Cipher Pharmaceuticals

 (ACYCLOVIR) 50mg buccal tablets for the treatment of herpes labialis caused by the HSV-1 virus.

 is said to represent a treatment breakthrough in the herpes labialis category because of its  vehicle and delivery system. It uses a proprietary Lauriad

 delivery technology that consists of a tablet that sticks to the gum above the canine tooth on the side of the lip that is infected with a cold sore. 8 mm in diameter and 2.2 – 2.6 mm in thickness, this white-to-slightly-yellow tablet is said to be tasteless and odorless. It reportedly dissolves gradually to provide a sustained release of medicine. Dentists now have the option to help patients with more than their teeth.

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	A Phase III study demonstrated that a single low dose of Sitavig improved all clinical parameters of labial herpes; in particular, it increased the percentage of blocked lesions and delayed by about 105 days the recurrence of the next herpes episode. It is well

known that the standard of care, systemic antiviral drugs, are typically prescribed at high doses in the treatment of labial herpes (HL). However, Sitavig is designed to be an innovative drug delivery system that provides a high sustained-release local exposure of acyclovir in oral mucosa, supporting its evaluation as single low dose in the treatment of HL.

	“We are very excited to inform the dental community about Sitavig,” said Charles Jenkins, vice president of marketing at Cipher. “Ninety percent of Americans have been exposed to HSV by the time they are 50, but there hasn’t been a real breakthrough product to address this problem in many years. Sitavig is revolutionary because unlike systemic drugs and topical prescription creams, Sitavig requires application to the gum only once

	"This is a very dynamic and extremely proactive approach to a cold sore recurrence, and studies show that when Sitavig is applied at first signs of episodic prodromal symptoms, it can often actually abort the episode entirely. What makes Sitavig extremely user-friendly

is that a patient can eat and drink normally once the tablet adheres to the gum, which is usually within a few minutes.”

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	In a multi-center, double blind, placebo-controlled, patient-initiated trial, 775 patients with recurrent HL were randomly assigned to either a single application of Sitavig 50 mg or matching placebo as soon as prodromal symptoms occurred. The primary endpoint was the time to healing (TTH) of primary vesicular lesion (mITT population). Other endpoints included incidence of blocked episodes, duration of herpes episodes and incidence and time to next recurrence evaluated during a nine-month follow-up (ITT population).

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	With Sitavig 50 mg, the incidence of blocked herpes episodes was increased by a relative rate of 24.2 percent (34.9 percent vs. 28.1 percent; p=0.042), and the median duration of herpes episodes was reduced (5.6 days vs 6.4 days, p=0.003). During the nine-month follow up, recurrence of herpes lesions was less frequent (64.2 percent vs. 73.6 percent; p=0.027) and delayed (median 205 days vs 165 days, p=0.041) in the Sitavig 50mg group. Patients were satisfied by the treatment, and adverse events were similar to placebo.

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	Nucleoside analogues acyclovir and its prodrug valacyclovir remain the reference treatment for recurrent herpes infection. After cellular intake and conversion to acyclovir triphosphate by cellular enzymes, acyclovir selectively inhibits HSV viral DNA replication. Its half-life inside the infected cell is short, about one hour. Systemic acyclovir concentrations are over the 50 percent inhibitory concentration (IC

: 22.5 ng/ml); however, they are low, delayed and transient in the deep layers of mucosa and skin and thus poorly target the mucosal reservoir of HSV-1.

	In this trial, a single administration of a low dose of acyclovir using Sitavig 50 mg is said to have resultedresulted in the prevention of some vesicular lesions. Consistently, the number and percentage of patients with “non-primary” (outside the lips) vesicular lesions were significantly lower in the Sitavig 50 mg (10.4 percent) than in the placebo group (15.7 percent). The prevention of vesicular lesions, whether primary or secondary, is likely related to the rapid and very high acyclovir concentrations in saliva and labial mucosa induced by Sitavig. These high acyclovir concentrations in saliva and labial mucosa may result in rapid and high acyclovir concentrations in the basal layer of mucosa where HSV-1 replicates.

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	The study showed that Sitavig 50 mg reduces by 22.7 percent the risk of experiencing a recurrence in a nine-month follow up. In addition, the next recurrence of a herpes episode was delayed by a mean of 105 days in patients whose herpes lesions recurred. Oral HSV-1 shedding is frequent, and shedding episodes of several days duration are caused by short overlapping reactivations of HSV-1. It could be speculated that rapid, high and sustained acyclovir concentrations in saliva and labial mucosa, at the site of the viral reactivation and at the moment of maximal replication, may reduce the mucosal viral reservoir and thus delay the recurrence of the next herpes episodes. However, these data on incidence and delay of the next recurrence need further confirmation as they were obtained on a subset of patients. If confirmed, these data may also reduce the inter-individual transmission of HSV-1 through a decrease in the oral shedding of patients with frequent HL episodes.

50 mg was acceptable. Application site irritation was slight and infrequent with this muco-adhesive buccal tablet (<1 percent). Acyclovir cream is known to induce local adverse effects and particularly burning, peeling and tingling. This has not been reported in the Sitavig 50 mg trial. Likewise, the incidence of headache was much lower than the incidence reported with systemic agents.

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	In summary, Sitavig 50 mg provided clinical benefit to patients independently of the lesion stage. It reduced the occurrence of vesicular lesions, primary or non-primary, which is the most important burden of the disease. It also prevented and delayed the recurrence of the next herpes episode. Therefore, Sitavig 50 mg buccal tablet is said to be an attractive alternative to systemic antiviral treatment for patients with recurrent HL when applied within one  hour after the occurrence of prodromal symptoms.

	Sitavig is indicated for the treatment of recurrent herpes labialis (cold sores) in immunocompetent adults. It should not be used in patients with known hypersensitivity to acyclovir, milk protein concentrate or other components of the product.

	Sitavig has not been studied in pregnant women or in immunocompromised patients, and no interaction studies have been performed. Its safety and efficacy have not been established in pediatric patients. Sitavig is a Pregnancy Category B product; therefore it should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. It is not known if Sitavig is excreted in breast milk; however, systemic absorption is minimal. In a controlled clinical trial, Sitavig’s most common side effects (greater than or equal to 1 percent) were: headache (3 percent), dizziness (1 percent), lethargy (1 percent), gingival pain (1 percent), aphthous stomatitis (1 percent), application-site pain (1 percent), application-site irritation (1 percent), erythema (1 percent) and rash (1 percent). In the same trial these side effects ranged from 0-3 percent for placebo.

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Articles

Cipher Pharmaceuticals Inc. introduced Sitavig® (ACYCLOVIR) 50mg buccal tablets for the treatment of herpes labialis caused by the HSV-1 virus.