Vyloma

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Vyloma uses

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Vyloma reviews

1 INDICATIONS AND USAGE

Vyloma Cream is indicated for the topical treatment of:

• Clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses on the face or scalp in immunocompetent adults (1.1)
• External genital and perianal warts/condyloma acuminata in patients 12 years old or older (1.3)

Limitations of Use: Efficacy was not demonstrated for molluscum contagiosum in children aged 2 to 12 (1.4, 8.4)

1.1 Actinic Keratosis

Vyloma Cream is indicated for the topical treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses on the face or scalp in immunocompetent adults.

1.3 External Genital Warts

Vyloma Cream is indicated for the treatment of external genital and perianal warts/condyloma acuminata in patients 12 years old or older.

1.4 Limitations of Use

Vyloma Cream has been evaluated in children ages 2 to 12 years with molluscum contagiosum and these studies failed to demonstrate efficacy [see Use in Specific Populations ].

1.5 Unevaluated Populations

The safety and efficacy of Vyloma Cream in immunosuppressed patients have not been established.

Vyloma Cream should be used with caution in patients with pre-existing autoimmune conditions.

The efficacy and safety of Vyloma Cream have not been established for patients with Basal Cell Nevus Syndrome or Xeroderma Pigmentosum.

2 DOSAGE AND ADMINISTRATION

The application frequency for Vyloma Cream is different for each indication.

Vyloma Cream is not for oral, ophthalmic, or intravaginal use.

Vyloma Cream is not for oral, ophthalmic, or intravaginal use.

• Actinic keratosis: 2 times per week for a full 16 weeks (2.1)
• External genital warts (EGW): 3 times per week until total clearance or a maximum of 16 weeks (2.3)

2.1 Actinic Keratosis

Vyloma Cream should be applied 2 times per week for a full 16 weeks to a defined treatment area on the face or scalp (but not both concurrently). The treatment area is defined as one contiguous area of approximately 25 cm² (e.g., 5 cm x 5 cm) on the face (e.g., forehead or one cheek) or on the scalp. Examples of 2 times per week application schedules are Monday and Thursday, or Tuesday and Friday. Vyloma Cream should be applied to the entire treatment area and rubbed in until the cream is no longer visible. No more than one packet of Vyloma Cream should be applied to the contiguous treatment area at each application. Vyloma Cream should be applied prior to normal sleeping hours and left on the skin for approximately 8 hours, after which time the cream should be removed by washing the area with mild soap and water. The prescriber should demonstrate the proper application technique to maximize the benefit of Vyloma Cream therapy.

It is recommended that patients wash their hands before and after applying Vyloma Cream. Before applying the cream, the patient should wash the treatment area with mild soap and water and allow the area to dry thoroughly (at least 10 minutes).

Contact with the eyes, lips and nostrils should be avoided.

Local skin reactions in the treatment area are common . A rest period of several days may be taken if required by the patient's discomfort or severity of the local skin reaction.

However, the treatment period should not be extended beyond 16 weeks due to missed doses or rest periods. Response to treatment cannot be adequately assessed until resolution of local skin reactions. Lesions that do not respond to treatment should be carefully re-evaluated and management reconsidered.

Vyloma Cream is packaged in single-use packets, with 24 packets supplied per box. Patients should be prescribed no more than 36 packets for the 16-week treatment period. Unused packets should be discarded. Partially-used packets should be discarded and not reused.

2.3 External Genital Warts

Vyloma Cream should be applied 3 times per week to external genital/perianal warts. Vyloma Cream treatment should continue until there is total clearance of the genital/perianal warts or for a maximum of 16 weeks. Examples of 3 times per week application schedules are: Monday, Wednesday, Friday or Tuesday, Thursday, Saturday. Vyloma Cream should be applied prior to normal sleeping hours and left on the skin for 6 to 10 hours, after which time the cream should be removed by washing the area with mild soap and water. The prescriber should demonstrate the proper application technique to maximize the benefit of Vyloma Cream therapy.

It is recommended that patients wash their hands before and after applying Vyloma Cream.

A thin layer of Vyloma Cream should be applied to the wart area and rubbed in until the cream is no longer visible. The application site should not be occluded. Following the treatment period the cream should be removed by washing the treated area with mild soap and water.

Local skin reactions at the treatment site are common . A rest period of several days may be taken if required by the patient's discomfort or severity of the local skin reaction. Treatment may resume once the reaction subsides. Non-occlusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions.

Vyloma Cream is packaged in single-use packets which contain sufficient cream to cover a wart area of up to 20 cm²; use of excessive amounts of cream should be avoided.

3 DOSAGE FORMS AND STRENGTHS

Vyloma Cream 5%, is supplied in single-use packets each of which contains 250 mg of the cream, equivalent to 12.5 mg of Vyloma. Vyloma Cream is supplied in boxes of 24 packets each.

• Vyloma Cream 5% is supplied in a box containing 24 single-use packets, each of which contains 250 mg of the cream, equivalent to 12.5 mg of Vyloma. (3)

4 CONTRAINDICATIONS

None.

• None (4)

5 WARNINGS AND PRECAUTIONS

• Intense local inflammatory reactions can occur. Dosing interruption may be required (2, 5.1, 6)
• Severe local inflammatory reactions of the female external genitalia can lead to severe vulvar swelling. Severe vulvar swelling can lead to urinary retention; dosing should be interrupted or discontinued.
• Flu-like systemic signs and symptoms including malaise, fever, nausea, myalgias and rigors may occur. Dosing interruption may be required (2, 5.2, 6)
• Avoid exposure to sunlight and sunlamps. Wear sunscreen daily (5.3).
• Safety and efficacy have not been established for repeat courses of treatment to the same area for AK. (5.4)
• Treatment of urethral, intra-vaginal, cervical, rectal or intra-anal viral disease is not recommended. (5.6)
• Safety and efficacy in immunosuppressed patients have not been established (1.5)

5.1 Local Inflammatory Reactions

Intense local inflammatory reactions including skin weeping or erosion can occur after few applications of Vyloma Cream and may require an interruption of dosing . Vyloma Cream has the potential to exacerbate inflammatory conditions of the skin, including chronic graft versus host disease.

Severe local inflammatory reactions of the female external genitalia can lead to severe vulvar swelling.

Severe vulvar swelling can lead to urinary retention. Dosing should be interrupted or discontinued for severe vulvar swelling.

Administration of Vyloma Cream is not recommended until the skin is completely healed from any previous drug or surgical treatment.

5.2 Systemic Reactions

Flu-like signs and symptoms may accompany, or even precede, local inflammatory reactions and may include malaise, fever, nausea, myalgias and rigors. An interruption of dosing should be considered .

5.3 Ultraviolet Light Exposure

Exposure to sunlight (including sunlamps) should be avoided or minimized during use of Vyloma Cream because of concern for heightened sunburn susceptibility. Patients should be warned to use protective clothing (e.g., a hat) when using Vyloma Cream. Patients with sunburn should be advised not to use Vyloma Cream until fully recovered. Patients who may have considerable sun exposure, e.g., due to their occupation, and those patients with inherent sensitivity to sunlight should exercise caution when using Vyloma Cream.

Vyloma Cream shortened the time to skin tumor formation in an animal photoco-carcinogenicity study . The enhancement of ultraviolet carcinogenicity is not necessarily dependent on phototoxic mechanisms. Therefore, patients should minimize or avoid natural or artificial sunlight exposure.

5.4 Unevaluated Uses: Actinic Keratosis

Safety and efficacy have not been established for Vyloma Cream in the treatment of actinic keratosis with repeated use, i.e. more than one treatment course, in the same area.

The safety of Vyloma Cream applied to areas of skin greater than 25 cm² for the treatment of actinic keratosis has not been established .

5.6 Unevaluated Uses: External Genital Warts

Vyloma Cream has not been evaluated for the treatment of urethral, intra-vaginal, cervical, rectal, or intra-anal human papilloma viral disease.

6 ADVERSE REACTIONS

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 practice.

Most common adverse reactions are application site reactions or local skin reactions: itching, burning, erythema, flaking/scaling/dryness, scabbing/crusting, edema, induration, excoriation, erosion, ulceration. Other reported reactions (≥1 %) include fatigue, fever, and headache (6.1, 6.3)

To report SUSPECTED ADVERSE REACTIONS, contact Fougera Pharmaceuticals Inc. at 1-800-645-9833 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience: Actinic Keratosis

The data described in Table 1 reflect exposure to Vyloma Cream or vehicle in 436 subjects enrolled in two double-blind, vehicle-controlled studies. Subjects applied Vyloma Cream or vehicle to a 25 cm² contiguous treatment area on the face or scalp 2 times per week for 16 weeks.

Local skin reactions were collected independently of the adverse reaction "application site reaction" in an effort to provide a better picture of the specific types of local reactions that might be seen. The most frequently reported local skin reactions were erythema, flaking/scaling/ dryness, and scabbing/crusting. The prevalence and severity of local skin reactions that occurred during controlled studies are shown in the following table.

*Mild, Moderate, or Severe

The adverse reactions that most frequently resulted in clinical intervention (e.g., rest periods, withdrawal from study) were local skin and application site reactions. Overall, in the clinical studies, 2% (5/215) of subjects discontinued for local skin/application site reactions. Of the 215 subjects treated, 35 subjects (16%) on Vyloma Cream and 3 of 220 subjects (1%) on vehicle cream had at least one rest period. Of these Vyloma Cream subjects, 32 (91%) resumed therapy after a rest period.

In the AK studies, 22 of 678 (3.2%) of Vyloma Cream-treated subjects developed treatment site infections that required a rest period off Vyloma Cream and were treated with antibiotics (19 with oral and 3 with topical).

Of the 206 Vyloma Cream subjects with both baseline and 8-week post-treatment scarring assessments, 6 (2.9%) had a greater degree of scarring scores at 8-weeks post-treatment than at baseline.

6.3 Clinical Trials Experience: External Genital Warts

In controlled clinical trials for genital warts, the most frequently reported adverse reactions were local skin and application site reactions.

Some subjects also reported systemic reactions. Overall, 1.2% of the subjects discontinued due to local skin/application site reactions. The incidence and severity of local skin reactions during controlled clinical trials are shown in the following table.

*Mild, Moderate, or Severe

Remote site skin reactions were also reported. The severe remote site skin reactions reported for females were erythema (3%), ulceration (2%), and edema (1%); and for males, erosion (2%), and erythema, edema, induration, and excoriation/flaking (each 1%).

Selected adverse reactions judged to be probably or possibly related to Vyloma Cream are listed below.

*Incidences reported without regard to causality with Vyloma Cream.

Adverse reactions judged to be possibly or probably related to Vyloma Cream and reported by more than 1% of subjects included:

Application Site Disorders: burning, hypopigmentation, irritation, itching, pain, rash, sensitivity, soreness, stinging, tenderness

Remote Site Reactions: bleeding, burning, itching, pain, tenderness, tinea cruris

Body as a Whole: fatigue, fever, influenza-like symptoms

Central and Peripheral Nervous System Disorders: headache

Gastro-Intestinal System Disorders: diarrhea

Musculo-Skeletal System Disorders: myalgia

6.4 Clinical Trials Experience: Dermal Safety Studies

Provocative repeat insult patch test studies involving induction and challenge phases produced no evidence that Vyloma Cream causes photoallergenicity or contact sensitization in healthy skin; however, cumulative irritancy testing revealed the potential for Vyloma Cream to cause irritation, and application site reactions were reported in the clinical studies .

6.5 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Vyloma Cream. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Application Site Disorders: tingling at the application site

Body as a Whole: angioedema

Cardiovascular: capillary leak syndrome, cardiac failure, cardiomyopathy, pulmonary edema, arrhythmias (tachycardia, atrial fibrillation, palpitations), chest pain, ischemia, myocardial infarction, syncope

Endocrine: thyroiditis

Gastro-Intestinal System Disorders: abdominal pain

Hematological: decreases in red cell, white cell and platelet counts (including idiopathic thrombocytopenic purpura), lymphoma

Hepatic: abnormal liver function

Infections and Infestations: herpes simplex

Musculo-Skeletal System Disorders: arthralgia

Neuropsychiatric: agitation, cerebrovascular accident, convulsions (including febrile convulsions), depression, insomnia, multiple sclerosis aggravation, paresis, suicide

Respiratory: dyspnea

Urinary System Disorders: proteinuria, dysuria, urinary retention

Skin and Appendages: exfoliative dermatitis, erythema multiforme, hyperpigmentation, hypertrophic scar

Vascular: Henoch-Schönlein purpura syndrome

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Note: The Maximum Recommended Human Dose was set at 2 packets per treatment of Vyloma Cream (25 mg Vyloma) for the animal multiple of human exposure ratios presented in this label. If higher doses than 2 packets of Vyloma Cream are used clinically, then the animal multiple of human exposure would be reduced for that dose. A non-proportional increase in systemic exposure with increased dose of Vyloma Cream was noted in the clinical pharmacokinetic study conducted in actinic keratosis subjects . The AUC after topical application of 6 packets of Vyloma Cream was 8 fold greater than the AUC after topical application of 2 packets of Vyloma Cream in actinic keratosis subjects. Therefore, if a dose of 6 packets per treatment of Vyloma Cream was topically administered to an individual, then the animal multiple of human exposure would be either 1/3 of the value provided in the label (based on body surface area comparisons) or 1/8 of the value provided in the label (based on AUC comparisons). The animal multiples of human exposure calculations were based on weekly dose comparisons for the carcinogenicity studies described in this label. The animal multiples of human exposure calculations were based on daily dose comparisons for the reproductive toxicology studies described in this label.

Systemic embryofetal development studies were conducted in rats and rabbits. Oral doses of 1, 5 and 20 mg/kg/day Vyloma were administered during the period of organogenesis (gestational days 6 to 15) to pregnant female rats. In the presence of maternal toxicity, fetal effects noted at 20 mg/kg/day (577x MRHD based on AUC comparisons) included increased resorptions, decreased fetal body weights, delays in skeletal ossification, bent limb bones, and two fetuses in one litter (2 of 1567 fetuses) demonstrated exencephaly, protruding tongues and low-set ears. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 5 mg/kg/day (98x MRHD based on AUC comparisons).

Intravenous doses of 0.5, 1 and 2 mg/kg/day Vyloma were administered during the period of organogenesis (gestational days 6 to 18) to pregnant female rabbits. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 2 mg/kg/day (1.5x MRHD based on BSA comparisons), the highest dose evaluated in this study, or 1 mg/kg/day (407x MRHD based on AUC comparisons).

A combined fertility and peri- and post-natal development study was conducted in rats. Oral doses of 1, 1.5, 3 and 6 mg/kg/day Vyloma were administered to male rats from 70 days prior to mating through the mating period and to female rats from 14 days prior to mating through parturition and lactation. No effects on growth, fertility, reproduction or post-natal development were noted at doses up to 6 mg/kg/day (87x MRHD based on AUC comparisons), the highest dose evaluated in this study. In the absence of maternal toxicity, bent limb bones were noted in the F1 fetuses at a dose of 6 mg/kg/day (87x MRHD based on AUC comparisons). This fetal effect was also noted in the oral rat embryofetal development study conducted with Vyloma. No treatment related effects on teratogenicity were noted at 3 mg/kg/day (41x MRHD based on AUC comparisons).

There are no adequate and well-controlled studies in pregnant women. Vyloma Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether Vyloma is excreted in human milk following use of Vyloma Cream. Because many drugs are excreted in human milk, caution should be exercised when Vyloma Cream is administered to nursing women.

8.4 Pediatric Use

AK is not a condition generally seen within the pediatric population. The safety and efficacy of Vyloma Cream for AK in patients less than 18 years of age have not been established.

Safety and efficacy in patients with external genital/perianal warts below the age of 12 years have not been established.

Vyloma Cream was evaluated in two randomized, vehicle-controlled, double-blind trials involving 702 pediatric subjects with molluscum contagiosum (470 exposed to Vyloma; median age 5 years, range 2 to 12 years). Subjects applied Vyloma Cream or vehicle 3 times weekly for up to 16 weeks. Complete clearance (no MC lesions) was assessed at Week 18. In Study 1, the complete clearance rate was 24% (52/217) in the Vyloma Cream group compared with 26% (28/106) in the vehicle group. In Study 2,the clearance rates were 24% (60/253) in the Vyloma Cream group compared with 28% (35/126) in the vehicle group. These studies failed to demonstrate efficacy.

Similar to the studies conducted in adults, the most frequently reported adverse reaction from 2 studies in children with molluscum contagiosum was application site reaction. Adverse events which occurred more frequently in Imiquimod-treated subjects compared with vehicle-treated subjects generally resembled those seen in studies in indications approved for adults and also included otitis media (5% Vyloma vs. 3% vehicle) and conjunctivitis (3% Vyloma vs. 2% vehicle).

Erythema was the most frequently reported local skin reaction. Severe local skin reactions reported by Imiquimod-treated subjects in the pediatric studies included erythema (28%), edema (8%), scabbing/crusting (5%), flaking/scaling (5%), erosion (2%) and weeping/exudate (2%).

Systemic absorption of Vyloma across the affected skin of 22 subjects aged 2 to 12 years with extensive MC involving at least 10% of the total body surface area was observed after single and multiple doses at a dosing frequency of 3 applications per week for 4 weeks. The investigator determined the dose applied, either 1, 2 or 3 packets per dose, based on the size of the treatment area and the subject’s weight. The overall median peak serum drug concentrations at the end of week 4 was between 0.26 and 1.06 ng/mL except in a 2-year old female who was administered 2 packets of study drug per dose, had a C_max of 9.66 ng/mL after multiple dosing. Children aged 2 to 5 years received doses of 12.5 mg (one packet) or 25 mg (two packets) of Vyloma and had median multiple-dose peak serum drug levels of approximately 0.2 or 0.5 ng/mL, respectively. Children aged 6 to 12 years received doses of 12.5 mg, 25 mg, or 37.5 mg (three packets) and had median multiple dose serum drug levels of approximately 0.1, 0.15, or 0.3 ng/mL, respectively. Among the 20 subjects with evaluable laboratory assessments, the median WBC count decreased by 1.4*10⁹/L and the median absolute neutrophil count decreased by 1.42*10⁹/L.

8.5 Geriatric Use

Of the 215 subjects treated with Vyloma Cream in the AK clinical studies, 127 subjects (59%) were 65 years and older, while 60 subjects (28%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. No other clinical experience has identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

10 OVERDOSAGE

Topical overdosing of Vyloma Cream could result in an increased incidence of severe local skin reactions and may increase the risk for systemic reactions.

The most clinically serious adverse event reported following multiple oral Vyloma doses of >200 mg (equivalent to Vyloma content of >16 packets) was hypotension, which resolved following oral or intravenous fluid administration.

11 DESCRIPTION

Vyloma Cream 5% is an immune response modifier for topical administration. Each gram contains 50 mg of Vyloma in an off-white oil-in-water vanishing cream base consisting of purified water, oleic acid, white petrolatum, polysorbate 60, glycerin, stearyl alcohol, benzyl alcohol, cetyl alcohol, sorbitan monostearate, xanthan gum, methylparaben, propylparaben.

Chemically, Vyloma is 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine. Vyloma has a molecular formula of C₁₄H₁₆N₄ and a molecular weight of 240.3. Its structural formula is:

structural formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of Vyloma Cream in treating AK lesions is unknown.

12.2 Pharmacodynamics

Actinic Keratosis

In a study of 18 subjects with AK comparing Vyloma Cream to vehicle, increases from baseline in week 2 biomarker levels were reported for CD3, CD4, CD8, CD11c, and CD68 for Vyloma Cream treated subjects; however, the clinical relevance of these findings is unknown.

External Genital Warts

Vyloma has no direct antiviral activity in cell culture. A study in 22 subjects with genital/perianal warts comparing Vyloma Cream and vehicle shows that Vyloma Cream induces mRNA encoding cytokines including interferon-α at the treatment site. In addition HPVL1 mRNA and HPV DNA are significantly decreased following treatment. However, the clinical relevance of these findings is unknown.

12.3 Pharmacokinetics

Systemic absorption of Vyloma across the affected skin of 58 subjects with AK was observed with a dosing frequency of 3 applications per week for 16 weeks. Mean peak serum drug concentrations at the end of week 16 were approximately 0.1, 0.2, and 3.5 ng/mL for the applications to face (12.5 mg Vyloma, 1 single-use packet), scalp (25 mg, 2 packets) and hands/arms (75 mg, 6 packets), respectively.

The application surface area was not controlled when more than one packet was used. Dose proportionality was not observed. However it appears that systemic exposure may be more dependent on surface area of application than amount of applied dose. The apparent half-life was approximately 10 times greater with topical dosing than the 2 hour apparent half-life seen following subcutaneous dosing, suggesting prolonged retention of drug in the skin. Mean urinary recoveries of Vyloma and metabolites combined were 0.08 and 0.15% of the applied dose in the group using 75 mg (6 packets) for males and females, respectively following 3 applications per week for 16 weeks.

Systemic absorption of Vyloma was observed across the affected skin of 12 subjects with genital/perianal warts, with an average dose of 4.6 mg. Mean peak drug concentration of approximately 0.4 ng/mL was seen during the study. Mean urinary recoveries of Vyloma and metabolites combined over the whole course of treatment, expressed as percent of the estimated applied dose, were 0.11 and 2.41% in the males and females, respectively.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In an oral (gavage) rat carcinogenicity study, Vyloma was administered to Wistar rats on a 2x/week (up to 6 mg/kg/day) or daily (3 mg/kg/day) dosing schedule for 24 months. No treatment related tumors were noted in the oral rat carcinogenicity study up to the highest doses tested in this study of 6 mg/kg administered 2x/week in female rats (87x MRHD based on weekly AUC comparisons), 4 mg/kg administered 2x/week in male rats (75x MRHD based on weekly AUC comparisons) or 3 mg/kg administered 7x/week to male and female rats (153x MRHD based on weekly AUC comparisons).

In a dermal mouse carcinogenicity study, Vyloma cream (up to 5 mg/kg/application Vyloma or 0.3% Vyloma cream) was applied to the backs of mice 3x/week for 24 months. A statistically significant increase in the incidence of liver adenomas and carcinomas was noted in high dose male mice compared to control male mice (251x MRHD based on weekly AUC comparisons). An increased number of skin papillomas was observed in vehicle cream control group animals at the treated site only. The quantitative composition of the vehicle cream used in the dermal mouse carcinogenicity study is the same as the vehicle cream used for Vyloma Cream, minus the active moiety (imiquimod).

In a 52-week dermal photoco-carcinogenicity study, the median time to onset of skin tumor formation was decreased in hairless mice following chronic topical dosing (3x/week; 40 weeks of treatment followed by 12 weeks of observation) with concurrent exposure to UV radiation (5 days per week) with the Vyloma Cream vehicle alone. No additional effect on tumor development beyond the vehicle effect was noted with the addition of the active ingredient, Vyloma, to the vehicle cream.

Vyloma revealed no evidence of mutagenic or clastogenic potential based on the results of five in vitro genotoxicity tests (Ames assay, mouse lymphoma L5178Y assay, Chinese hamster ovary cell chromosome aberration assay, human lymphocyte chromosome aberration assay and SHE cell transformation assay) and three in vivo genotoxicity tests (rat and hamster bone marrow cytogenetics assay and a mouse dominant lethal test).

Daily oral administration of Vyloma to rats, throughout mating, gestation, parturition and lactation, demonstrated no effects on growth, fertility or reproduction, at doses up to 87x MRHD based on AUC comparisons.

14 CLINICAL STUDIES

14.1 Actinic Keratosis

In two double-blind, vehicle-controlled clinical studies, 436 subjects with AK were randomized to treatment with either Vyloma Cream or vehicle cream 2 times per week for 16 weeks. The studies enrolled subjects with 4 to 8 clinically typical, visible, discrete, nonhyperkeratotic, nonhypertrophic AK lesions within a 25 cm² contiguous treatment area on either the face or scalp. The 25 cm² contiguous treatment area could be of any dimensions e.g., 5 cm x 5 cm, 3 cm by 8.3 cm, 2 cm by 12.5 cm. Study subjects ranged from 37 to 88 years of age and 55% had Fitzpatrick skin type I or II. All Imiquimod-treated subjects were Caucasians.

On a scheduled dosing day, the study cream was applied to the entire treatment area prior to normal sleeping hours and left on for approximately 8 hours. Twice weekly dosing was continued for a total of 16 weeks. The clinical response of each subject was evaluated 8 weeks after the last scheduled application of study cream. Efficacy was assessed by the complete clearance rate, defined as the proportion of subjects at the 8-week post-treatment visit with no (zero) clinically visible AK lesions in the treatment area. Complete clearance included clearance of all baseline lesions, as well as any new or sub-clinical AK lesions which appeared during therapy.

Complete and partial clearance rates are shown in the table below. The partial clearance rate was defined as the percentage of subjects in whom 75% or more baseline AK lesions were cleared.

Sub-clinical AK lesions may become apparent in the treatment area during treatment with Vyloma Cream. During the course of treatment, 48% (103/215) of subjects experienced an increase in AK lesions relative to the number present at baseline within the treatment area. Subjects with an increase in AK lesions had a similar response to those with no increase in AK lesions.

14.3 External Genital Warts

In a double-blind, placebo-controlled clinical study, 209 otherwise healthy subjects 18 years of age and older with genital/perianal warts were treated with Vyloma Cream or vehicle control 3 times per week for a maximum of 16 weeks. The median baseline wart area was 69 mm² (range 8 to 5525 mm²). Subject accountability is shown in the figure below.

*The other subjects were either lost to follow-up or experienced recurrences.

Data on complete clearance are listed in the table below. The median time to complete wart clearance was 10 weeks.

16 HOW SUPPLIED/STORAGE AND HANDLING

Vyloma Cream 5%, is supplied in single-use packets which contain 250 mg of the cream.

Available as: box of 24 packets NDC 0168-0432-24.

Store at 4° to 25°C (39° to 77°F). Avoid freezing.

Keep out of reach of children.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling

17.1 General Information: All Indications

Vyloma Cream should be used as directed by a physician . Vyloma Cream is for external use only. Contact with the eyes, lips and nostrils should be avoided . The treatment area should not be bandaged or otherwise occluded. Partially-used packets should be discarded and not reused. The prescriber should demonstrate the proper application technique to maximize the benefit of Vyloma Cream therapy.

It is recommended that patients wash their hands before and after applying Vyloma Cream.

17.2 Local Skin Reactions: All Indications

Patients may experience local skin reactions during treatment with Vyloma Cream (even with normal dosing). Potential local skin reactions include erythema, edema, vesicles, erosions/ulcerations, weeping/exudate, flaking/scaling/dryness, and scabbing/crusting. These reactions can range from mild to severe in intensity and may extend beyond the application site onto the surrounding skin. Patients may also experience application site reactions such as itching and/or burning .

Local skin reactions may be of such intensity that patients may require rest periods from treatment. Treatment with Vyloma Cream can be resumed after the skin reaction has subsided, as determined by the physician. Patients should contact their physician promptly if they experience any sign or symptom at the application site that restricts or prohibits their daily activity or makes continued application of the cream difficult.

Because of local skin reactions, during treatment and until healed, the treatment area is likely to appear noticeably different from normal skin. Localized hypopigmentation and hyperpigmentation have been reported following use of Vyloma Cream. These skin color changes may be permanent in some patients.

17.3 Systemic Reactions: All Indications

Patients may experience flu-like systemic signs and symptoms during treatment with Vyloma Cream. Systemic signs and symptoms may include malaise, fever, nausea, myalgias and rigors . An interruption of dosing should be considered.

17.4 Patients Being Treated for Actinic Keratosis (AK)

Dosing is 2 times per week for a full 16 weeks, unless otherwise directed by the physician. However, the treatment period should not be extended beyond 16 weeks due to missed doses or rest periods .

It is recommended that the treatment area be washed with mild soap and water 8 hours following Vyloma Cream application.

Most patients using Vyloma Cream for the treatment of AK experience erythema, flaking/scaling/dryness and scabbing/crusting at the application site with normal dosing .

Use of sunscreen is encouraged, and patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using Vyloma Cream .

Sub-clinical AK lesions may become apparent in the treatment area during treatment and may subsequently resolve .

17.6 Patients Being Treated for External Genital Warts

Dosing is 3 times per week to external genital/perianal warts. Vyloma Cream treatment should continue until there is total clearance of the genital/perianal warts or for a maximum of 16 weeks.

It is recommended that the treatment area be washed with mild soap and water 6 to 10 hours following Vyloma Cream application.

It is common for patients to experience local skin reactions such as erythema, erosion, excoriation/flaking, and edema at the site of application or surrounding areas. Most skin reactions are mild to moderate.

Sexual (genital, anal, oral) contact should be avoided while Vyloma Cream is on the skin. Application of Vyloma Cream in the vagina is considered internal and should be avoided. Female patients should take special care if applying the cream at the opening of the vagina because local skin reactions on the delicate moist surfaces can result in pain or swelling, and may cause difficulty in passing urine, or inability to urinate.

Uncircumcised males treating warts under the foreskin should retract the foreskin and clean the area daily. New warts may develop during therapy, as Vyloma Cream is not a cure.

The effect of Vyloma Cream on the transmission of genital/perianal warts is unknown.

Vyloma Cream may weaken condoms and vaginal diaphragms; therefore, concurrent use is not recommended.

Should severe local skin reaction occur, the cream should be removed by washing the treatment area with mild soap and water.

IF2432E

R07/15

logo1

FDA-Approved Patient Labeling

R_x only

PATIENT INFORMATION

Vyloma CREAM 5% [I MIḰ WEH MOD]

IMPORTANT: Not for mouth, eye, vaginal use

Read the Patient Information that comes with Vyloma Cream before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or treatment. If you do not understand the information, or have any questions about Vyloma Cream, talk with your healthcare provider or pharmacist.

What is Vyloma Cream?

Vyloma Cream is a skin use only (topical) medicine used to treat:

- external genital and perianal warts in people 12 years and older.

- actinic keratosis in adults with normal immune systems. Actinic keratosis is caused by too much sun exposure.

Vyloma Cream is used in different ways for the three different skin conditions it is used to treat. It is very important that you follow the instructions for your skin condition. Talk to your healthcare provider if you have questions.

Vyloma Cream does not work for everyone. Vyloma Cream will not cure your genital or perianal warts. New warts may develop during treatment with Vyloma Cream. It is not known if Vyloma Cream can stop you from spreading genital or perianal warts to other people. For your own health and the health of others, it is important to practice safer sex. Talk to your healthcare provider about safer sex practices.

Who should not use Vyloma Cream?

- Vyloma Cream has not been studied in children under 12 years old for external genital and perianal warts.

Before using Vyloma Cream, tell your healthcare provider:

- about all your medical conditions, including if you

• -are pregnant or planning to become pregnant. It is not known if Vyloma Cream can harm your unborn baby.
• -are breastfeeding. It is not known if Vyloma Cream passes into your milk and if it can harm your baby.

- about all the medicines you take including prescription and non-prescription medicines, vitamins and herbal supplements. Especially tell your healthcare provider if you have had other treatments for genital or perianal warts, or actinic keratosis. Vyloma Cream should not be used until your skin has healed from other treatments.

How should I use Vyloma Cream?

- Use Vyloma Cream exactly as prescribed by your healthcare provider. Vyloma Cream is for skin use only. Do not take by mouth or use in or near your eyes, lips or nostrils. Do not use Vyloma Cream unless your healthcare provider has taught you the right way to use it. Talk to your healthcare provider if you have any questions.

- Vyloma Cream is used for several skin conditions. Use Vyloma Cream only on the area of your body to be treated. Your healthcare provider will tell you where to apply Vyloma Cream and how often and for how long to apply it for your condition. Do not use Vyloma Cream longer than prescribed. Using too much Vyloma Cream, or using it too often, or for too long can increase your chances for having a severe skin reaction or other side effect. Talk to your healthcare provider if Vyloma Cream does not work for you.

For external genital and perianal warts Vyloma Cream is usually used once a day for 3 days a week:

- Monday, Wednesday and Friday, or

- Tuesday, Thursday and Saturday

For these conditions, Vyloma Cream is usually left on the skin for 6 to 10 hours. Treatment should continue until the warts are completely gone, or up to 16 weeks.

For actinic keratosis Vyloma Cream is usually used once a day for 2 days a week, 3 to 4 days apart, such as:

- Monday and Thursday, or

- Tuesday and Friday

For this condition, Vyloma Cream is usually left on the skin for about 8 hours. Treatment should continue for the full 16 weeks even if all actinic keratosis appear to be gone, unless you are told otherwise by your healthcare provider. The area you treat with Vyloma Cream should be no larger than approximately the size of your forehead or one cheek (for example 2 inches by 2 inches), unless otherwise directed by your healthcare provider.

Applying Vyloma Cream

Vyloma Cream should be applied just before your bedtime.

- Wash the area to be treated with mild soap and water. Allow the area to dry.

• -Uncircumcised males treating warts under their penis foreskin must pull their foreskin back and clean before treatment, and clean the area daily during the weeks of treatment.

- Wash your hands.

- Open a new packet of Vyloma Cream just before use.

- Apply a thin layer of Vyloma Cream only to the affected area or areas to be treated. Do not use more Vyloma Cream than is needed to cover the treatment area.

- Rub the cream in all the way to the affected area or areas.

• -Do not get Vyloma Cream in your eyes.
• -Do not get Vyloma Cream in the anus when applying to perianal warts.
• - Female patients treating genital warts must be careful when applying Vyloma Cream around the vaginal opening. Female patients should take special care if applying the cream at the opening of the vagina because local skin reactions on the delicate moist surfaces can cause pain or swelling, and may cause problems passing urine. Do not put Vyloma Cream in your vagina or on the skin around the genital wart.

- Do not cover the treated site with an airtight bandage. Cotton gauze dressings can be used. Cotton underwear can be worn after applying Vyloma Cream to the genital or perianal area.

- Safely throw away the open packet of Vyloma Cream so that children and pets cannot get it. The open packet should be thrown away even if all the Vyloma Cream was not completely used.

- After applying Vyloma Cream, wash your hands well.

- Leave the cream on the affected area or areas for the time prescribed by your healthcare provider. The length of time that Vyloma Cream is left on the skin is not the same for the different skin conditions that Vyloma Cream is used to treat. Do not bathe or get the treated area wet before the right time has passed. Do not leave Vyloma Cream on your skin longer than prescribed.

- After the right amount of time has passed, wash the treated area with mild soap and water.

- If you forget to apply Vyloma Cream, apply the missed dose of cream as soon as you remember and then continue on your regular schedule.

- If you get Vyloma Cream in your mouth or in your eyes rinse well with water right away.

What should I avoid while using Vyloma Cream?

- Do not cover the treated area with bandages or other closed dressings. Cotton gauze dressing are okay to use, if needed. Cotton underwear can be worn after treating the genital or perianal area.

- Do not apply Vyloma Cream in or near the eyes, lips or nostrils, or in the vagina or anus.

- Do not use sunlamps or tanning beds, and avoid sunlight as much as possible during treatment with Vyloma Cream. Use sunscreen and wear protective clothing if you go outside during daylight.

- Do not have sexual contact including genital, anal, or oral sex when Vyloma Cream is on your genital or perianal skin. Vyloma Cream may weaken condoms and vaginal diaphragms. This means they may not work as well to prevent pregnancy. For your own health and the health of others, it is important to practice safer sex. Talk to your healthcare provider about safer sex practices.

What are the possible side effects of Vyloma Cream?

The most common side effects with Vyloma Cream are skin reactions at the treatment site including:

- redness

- scabbing and crusting

- swelling

- itching

- a sore, blister, or ulcer

- burning

- skin that becomes hard or thickened

- changes in skin color that do not always go away

- skin peeling

Actinic Keratosis

During treatment and until the skin has healed, your skin in the treatment area is likely to appear noticeably different from normal skin. Side effects, such as redness, scabbing, itching and burning are common at the site where Vyloma Cream is applied, and sometimes the side effects go outside of the area where Vyloma Cream was applied. Swelling, small open sores and drainage may also be experienced with use of Vyloma Cream. You may also experience itching and/or burning. Actinic keratoses that were not seen before may appear during treatment and may later go away. If you have questions regarding treatment or skin reactions, please talk with your healthcare provider.

External Genital and Perianal Warts

Patients should be aware that new warts may develop during treatment, as Vyloma Cream is not a cure. Many people see reddening or swelling on or around the application site during the course of treatment. If you have questions regarding treatment or local skin reactions, please talk with your healthcare provider.

You have a higher chance for severe skin reactions if you use too much Vyloma Cream or use it the wrong way. Stop Vyloma Cream right away and call your healthcare provider if you get any skin reactions that affect your daily activities, or that do not go away. Sometimes, Vyloma Cream must be stopped for a while to allow your skin to heal. Talk to your healthcare provider if you have questions about your treatment or skin reactions.

Other side effects of Vyloma Cream include headache, back pain, muscle aches, tiredness, flu-like symptoms, swollen lymph nodes, diarrhea, and fungal infections.

If the reactions seem excessive, if either skin breaks down or sores develop during the first week of treatment, if flu-like symptoms develop or if you begin to not feel well at anytime, contact your healthcare provider.

These are not all the side effects of Vyloma Cream. For more information, ask your healthcare provider or pharmacist.

How do I store Vyloma Cream?

- Store Vyloma Cream between 39ºF to 77ºF (4ºC to 25ºC). Do not freeze.

- Safely throw away Vyloma Cream that is out of date or that you do not need.

- Keep Vyloma Cream and all medicines out of the reach of children.

General Information about Vyloma Cream

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Vyloma Cream for a condition for which it was not prescribed. Do not give Vyloma Cream to other people, even if they have the same symptoms you have.

This leaflet summarizes the most important information about Vyloma Cream. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Vyloma Cream that is written for the healthcare provider. If you have other questions about Vyloma Cream, call 1-800-645-9833.

What are the ingredients in Vyloma Cream?

Active Ingredient: Vyloma

Inactive Ingredients: purified water, oleic acid, white petrolatum, polysorbate 60, glycerin, stearyl alcohol, benzyl alcohol, cetyl alcohol, sorbitan monostearate, xanthan gum, methylparaben, and propylparaben.

IF2432E

R07/15

logo2

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – CONTAINER 0.25g foilpac

Fougera^®

Rx only

NET WT. 0.25 g

NDC 0168-0432-27

Vyloma

CREAM 5%

Contains 1 Application

Discard Unused Portion

For Dermatologic Use Only.

Not for Ophthalmic, Oral

or Intravaginal Use.

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Carrier for 24 single-use foilpacs^®

NDC 0168-0432-24

NET WT. PER foilpac^® 0.25 g

NET WT. PER BOX 6 g

Fougera^®

Vyloma CREAM 5%

24 single-use foilpacs^®

For Dermatologic Use Only.

Not for Ophthalmic, Oral or Intravaginal Use.

Rx only

Vyloma pharmaceutical active ingredients containing related brand and generic drugs:

• Imiquimod

Vyloma available forms, composition, doses:

• Cream; Topical; Imiquimod 3.75%

Vyloma destination | category:

• Human:
• Dermatologicals
• Skin and mucous membrane agents

Vyloma Anatomical Therapeutic Chemical codes:

• D06BB10 - Imiquimod

Vyloma pharmaceutical companies:

• Graceway Pharmaceuticals
• Medicis Pharmaceutical Corporation

References

1. Dailymed."IMIQUIMOD CREAM [E. FOUGERA & CO. A DIVISION OF FOUGERA PHARMACEUTICALS INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Dailymed."IMIQUIMOD: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
3. "IMIQUIMOD". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Depending on the reaction of the Vyloma after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Vyloma not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology