Imiquimod

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Cream, External:

Aldara: 5% (12 ea) [contains benzyl alcohol, cetyl alcohol, methylparaben, propylparaben, sorbitan monostearate(sorbitan stearate)]

Zyclara: 3.75% (28 ea) [contains benzyl alcohol, cetyl alcohol, methylparaben, propylparaben]

Zyclara Pump: 2.5% (7.5 g); 3.75% (7.5 g) [contains benzyl alcohol, cetyl alcohol, methylparaben, propylparaben]

Generic: 3.75% (7.5 g); 5% (1 ea, 12 ea, 24 ea)

Pharmacology

Mechanism of Action

Imiquimod, an immune response modifier, is a Toll-like receptor 7 agonist that activates immune cells. Topical application to the skin is associated with increases in markers for cytokines and immune cells.

Pharmacokinetics/Pharmacodynamics

Absorption

Minimal; systemic absorption more dependent upon surface area of application as opposed to dose

Excretion

Urine (<3% of applied dose as imiquimod and metabolites)

Time to Peak

9 to 12 hours

Use: Labeled Indications

Actinic keratosis (2.5%, 3.75% and 5% cream): Topical treatment of clinically typical, nonhyperkeratotic, nonhypertrophic, visible or palpable actinic keratoses on the full face or scalp in immunocompetent adults.

Genital and perianal warts (3.75% and 5% cream): Treatment of external genital and perianal warts (condyloma acuminata) in patients 12 years and older.

Superficial basal cell carcinoma (Aldara 5% cream): Topical treatment of biopsy-confirmed, primary superficial basal cell carcinoma in immunocompetent adults with a maximum tumor diameter of 2 cm located on the trunk (excluding anogenital skin), neck, or extremities (excluding hands and feet), only when surgical methods are medically less appropriate and patient follow-up can be reasonably assured.

Limitations of use: Safety and efficacy has not been established in immunosuppressed patients and in patients with basal cell nevus syndrome or xeroderma pigmentosum, or for prevention or transmission of HPV. Imiquimod should be used with caution in patients with preexisting autoimmune conditions. Imiquimod has been evaluated in pediatrics ages 2 to 12 with molluscum, contagiosum, however, studies failed to demonstrate efficacy.

Use: Off Label

Cutaneous flat wartc

Data from a small set of case reports supports the use of imiquimod in the adjuvant management of cutaneous flat warts Kim 2006. Additional data may be necessary to further define the role of imiquimod in this condition.

Herpes simplex virus (HSV) infection, acyclovir-resistantyes

Based on the Centers for Disease Control and Prevention (CDC) sexually transmitted diseases treatment guidelines, imiquimod might be effective as an alternative agent for the treatment of acyclovir-resistant HSV infections, although limited evidence is available and more studies are needed.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to imiquimod or any component of the formulation

Dosage and Administration

Dosing: Adult

Actinic keratosis: Topical:

2.5% and 3.75% cream: Apply thin film (using up to 2 packets or 2 full pump actuations) once daily before bedtime for 2 weeks to the skin of the affected area (either the entire face or balding scalp, but not both concurrently); leave on for ~8 hours, then remove with mild soap and water. After a 2-week period of no treatment, repeat with a second 2-week treatment (do not extend treatment cycles because of missed doses or rest periods). Maximum to be prescribed: 56 packets or 2 x 7.5 g pumps per 2 cycles of treatment. Treatment should continue for the full treatment course even if all actinic keratoses appear to be gone (do not extend the treatment period because of missed doses or rest periods).

5% cream: Apply 2 times per week (using up to 1 packet per application), prior to normal sleeping hours, to a defined treatment area(s) on the face or scalp (but not both concurrently; treatment should be limited to areas ≤25 cm²); leave on for ~8 hours, then remove with mild soap and water. Maximum to be prescribed: 36 packets per 16-week treatment period. Treatment should continue for 16 weeks (do not extend the treatment period beyond 16 weeks because of missed doses or rest periods).

Cutaneous flat warts (off-label use): Topical (5% cream): Apply once daily at bedtime until warts completely disappear up to a maximum of 12 weeks (Kim 2006). Additional data may be necessary to further define the role of imiquimod in this condition.

Genital and perianal warts: Topical:

3.75% cream: Apply a thin layer once daily (using up to 1 packet or 1 full actuation of pump) prior to bedtime; leave on skin for ~8 hours, then remove with mild soap and water. Continue treatment until there is total clearance of the warts or for a maximum duration of therapy of 8 weeks. Maximum to be prescribed: 56 packets or 2 x 7.5 g pumps per course of treatment.

5% cream: Apply a thin layer 3 times per week (on alternate days) prior to bedtime; leave on skin for 6 to 10 hours, then remove with mild soap and water. Continue until there is total clearance of the genital/perianal warts or for a maximum duration of therapy of 16 weeks.

Herpes simplex virus (HSV) infection, acyclovir-resistant (off-label use): Topical: Apply to lesions once daily for 5 consecutive days (CDC [Workowski 2015]). Note: Imiquimod strength is not specified in guidelines; however, 5% cream has been utilized in case reports (Abbo 2007; Brummitt 2006; Perkins 2011).

Superficial basal cell carcinoma (Aldara 5% cream): Topical: Apply once daily 5 days per week, prior to normal sleeping hours, for 6 weeks; leave on skin for ~8 hours, then remove with mild soap and water. Apply enough cream to cover the treatment area, including 1 cm of skin surrounding the tumor. Tumor treatment area should not exceed 3 cm (maximum of 2 cm tumor diameter plus a 1 cm margin of skin around the tumor). The diameter of cream droplet applied should range from 4 mm to 7 mm for tumor areas of 0.5 cm to 2 cm, respectively. Maximum to be prescribed: 36 packets during the 6-week treatment period. Safety/efficacy of repeated use in a previously treated area have not been established.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Genital and perianal warts (3.75% and 5% cream): Children ≥12 years and Adolescents: Topical: Refer to adult dosing.

Dosing adjustment for toxicity: Children ≥12 years and Adolescents:

Local skin reactions (eg, erythema, edema, skin erosion/weeping, scabbing): Temporarily interrupt treatment for up to several days for severe or intolerable reactions; may consider resuming therapy once reaction subsides.

Systemic/flu-like reactions (eg, malaise, fever, rigors): Consider temporary interruption of therapy.

Vulvar swelling: Interrupt or discontinue therapy for severe vulvar swelling.

Dosing: Adjustment for Toxicity

Local skin reactions (eg, erythema, edema, skin erosion/weeping, scabbing): Temporarily interrupt treatment for up to several days for severe or intolerable reactions; may consider resuming therapy once reaction subsides.

Systemic/flu-like reactions (eg, malaise, fever, rigors): Consider temporary interruption of therapy.

Vulvar swelling: Interrupt or discontinue therapy for severe vulvar swelling.

Administration

Topical: Wash hands prior to and following application. For topical use only; not for ophthalmic, oral, intra-anal, or intravaginal use. Avoid use in or on the lips and nostrils; do not use in or near the eyes. Do not occlude the application site. Pump (Zyclara) should be primed prior to first use only by pressing top of pump completely down repeatedly until cream appears; discard cream obtained during priming; no further priming is required throughout therapy.

Actinic keratosis: The treatment area should be washed with mild soap and thoroughly dried (~10 minutes) prior to application. Apply 5% cream over a single contiguous area (~25 cm²) on the face or scalp or 2.5% and 3.75% cream over an area on the face or scalp. Both face and scalp should not be treated concurrently. Apply a thin layer to the affected area and rub in until the cream is no longer visible. A transient increase in actinic keratosis lesion counts may be observed during treatment.

Genital/perianal warts: Apply a thin layer to external or perianal wart area and rub in until the cream is no longer visible. Avoid use of excessive amounts of cream. Nonocclusive dressings (such as cotton gauze or cotton underwear) may be used in the management of skin reactions.

Superficial basal cell carcinoma (Aldara): Treatment area should have a maximum diameter no more than 2 cm on the trunk, neck, or extremities (excluding the hands, feet, and anogenital skin). Treatment area should include a 1 cm margin around the tumor. Wash and thoroughly dry treatment area prior to application; apply a thin layer to the affected area (and margin) and rub in until the cream is no longer visible.

Storage

2.5% and 3.75% cream: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); do not freeze. Store pump upright. Discard pump after a full course of therapy has been completed. Discard partially used packets; do not reuse.

5% cream: Store at 4°C to 25°C (39°F to 77°F); do not freeze. Discard partially used packets; do not reuse.

Vyloma (Canadian product; not available in the US): Store at 15°C to 25°C (59°F to 77°F); do not freeze.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

Note: Frequency of reactions vary and are related to the degree of inflammation associated with the treated disease, number of weekly applications, product formulation, and individual sensitivity.

>10%:

Dermatologic: Localized erythema (58% to 100%; remote: 2%), xeroderma (local; including flaking, scaling; 18% to 93%; remote: 1%), crusted skin (local; 4% to 93%), skin sclerosis (local; 5% to 84%), dermal ulcer (local; 4% to 62%; remote: 2%), localized vesiculation (2% to 31%), excoriation (local; remote: 1%)

Infection: Fungal infection (2% to 11%)

Local: Localized edema (12% to 78%; remote: 1%), application site discharge (22% to 51%), local pruritus (3% to 32%), localized burning (9% to 26%)

Respiratory: Upper respiratory tract infection (15% to 33%)

1% to 10%:

Cardiovascular: Chest pain, localized blanching

Central nervous system: Headache (2% to 6%), fatigue (1% to 4%), dizziness (<1% to 3%), local discomfort (soreness; ≤3%), rigors (1%), anxiety, pain, tingling of skin (local)

Dermatologic: Skin pain (local; 1% to 8%), skin hypertrophy (local; 3%), skin infection (local; 1% to 3%), eczema (2%), cheilitis (≤2%), alopecia (1%), dermal hemorrhage (local), localized rash, papule (local), seborrhoeic keratosis, skin tenderness (local), stinging of the skin (local), tinea (cruris)

Endocrine & metabolic: Increased serum glucose

Gastrointestinal: Nausea (1% to 4%), diarrhea (1% to 3%), anorexia (≤3%), vomiting (1%), dyspepsia

Genitourinary: Bacterial vaginosis (3%), urinary tract infection (1%)

Hematologic & oncologic: Squamous cell carcinoma (4%), lymphadenopathy (2% to 3%)

Infection: Herpes simplex (≤3%)

Local: Local irritation (3% to 6%)

Neuromuscular & skeletal: Arthralgia (1% to 3%), myalgia (≥1%), back pain

Respiratory: Sinusitis (7%), flu-like symptoms (<1% to 4%), cough, pharyngitis, rhinitis

Miscellaneous: Fever (≤3%)

Postmarketing and/or case reports: Abdominal pain, acute exacerbations of multiple sclerosis, agitation, anemia, angioedema, atrial fibrillation, capillary leak syndrome, cardiac failure, cardiomyopathy, cellulitis (local), cerebrovascular accident, chills, depression, dermatitis, dyspnea, dysuria, erythema multiforme, erythema (scrotal), exacerbation of psoriasis, exacerbation of ulcerative colitis, exfoliative dermatitis, febrile seizures, Henoch-Schönlein purpura (IgA vasculitis), hepatic insufficiency, herpes zoster, hyperpigmentation, immune thrombocytopenia (ITP), insomnia, ischemia, lethargy, leukopenia, malignant lymphoma, myocardial infarction, pain (scrotal), palpitations, pancytopenia, paresis, proteinuria, psoriasis, pulmonary edema, scrotal edema, seizure, squamous cell carcinoma, supraventricular tachycardia, syncope, tachycardia, thrombocytopenia, thyroiditis, ulcerative colitis, ulcer (scrotal), urinary retention, urticaria, vertebral disk disease (spondylitis onset or exacerbated)

Warnings/Precautions

Concerns related to adverse effects:

• Local inflammatory reactions: Intense local inflammatory reactions (including skin weeping or erosion) may occur after a few applications; may require treatment interruption and may be accompanied by systemic symptoms (fever, malaise, myalgia); reactions may extend beyond the application site. Imiquimod has the potential to exacerbate inflammatory conditions of the skin (including chronic graft-versus-host disease).
• Photosensitivity: Due to the potential for increased sensitivity to sunlight, avoid or minimize sunlight exposure (including sunlamps or other artificial sunlight exposure) during treatment. Advise patients to wear protective clothing (eg, a hat) during treatment. Patients with sunburn should not to use imiquimod until full recovery form sunburn. Patients with a potential for considerable sun exposure (eg, due to their occupations) or inherent sensitivity to sunlight should use caution during imiquimod treatment.
• Systemic reactions: Flu-like symptoms (arthralgias, chills, fatigue, fever, malaise, myalgias, nausea, rigors) may accompany or precede local inflammatory reactions; may require treatment interruption.
• Vulvar swelling: Severe local inflammation of female external genitalia following topical application may lead to severe vulvar swelling and urinary retention; interrupt or discontinue treatment for severe symptoms.

Disease related concerns:

• Actinic keratosis: Safety and efficacy have not been established in the treatment of actinic keratosis with repeat use (more than 1 treatment course) in the same area. Safety of imiquimod 5% applied to areas of skin larger than 25 cm² has not been established. Lymphadenopathy has occurred in patients being treated for actinic keratosis; lymphadenopathy resolved within 4 weeks after completion of treatment.
• Autoimmune disorders: Safety and efficacy in immunosuppressed patients have not been established. Use with caution in patients with preexisting autoimmune disorders (onset or exacerbation of disease has been reported).
• Basal cell carcinoma: Use should be limited to superficial carcinomas with a maximum diameter of 2 cm. Safety and efficacy in treatment of other types of basal cell carcinoma (BCC) lesions of the face, head, and anogenital area, or other subtypes of BCC (including nodular and morpheaform), have not been established. Patients with superficial BCC treated with imiquimod should have regular follow up of the treatment site.
• Human papilloma viral disease: Imiquimod has not been evaluated for the treatment of urethral, intravaginal, cervical, rectal, or intra-anal human papilloma viral disease and is not recommended for these conditions.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage forms specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP 1997; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.

Other warnings/precautions:

• Appropriate use: Not intended for oral, nasal, intravaginal, or ophthalmic use. Administration is not recommended until tissue is healed from any previous drug or surgical treatment. Treatment should not be prolonged beyond recommended period due to missed doses or rest periods. Safety and efficacy have not been established for basal cell nevus syndrome, in immunocompromised patients, or for xeroderma pigmentosum. Safety and efficacy of the 2.5% cream in the treatment of external genital warts have not been established.

Monitoring Parameters

Assess response to therapy periodically (reduction in lesion size is indicative of a therapeutic response); monitor for local skin reactions and for signs and symptoms of hypersensitivity to imiquimod.

Pregnancy

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies following oral administration. Imiquimod may weaken condoms and vaginal diaphragms. Imiquimod appears to pose a low risk, but use in pregnant women should be avoided until additional data are available (CDC [Workowski 2015]).

Patient Education

What is this drug used for?

• It is used to treat genital warts.
• It is used to treat perianal warts.
• It is used to treat skin harmed by the sun and some skin cancers.

Frequently reported side effects of this drug

• Burning
• Skin scabbing and crusting
• Dry skin
• Itching
• Flaking
• Oozing
• Pain
• Redness
• Skin sores
• Sinus pain
• Common cold symptoms
• Loss of strength and energy
• Skin discoloration
• Swelling
• Headache
• Nausea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Flu-like symptoms
• Severe skin irritation
• Severe skin reaction
• Bleeding
• Swollen glands
• Unable to pass urine
• Vaginal pain or swelling
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.