, leukopenia, lymphadenopathy, thrombocytopenia.
Hepatobiliary Tract and Pancreas: Elevated liver function tests, hepatitis, hyperbilirubinemia, jaundice, reversible rises in liver related enzymes.
Renal and urinary disorders: increases in blood urea and creatinine, acute renal failure, renal pain (may be associated with renal failure and crystalluria).
Musculoskeletal: Myalgia.
Skin: Alopecia, erythema multiforme, photosensitivity rash, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.
Special Senses: Visual abnormalities.
Respiratory: Dyspnea.
Accelerated diffuse hair loss (has been associated with a wide variety of disease processes and medicines, the relationship of the event to aciclovir therapy is uncertain).
Dermatologic/Hypersensitivity Reactions: Anaphylaxis, angioedema.
Other Adverse Effects: Hypotension, thirst.

See Table 4.

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Store at temperatures not exceeding 30°C.

Antivirals

J05AB01 - aciclovir ; Belongs to the class of nucleosides and nucleotides excluding reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.

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