Imiquimod

• Imiquimod Cream, 3.75% is indicated for the topical treatment of clinically typical, visible, or palpable actinic keratoses (AK) of the face or balding scalp in immunocompetent adults. (
  
  
  1.1 Actinic Keratosis

  Imiquimod Cream, 3.75% is indicated for the topical treatment of clinically typical, visible or palpable actinic keratoses (AK) of the face or balding scalp in immunocompetent adults.
  )
  
• Imiquimod Cream, 3.75% is indicated for the topical treatment of external genital and perianal warts (EGW) in immunocompetent patients 12 years of age or older. (
  
  
  1.2 External Genital Warts

  Imiquimod Cream, 3.75% is indicated for the topical treatment of external genital and perianal warts (EGW) in immunocompetent patients 12 years of age and older.
  )
  

For topical use only; Imiquimod Cream is not for oral, ophthalmic, intra-anal or intravaginal use.

Imiquimod Cream, 3.75% is a white to faintly yellow cream available in pump bottles. Each pump bottle, when actuated after priming, delivers 0.235 grams of cream.

Available data from case reports and case series have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes when imiquimod is used during pregnancy. There are no controlled or large-scale epidemiologic studies and no exposure registries with imiquimod use in pregnant women. In animal reproduction studies, there were no adverse developmental effects observed after oral administration of imiquimod in pregnant rats and intravenous administration of imiquimod in pregnant rabbits during organogenesis at doses up to 28 times and 115 times, respectively, the maximum recommended human dose (MRHD)

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, and other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

The MRHD was set at two packets per treatment of Imiquimod Cream, 3.75%, (18.75 mg imiquimod) for the animal multiples of human exposure presented 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 to pregnant female rats. In the presence of maternal toxicity, fetal effects noted at 20 mg/kg/day (163 times the MRHD based on AUC comparison) 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 malformation were noted at 5 mg/kg/day (28 times the MRHD based on AUC comparison).

Intravenous doses of 0.5, 1, and 2 mg/kg/day imiquimod were administered during the period of organogenesis to pregnant female rabbits. No treatment-related effects on embryofetal toxicity or malformation were noted at 2 mg/kg/day (2.1 times the MRHD based on BSA comparison), the highest dose evaluated in this study, or 1 mg/kg/day (115 times the MRHD based on AUC comparison).

A combined fertility and peri- and postnatal 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 postnatal development were noted at doses up to 6 mg/kg/day (25 times the MRHD based on AUC comparison), 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 (25 times the MRHD based on AUC comparison). This fetal effect was also noted in the oral rat embryofetal development study conducted with imiquimod. No treatment-related malformations were noted at 3 mg/kg/day (12 times the MRHD based on AUC comparison).

• Local Skin Reactions:
  Intense local inflammatory reactions can occur (e.g., skin weeping, erosion). Dosage interruption may be required. Severe vulvar swelling may occur and lead to urinary retention; interrupt dosing or discontinue for severe vulvar swelling. (
  
  
  2.2 Dosage and Administration for Actinic Keratosis

  Use Imiquimod Cream, 3.75% for the treatment of AK. Apply a thin layer of Imiquimod Cream once daily before bedtime to the area with AK (either entire face or balding scalp) for two 2-week treatment cycles separated by a 2-week no-treatment period. Rub in until the cream is no longer visible. Apply up to 0.5 grams (two packets or two full actuations of the pump) of Imiquimod Cream at each application. Leave Imiquimod Cream on the skin for approximately 8 hours and then remove with mild soap and water.

  For local skin reactions, a dosage interruption of several days may be taken if required based on the patient’s discomfort or severity of the local skin reaction

  [see Warnings and Precautions (5.1)]

  . Do not extend either 2-week treatment cycle due to missed doses or rest periods.

  Assess response to treatment after resolution of local skin reactions.

  A transient increase in lesion counts may be observed during treatment; however, continue dosing as prescribed. Continue treatment for the full treatment course even if all AK appear to be gone.
  ,
  
  
  5.1 Local Skin Reactions

  Local skin reactions including skin weeping or erosion have been reported with use of Imiquimod Cream and can occur after a few applications

  [see

  Adverse Reactions (6)].

  Concomitant use of Imiquimod Cream and any other imiquimod products, in the same treatment area, may increase the risk for and severity of local skin reactions.

  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 and to urinary retention.

  Avoid sexual (genital, anal, oral) contact while Imiquimod Cream is on the skin.

  To reduce the risk of local skin reactions and manage local skin reactions that occur with Imiquimod Cream treatment:

  • Avoid concomitant use of Imiquimod Cream with any other imiquimod product in the same treatment area.
  • Avoid application of Imiquimod Cream to skin that is not intact (i.e., any area with an abrasion, cut, burn, rash, infection, or other condition that has altered skin integrity).
  • An interruption of dosing may be required for local skin reactions
    [see
    Dosage and Administration (2.2, 2.3)]
    . Interrupt dosing or discontinue Imiquimod Cream for severe vulvar swelling
    [see
    Dosage and Administration (2.3)]
    .
  • If severe local skin reactions occur, instruct patients to remove Imiquimod Cream by washing the treatment area with mild soap and water.
  )
  
• Systemic Reactions
  : Flu-like signs and symptoms have occurred. Consider dosage interruption for systemic reactions. (
  
  
  5.1 Local Skin Reactions

  Local skin reactions including skin weeping or erosion have been reported with use of Imiquimod Cream and can occur after a few applications

  [see

  Adverse Reactions (6)].

  Concomitant use of Imiquimod Cream and any other imiquimod products, in the same treatment area, may increase the risk for and severity of local skin reactions.

  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 and to urinary retention.

  Avoid sexual (genital, anal, oral) contact while Imiquimod Cream is on the skin.

  To reduce the risk of local skin reactions and manage local skin reactions that occur with Imiquimod Cream treatment:

  • Avoid concomitant use of Imiquimod Cream with any other imiquimod product in the same treatment area.
  • Avoid application of Imiquimod Cream to skin that is not intact (i.e., any area with an abrasion, cut, burn, rash, infection, or other condition that has altered skin integrity).
  • An interruption of dosing may be required for local skin reactions
    [see
    Dosage and Administration (2.2, 2.3)]
    . Interrupt dosing or discontinue Imiquimod Cream for severe vulvar swelling
    [see
    Dosage and Administration (2.3)]
    .
  • If severe local skin reactions occur, instruct patients to remove Imiquimod Cream by washing the treatment area with mild soap and water.
  )
  
• Ultraviolet Light Exposure Risks
  :
  
  
  Avoid or minimize exposure to
  
  
  sunlight and sunlamps. Wear protective clothing. (
  
  
  5.3 Ultraviolet Light Exposure Risks

  Imiquimod Cream may cause heightened sunburn susceptibility. Avoid or minimize exposure to sunlight (including sunlamps) during use of Imiquimod Cream. Instruct patients to use sunscreen and wear protective clothing (e.g., a hat). Advise patients not to use Imiquimod Cream until fully recovered from a sunburn.
  )