imiquimod

E. FOUGERA & CO. A division of Fougera Pharmaceuticals Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONfougera IMIQUIMOD CREAM 5%R only[I MIḰ WEH MOD]These highlights do not include all the information needed to use Imiquimod Cream safely and effectively.See full prescribing information for Imiquimod Cream.Imiquimod CreamFor topical use onlyInitial U.S. Approval 1997 INDICATIONS AND USAGEImiquimod Cream is indicated for the topical treatment of: Clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses (AK) 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 2-12 (1.4, 8.4) DOSAGE AND ADMINISTRATIONImiquimod Cream is not for oral, ophthalmic, or intravaginal use. (2) 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) DOSAGE FORMS AND STRENGTHS Imiquimod 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 imiquimod. (3) CONTRAINDICATIONS None (4) WARNINGS AND PRECAUTIONS Intense local inflammatory reactions can occur (e.g., skin weeping, erosion). 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) Side EffectsMost common adverse reactions (incidence >28%) 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 E. Fougera & Co. at 1 -800-645-9833 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 IMIQUIMOD INDICATIONS AND USAGE
  • 1.1 Actinic Keratosis
  • 1.3 External Genital Warts
  • 1.4 Limitations of Use
  • 1.5 Unevaluated Populations
• 2 IMIQUIMOD DOSAGE AND ADMINISTRATION
  • 2.1 Actinic Keratosis
  • 2.3 External Genital Warts
• 3 DOSAGE FORMS AND STRENGTHS
• 4 IMIQUIMOD CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Local Inflammatory Reactions
  • 5.2 Systemic Reactions
  • 5.3 Ultraviolet Light Exposure
  • 5.4 Unevaluated imiquimod Uses: Actinic Keratosis
  • 5.6 Unevaluated imiquimod Uses: External Genital Warts
• 6 IMIQUIMOD ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience: Actinic Keratosis
  • 6.3 Clinical Trials Experience: External Genital Warts
  • 6.4 Clinical Trials Experience: Dermal Safety Studies
  • 6.5 Postmarketing Experience
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
• 10 OVERDOSAGE
• 11 IMIQUIMOD DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.1 Actinic Keratosis
  • 14.3 External Genital Warts
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 General Information: All Indications
  • 17.2 Local Skin Reactions: All Indications
  • 17.3 Systemic Reactions: All Indications
  • 17.4 Patients Being Treated for Actinic Keratosis (AK)
  • 17.6 Patients Being Treated for External Genital Warts

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Actinic Keratosis

Imiquimod 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

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

1.4 Limitations of Use

Imiquimod 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 (8.4)].

1.5 Unevaluated Populations

The safety and efficacy of imiquimod cream in immunosuppressed patients have not been established. Imiquimod Cream should be used with caution in patients with pre-existing autoimmune conditions.

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

2 DOSAGE AND ADMINISTRATION

The application frequency for Imiquimod Cream is different for each indication.
Imiquimod is not for oral, ophthalmic, or intravaginal use.

2.1 Actinic Keratosis

Imiquimod 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. Imiquimod 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 Imiquimod Cream should be applied to the contiguous treatment area at each application. Imiquimod 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 Imiquimod Cream therapy.

It is recommended that patients wash their hands before and after applying Imiquimod 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. [see Adverse Reactions (6.1, 6.5)] 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.

Imiquimod 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

Imiquimod Cream should be applied 3 times per week to external genital/perianal warts. Imiquimod 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. Imiquimod Cream should be applied prior to normal sleeping hours and left on the skin for 6 -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 Imiquimod Cream therapy.

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

A thin layer of Imiquimod 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. [see Adverse Reactions (6.3, 6.5)]. 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.

Imiquimod 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

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

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Local Inflammatory Reactions

Intense local inflammatory reactions including skin weeping or erosion can occur after few applications of imiquimod cream and may require an interruption of dosing. [see Dosage and Administration (2) and Adverse Reactions (6)]. Imiquimod 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 imiquimod 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. [see Adverse Reactions (6)].

5.3 Ultraviolet Light Exposure

Exposure to sunlight (including sunlamps) should be avoided or minimized during use of imiquimod cream because of concern for heightened sunburn susceptibility. Patients should be warned to use protective clothing (e.g., a hat) when using imiquimod cream. Patients with sunburn should be advised not to use imiquimod 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 imiquimod cream.

Imiquimod cream shortened the time to skin tumor formation in an animal photoco-carcinogenicity study [see Nonclinical Toxicology (13.1)]. 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 imiquimod cream in the treatment of actinic keratosis with repeated use, i.e. more than one treatment course, in the same area.

The safety of imiquimod cream applied to areas of skin greater than 25 cm² (e.g. 5 cm X 5 cm) for the treatment of actinic keratosis has not been established [see Clinical Pharmacology (12.3)].

5.6 Unevaluated Uses: External Genital Warts

Imiquimod 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.

6.1 Clinical Trials Experience: Actinic Keratosis

The data described in Table 1 reflect exposure to imiquimod cream or vehicle in 436 subjects enrolled in two double-blind, vehicle-controlled studies. Subjects applied imiquimod 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.

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 imiquimod cream and 3 of 220 subjects (1%) on vehicle cream had at least one rest period. Of these imiquimod cream subjects, 32 (91%) resumed therapy after a rest period.

In the AK studies, 22 of 678 (3.2%) of imiquimod cream-treated subjects developed treatment site infections that required a rest period off imiquimod cream and were treated with antibiotics (19 with oral and 3 with topical). Of the 206 imiquimod 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% (4/327) 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.

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 imiquimod cream are listed below.

Adverse reactions judged to be possibly or probably related to imiquimod 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 imiquimod cream causes photoallergenicity or contact sensitization in healthy skin; however, cumulative irritancy testing revealed the potential for imiquimod cream to cause irritation, and application site reactions were reported in the clinical studies [see Adverse Reactions (6)].

6.5 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of imiquimod 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-Schonlein purpura syndrome

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:
Note: The Maximum Recommended Human Dose (MRHD) was set at 2 packets per treatment of imiquimod cream (25 mg imiquimod) for the animal multiple of human exposure ratios presented in this label. If higher doses than 2 packets of imiquimod 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 imiquimod cream was noted in the clinical pharmacokinetic study conducted in actinic keratosis subjects [see Clinical Pharmacology (12.3)]. The AUC after topical application of 6 packets of imiquimod cream was 8 fold greater than the AUC after topical application of 2 packets of imiquimod cream in actinic keratosis subjects. Therefore, if a dose of 6 packets per treatment of imiquimod 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 imiquimod were administered during the period of organogenesis (gestational days 6 – 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 imiquimod were administered during the period of organo-genesis (gestational days 6 – 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 imiquimod 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 imiquimod. 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. Imiquimod 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 imiquimod is excreted in human milk following use of Imiquimod Cream. Because many drugs are excreted in human milk, caution should be exercised when Imiquimod 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 imiquimod cream for AK in patients less than 18 years of age has not been established.

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

Imiquimod cream was evaluated in two randomized, vehicle-controlled, double-blind trials involving 702 pediatric subjects with molluscum contagiosum (MC) (470 exposed to Imiquimod; median age 5 years, range 2-12 years). Subjects applied imiquimod 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 imiquimod cream group compared with 26% (28/106) in the vehicle group. In Study 2,the clearance rates were 24% (60/253) in the imiquimod 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% imiquimod vs. 3% vehicle) and conjunctivitis (3% imiquimod 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 imiquimod 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 Cmax of 9.66 ng/mL after multiple dosing. Children aged 2-5 years received doses of 12.5 mg (one packet) or 25 mg (two packets) of imiquimod and had median multiple-dose peak serum drug levels of approximately 0.2 or 0.5 ng/mL, respectively.

Children aged 6-12 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 imiquimod 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 Imiquimod 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 imiquimod doses of >200 mg (equivalent to imiquimod content of >16 packets) was hypotension, which resolved following oral or intravenous fluid administration.

11 DESCRIPTION

Imiquimod Cream 5% is an immune response modifier for topical administration. Each gram contains 50 mg of imiquimod 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, imiquimod is 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine. Imiquimod has a molecular formula of C₁₄H₁₆N₄ and a molecular weight of 240.3. Its structural formula is: