Sitavig

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take probenecid (Probalan).

This is not a complete list of Sitavig drug interactions. Ask your doctor or pharmacist for more information.

Tell your doctor if you are breastfeeding or plan to breastfeed. It is not known if Sitavig is excreted in human breast milk or if it will harm your nursing baby.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Canker sores
• pain in the gums
• sores, ulcers, or white spots on the tongue or inside the mouth

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Flushing or redness of the skin
• rash
• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
• unusually warm skin

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• Tell all of your health care providers that you take Sitavig. This includes your doctors, nurses, pharmacists, and dentists.
• This medicine will not cure cold sores. Talk with your doctor.
• Do not give this medicine to younger children. The chance of choking may be raised.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Sitavig while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

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

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.

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 8H 11N 5O 3 and a molecular weight of 225. The structural formula is shown in Figure 1.

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.

    Mechanism of Action

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

   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.

    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.

The most common side effects include:

• headache and pain where Sitavig is applied.

These are not all the possible side effects of Sitavig. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Applies to acyclovir: buccal tablet, compounding powder, intravenous powder for injection, intravenous solution, oral capsule, oral suspension, oral tablet

General

The more commonly reported adverse reactions include malaise, nausea, vomiting, diarrhea, and headache.[Ref]

Gastrointestinal

Nausea and vomiting are more frequent in elderly subjects.[Ref]

Common (1% to 10%): Nausea, vomiting, diarrhea, abdominal pain, gingival pain (buccal tablet), aphthous stomatitis (buccal tablet)
Uncommon (0.1% to 1%): Sore throat
Postmarketing reports: Gastrointestinal distress[Ref]

Renal

Rare (0.01% to 0.1%): Elevated blood urea nitrogen, elevated creatinine,
Very rare (less than 0.01%): Acute renal failure, renal pain
Frequency not reported: Crystalluria, renal impairment
Postmarketing reports: Renal failure, hematuria[Ref]

Renal pain may be associated with renal failure and crystalluria. Renal impairment is generally reversible but may progress to acute renal failure.[Ref]

Local

Common (1% to 10%): Application site pain and application site irritation, local inflammation at injection site, phlebitis
Frequency not reported: Tissue necrosis[Ref]

Severe local inflammatory reactions, including tissue necrosis, have occurred following infusion into extravascular tissues. Application site pain and application site irritation have occurred with the buccal tablets.[Ref]

Nervous system

Dizziness, somnolence, and coma more frequent in elderly subjects.[Ref]

Common (1% to 10%): Headache, dizziness
Very rare (less than 0.01%): Ataxia, coma, convulsions, encephalopathy, dysarthria
Frequency not reported: Giddiness, shaking, taste disturbance, medication taste
Postmarketing reports: Decreased consciousness, delirium, paresthesia, seizure, tremors[Ref]

Dermatologic

Common (1% to 10%): Erythema, rashes (including photosensitivity), pruritus, hives
Uncommon (0.1% to 1%): Urticaria, accelerated diffuse hair loss
Frequency not reported: Diaphoresis
Postmarketing reports: Alopecia, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis[Ref]

Cardiovascular

Frequency not reported: Palpitation, chest pain
Postmarketing reports: Hypotension, peripheral edema[Ref]

Hematologic

Very rare (less than 0.01%): Anemia, leukopenia, thrombocytopenia, neutropenia
Frequency not reported: Hematologic changes including megaloblastic anemia
Postmarketing reports: Leukocyclastic vasculitis, lymphadenopathy, disseminated intravascular coagulation, hemolysis[Ref]

Hepatic

Rare (0.01% to 0.1%): Reversible bilirubin and liver related enzymes
Very rare (less than 0.01%): Hepatitis, jaundice
Postmarketing reports: Hyperbilirubinemia[Ref]

Hypersensitivity

Rare (0.01% to 0.1%): Anaphylaxis
Frequency not reported: Angioedema[Ref]

Ocular

Frequency not reported: Pars planitis
Postmarketing reports: Visual abnormalities[Ref]

Musculoskeletal

Uncommon (0.1% to 1%): Leg pain
Postmarketing reports: Myalgia[Ref]

Other

Common (1% to 10%): Lethargy, fatigue, fever
Frequency not reported: Vertigo
Postmarketing reports: Fever[Ref]

Genitourinary

Frequency not reported: Menstrual abnormalities, abnormal urinalysis (characterized by an increase in formed elements in urine sediment) anuria, dysuria, hematuria[Ref]

Metabolic

Uncommon (0.1% to 1%): Anorexia
Frequency not reported: Thirst[Ref]

Psychiatric

Hallucinations, psychosis, confusion, aggressive behavior, agitation may be more marked in older adults and those with renal impairment.[Ref]

Very rare (less than 0.01%): Agitation, confusion, hallucinations, psychotic symptoms
Frequency not reported: Depression, insomnia
Postmarketing reports: Aggressive behavior[Ref]

Respiratory

Rare (0.01% to 0.1%): Dyspnea[Ref]

Some side effects of Sitavig may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.