Sitavig: Package Insert and Label Information

SITAVIG- acyclovir tablet, delayed release
Cipher Pharmaceuticals US LLC

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use SITAVIG safely and effectively. See full prescribing information for SITAVIG.

SITAVIG (acyclovir) buccal tablets 50mg

Initial U.S. Approval: 1982

INDICATIONS AND USAGE

SITAVIG is indicated for the treatment of recurrent herpes labialis (cold sores) in immunocompetent adults (1).

DOSAGE AND ADMINISTRATION

  • Application of one SITAVIG 50 mg buccal tablet as a single dose to the upper gum (canine fossa) region (2.1).
  • SITAVIG should be applied within one hour after the onset of prodromal symptoms and before the appearance of any signs of herpes labailis.
  • Do not crush, chew, suck or swallow tablets ( 2.2)

DOSAGE FORMS AND STRENGTHS

50 mg buccal tablets (3).

CONTRAINDICATIONS

Known hypersensitivity to acyclovir, milk protein concentrate, or any other component of the product (4).

ADVERSE REACTIONS

Most common adverse reactions (> or =1%) are: headache and application site pain (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Cipher Pharmaceuticals U.S. LLC at 1-800-499-4468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Due to low dose and minimal systemic absorption of SITAVIG, drug interactions are unlikely (7).

USE IN SPECIFIC POPULATIONS

  • Nursing Mothers: Caution should be exercised when administered to a nursing woman (8.3).

See 17 for PATIENT COUNSELING INFORMATION AND FDA-Approved Patient Labeling

Revised: 10/2015

FULL PRESCRIBNG INFORMATION: CONTENTS *

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Basic Dosing Information

2.2 Administration Instructions

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Labor and Delivery

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Immunocompromised Patients

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

12.4 Microbiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment ofFertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Instructions for Use

17.2 Adverse Reactions

* Sections or subsections omitted from the full prescribing informationare not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

SITAVIG is indicated for the treatment of recurrent herpes labialis (cold sores) in immunocompetent adults.

2 DOSAGE AND ADMINISTRATION

2.1 Basic Dosing Information

One SITAVIG 50 mg buccal tablet should be applied as a single dose to the upper gum region (canine fossa).

2.2 Administration Instructions

SITAVIG should be applied within one hour after the onset of prodromal symptoms and before the appearance of any signs of herpes labialis lesions. The tablet should be applied with a dry finger immediately after taking it out of the blister. The tablet should be placed to the upper gum just above the incisor tooth (canine fossa) and held in place with a slight pressure over the upper lip for 30 seconds to ensure adhesion. For comfort the rounded side should be placed to the upper gum, but either side of the tablet can be applied. Tablet should be applied on the same side of the mouth as the herpes labialis symptoms.

Once applied, SITAVIG stays in position and gradually dissolves during the day. [See Clinical Pharmacology (12.3)]. In addition,

  • SITAVIG should not be crushed, chewed, sucked or swallowed.
  • Food and drink can be taken normally when SITAVIG is in place. Avoid any situation which may interfere with adhesion of the tablet such as chewing gum, touching or pressing the tablet after placement, wearing upper denture, and brushing teeth. If the teeth need to be cleaned while the tablet is in place, rinse the mouth gently. Drink plenty of liquids in the case of dry mouth.
  • If SITAVIG does not adhere or falls off within the first 6 hours, the same tablet should be repositioned immediately. If the tablet cannot be repositioned, a new tablet should be placed.
  • If SITAVIG is swallowed within the first 6 hours, the patient should drink a glass of water and a new tablet should be applied. [See Patient Counseling Information (17)].
  • SITAVIG does not need to be reapplied if the tablet falls out or is swalloed after the first 6 hours

3 DOSAGE FORMS AND STRENGTHS

SITAVIG is a buccal tablet containing 50 mg of acyclovir. SITAVIG tablets are round, off-white tablets, with a rounded side and a flat side. The tablets are marked with an “AL21” on the flat side.

4 CONTRAINDICATIONS

SITAVIG is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis) to acyclovir, milk protein concentrate, or any other component of the product.

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The overall safety of SITAVIG was assessed in 378 adult subjects having at least 4 herpes labialis episodes the previous year.

One randomized, double-blind, placebo controled trial was conducted in patients with recurrent herpes labialis (cold sores). In this trial, 378 HSV infected subjects used SITAVIG as a single dose, and 397 subjects used placebo.

Selected treatment emergent adverse events without regard to causality and reported in at least 1% of patients can be seen in Table 1.

Table 1:

Selected Treatment Emergent Adverse Events reported in at least 1% of patients
Event

SITAVIG

N = 378

Placebo

N = 397

Nervous System Disorders

Headache

Dizziness

Lethargy

3%

1%

1%

3%

1%

0

Gastrointestinal system Disorders

Gingival Pain

Aphthous Stomatitis

1%

1%

0.38%

0

Administration Site Conditions

Application Site Pain

Application Site Irritation

1%

1%

1%

0

Skin and Subcutaneous Disorders

Erythema

Rash

1%

1%

0.3%

0.3%

The treatment emergent adverse events considered related to the treatment that occurred in greater than or equal to 1% of patients included headache (1% SITAVIG vs. 2% placebo) and application site pain (1% both arms). There was no discontinuation of SITAVIG due to adverse drug reactions. Most treatment related to adverse events were mild or moderate in severity. One report of headache from both treatment arms was classified as severe.

7 DRUG INTERACTIONS

No interaction studies have been performed with SITAVIG. Acyclovir is primarily eliminated unchanged in the urine via active tubular secretion. Drugs administered concomitantly that compete with tubular secretion may increase acyclovir plasma concentrations. However, due to the low dose and minimal systemic absorption of SITAVIG, systemic drug interactions are unlikely.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

No studies with SITAVIG have been performed in pregnant women. Systemic exposure of acyclovir following buccal administration of SITAVIG is minimal. SITAVIG should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. There are no adequate and well-controlled studies of systemic acyclovir in pregnant women. A prospective epidemiologic registry of acyclovir use during pregnancy between 1984 and 1999 followed 749 pregnancies in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximated that found in the general population. However, the size of the registry was insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses.

Animal Data

Animal reproduction studies have not been conducted with SITAVIG. Acyclovir was not teratogenic in the mouse, rabbit or rat at exposures greatly in excess of human exposure.

8.2 Labor and Delivery

SITAVIG should not be administered during labor and delivery as there is no experience with SITAVIG.

8.3 Nursing Mothers

It is not known whether topically applied acyclovir is excreted in breast milk. Systemic exposure following buccal administration is minimal. After oral administration of acyclovir, concentrations have been documented in breast milk in 2 women and ranged from 0.6 to 4.1 times the corresponding plasma levels. These concentrations would potentially expose the nursing infant to a dose of acyclovir up to 0.3 mg/kg/day. There is no experience with SITAVIG in nursing mothers. SITAVIG should be administered to a nursing mother with caution.

8.4 Pediatric Use

Safety and effectiveness of SITAVIG in pediatric patients have not been established. The ability of pediatric patients to comply with the application instructions has not been evaluated. Use in younger children is not recommended due to potential risk of choking.

8.5 Geriatric Use

Clinical studies of SITAVIG did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Immunocompromised Patients

The safety of SITAVIG has not been studied in immunocompromised subjects.

10 OVERDOSAGE

Acyclovir absorption and systemic exposure following application of SITAVIG are minimal. Overdose is therefore unlikely [see Clinical Pharmacology ( 12.3)] .

Symptomatic and supportive care is the basis for management.

11 DESCRIPTION SECTION

SITAVIG (acyclovir) buccal tablet is applied topically to the gum and releases acyclovir as the buccal tablet gradually dissolves [see Clinical
Pharmacology ( 12.3)] . Acyclovir is a synthetic purine nucleoside analogue active against herpes viruses. The chemical name of acyclovir is 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one; it has a molecular formula of C 8 H 11 N 5 O 3 and a molecular weight of 225. The structural formula is shown in Figure 1.

Structure

Acyclovir drug substance is a white or almost white crystalline powder. SITAVIG contains 50 mg of acyclovir, USP and the following inactive
ingredients: hypromellose, USP; milk protein concentrate; sodium lauryl sulfate, NF; magnesium stearate, NF; microcrystalline cellulose,
NF; povidone, USP; colloidal silicon dioxide, NF.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Acyclovir is an antiviral drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

Absorption and Distribution


Salivary

Single dose application of SITAVIG containing 50 mg of acyclovir to the buccal mucosa in 12 healthy volunteers provided mean maximum
salivary concentrations of 440 μg/mL 8 hours after application of the tablet. The pharmacokinetic parameters of acyclovir in the saliva of
healthy volunteers are provided in Table 2 .

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

Salivary PK Parameters(N = 12) Mean ±SD (Min — Max)

AUC 0-24h (mcg.h/mL) 2900 ± 2400 (849 — 9450)
C max (mcg/mL) 440 ± 241 (149 – 959)
T max (hour) 7.95 ± 4.08 (3.07 – 18.05)

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 single-dose 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.

12.4 Microbiology

Mechanism of Action


Acyclovir is a synthetic purine nucleoside that is phosphorylated intracellularly by the viral encoded thymidine kinase (TK) of HSV into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In a biochemical reaction, acyclovir triphosphate inhibits replication of herpes viral DNA by competing with nucleotides for binding to the viral DNA polymerase and by incorporation into and termination of the growing viral DNA chain. The cellular thymidine kinase of normal, uninfected cells does not use acyclovir effectively as a substrate, hence toxicity to mammalian host cells is low.

Antiviral activity


The quantitative relationship between the cell culture susceptibility of herpes viruses to antivirals 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 median EC50 value of acyclovir against clinical herpes virus isolates (subjects
receiving placebo) was 1.3 μM (range: < 0.56 to 3.3 μM).


Drug Resistance


Resistance of HSV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical
isolates of HSV with reduced susceptibility to acyclovir have been recovered from immunocompromised subjects, especially with
advanced HIV infection. While most of the acyclovir-resistant mutant isolates from immunocompromised subjects thus far have been
found to be TK-deficient, other mutant isolates involving the viral TK gene (TK partial and TK altered) or DNA polymerase have been
identified. TK-negative mutants may cause severe disease in infants and immunocompromised adults.

The possibility of viral resistance to acyclovir should be considered in immunocompromised subjects who show poor clinical response during therapy.

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