SITAVIG Delayed-release tablet Ref.[28039] Active ingredients: Aciclovir

Absorption and Distribution

Salivary

The pharmacokinetic parameters of acyclovir after a single dose of SITAVIG in the saliva and plasma of healthy volunteers are provided in Table 2.

Table 2. Pharmacokinetic (PK) Parameters of Acyclovir in Saliva and Plasma Following Application of a Single SITAVIG 50 mg Tablet in Healthy Volunteers (N=12):

^* Acyclovir plasma concentrations had a delayed appearance (undetectable at 5 hours) and were below the concentrations required for antiviral activity (range: 17.5 to 55.3 nanogram per mL).
^† Median (Min – Max).

In the Phase 3 study, the levels of acyclovir in saliva were measured within 24 hours of SITAVIG application in 56 patients with recurrent herpes labialis (mean value 88.1 micrograms per mL) and were within the range of those observed in the PK study in healthy volunteers.

In healthy volunteers, the median duration of buccal adhesion was 14 hours following application of a single SITAVIG 50 mg tablet.

Plasma

Plasma concentrations of acyclovir were measured in 12 healthy volunteers after a singledose application of SITAVIG 50 mg buccal tablet. Acyclovir concentrations had a delayed appearance (undetectable at 5 hours) and were below the concentrations required for antiviral activity (range: 17.5 to 55.3 nanogram per mL).

Metabolism and Excretion

Acyclovir is metabolized to 9-[(carboxymethoxy)methyl]guanine (CMMG) and 8-hydroxy-acyclovir (8-OH-ACV) by oxidation and hydroxylation, and is primarily excreted unchanged by the kidneys.

Food Effect

There was no formal food effect study conducted with SITAVIG; however, in clinical studies patients were allowed to eat and drink while taking SITAVIG.

Mechanism of Action

Acyclovir is a synthetic purine deoxynucleoside analogue with inhibitory activity against herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) DNA polymerases. It inhibits HSV-1 and HSV-2 replication in cell culture and in vivo.

The inhibitory activity of acyclovir is selective due to its affinity for the enzyme thymidine kinase encoded by HSV. This viral enzyme converts acyclovir into acyclovir monophosphate, a deoxynucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In biochemical assays, acyclovir triphosphate inhibits replication of α-herpes viral DNA. This inhibition is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation into and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase.

Antiviral activity

The quantitative relationship between the susceptibility of herpes viruses to antivirals in cell culture and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (EC₅₀), vary greatly depending upon a number of factors. Using plaque-reduction assays on Vero cells, the EC₅₀ values of acyclovir against herpes virus isolates ranged from 0.09 to 60 µM (0.02 to 13.5 µg/mL) for HSV-1 and from 0.04 to 44 µM (0.01 to 9.9 μg/mL) for HSV-2.

Resistance

In Cell Culture

Acyclovir-resistant HSV-1 and HSV-2 strains were isolated in cell culture. Acyclovirresistant HSV resulted from mutations in the viral thymidine kinase (TK; pUL23) and DNA polymerase (POL; pUL30) genes. Frameshifts were commonly isolated and result in premature truncation of the HSV TK product with consequent decreased susceptibility to acyclovir. Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered). In cell culture the following resistance-associated substitutions in TK of HSV-1 and HSV-2 were observed (Table 3).

Table 3. Summary of Acyclovir (ACV) Resistance-associated Amino Acid Substitutions in Cell Culture:

In HSV-Infected Patients

Clinical HSV-1 and HSV-2 isolates obtained from patients who failed treatment for their α-herpesvirus infections were evaluated for genotypic changes in the TK and POL genes and for phenotypic resistance to acyclovir (Table 4). HSV isolates with frameshift mutations and resistance-associated substitutions in TK and POL were identified. The listing of substitutions in the HSV TK and POL leading to decreased susceptibility to acyclovir is not all inclusive and additional changes will likely be identified in HSV variants isolated from patients who fail acyclovir-containing regimens. The possibility of viral resistance to acyclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy.

Table 4. Summary of ACV Resistance-associated Amino Acid Substitutions Observed in Treated Patients:

Note: Many additional pathways to acyclovir resistance likely exist.

Cross-resistance

Cross-resistance has been observed among HSV isolates carrying frameshift mutations and resistance-associated substitutions, which confer reduced susceptibility to penciclovir (PCV), famciclovir (FCV), and foscarnet (FOS) [Table 5].

Table 5. Summary of Amino Acid Substitutions Conferring Cross-Resistance to PCV, FCV or FOS:

Systemic exposure following buccal administration of acyclovir is minimal. Results from previous studies of carcinogenesis, mutagenesis and fertility for acyclovir are not included in the full prescribing information for SITAVIG due to the minimal exposure that results from buccal administration. Information on these studies following systemic exposure is available in the full prescribing information for acyclovir products approved for oral and parenteral administration.

Study in Patients with Recurrent Herpes Labialis (cold sores)

The efficacy and safety of SITAVIG was evaluated in a randomized, double-blind, placebo-controlled, patient-initiated, multicenter trial comparing SITAVIG 50 mg administered as a single dose (n=378) to placebo (n=397) in patients with recurrent herpes labialis (cold sores). A total of 376 SITAVIG treated patients and 395 placebo treated patients were included in the Intent to Treat (ITT) efficacy population defined as all patients who took study treatment and who had a start date and time of treatment initiation recorded. The mean age was 41.0 years (range: 18-80 years) and the majority of patients were female (68.6%), and Caucasian (94.9%). All patients had at least 4 herpes episodes in the previous year of whom 68.4% had ≥5 episodes. Patients were instructed to initiate treatment within one hour after the onset of prodromal symptoms and before the appearance of any signs of herpes labialis lesions by applying the tablet to the buccal mucosa in the canine fossa. If the tablet was detached within the first 6 hours, subjects were instructed to reapply a tablet.

The mean and median durations of the recurrent herpes labialis episode (ITT population, n=771) were approximately half a day shorter in patients treated with SITAVIG compared with patients treated with placebo.