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Imiquimod

Pronunciation

Pronunciation

(i mi KWI mod)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Cream, External:

Aldara: 5% (12 ea, 24 ea [DSC]) [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: 5% (1 ea, 12 ea, 24 ea)

Brand Names: U.S.

  • Aldara
  • Zyclara
  • Zyclara Pump

Pharmacologic Category

  • Skin and Mucous Membrane Agent
  • Topical Skin Product

Pharmacology

Precise mechanism of action is unknown; Toll-like receptor 7 agonist that induces cytokines, including interferon-alpha and others

Absorption

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

Excretion

Urine (≤2% of applied dose as imiquimod and metabolites)

Time to Peak

9-12 hours

Special Populations: Renal Function Impairment

No data available.

Special Populations: Hepatic Function Impairment

No data available.

Use: Labeled Indications

Aldara: Treatment of external genital and perianal warts/condyloma acuminata; nonhyperkeratotic, nonhypertrophic actinic keratosis on face or scalp; superficial basal cell carcinoma (sBCC) with a maximum tumor diameter of 2 cm located on the trunk (excluding anogenital skin), neck, or extremities (excluding hands or feet)

Vyloma (Canadian availability; not available in the US): Treatment of external genital and perianal warts/condyloma acuminata

Zyclara:

US labeling: Treatment of external genital and perianal warts/condyloma acuminata (3.75% formulation); treatment of clinically typical visible or palpable, actinic keratoses on face or scalp (2.5% or 3.75% formulation)

Canadian labeling: Treatment of clinically typical visible or palpable, actinic keratoses on face or scalp

Use: Unlabeled

Treatment of common warts

Contraindications

U.S. labeling: There are no contraindications listed within the approved manufacturer’s labeling.

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

Dosing: Adult

Note: Imiquimod treatment should not be prolonged beyond recommended period due to missed doses or rest periods.

U.S. labeling:

Perianal warts/condyloma acuminata: Topical:

Aldara: Apply a thin layer 3 times/week on alternative days prior to bedtime and leave on skin for 6-10 hours. Remove by washing with mild soap and water. Continue imiquimod treatment until there is total clearance of the genital/perianal warts or a maximum duration of therapy of 16 weeks.

Zyclara 3.75%: Apply a thin layer using up to 1 packet or 1 full actuation of pump once daily prior to bedtime and leave on skin for ~8 hours. Remove with mild soap and water. Continue treatment until there is total clearance of the warts or a maximum duration of therapy of 8 weeks. Patient should not receive more than 56 packets or 2 x 7.5 g pumps or 1 x 15 g pump per course of treatment.

Actinic keratosis: Topical: Note: Prescribed course of therapy should be completed even if all lesions appear to be gone. Safety and efficacy of repeated use in a previously treated area has not been established.

Aldara: Treatment should be limited to areas ≤25 cm2; apply 2 times/week for 16 weeks to a treatment area on face or scalp (but not both concurrently); no more than 1 packet should be applied at each application and no more than 36 packets applied per 16 weeks; apply prior to bedtime and leave on skin for ~8 hours. Remove with mild soap and water.

Zyclara 2.5%, 3.75%: Treatment consists of 2 cycles (14 days each) separated by 1 rest period (14 days) with no treatment. Apply up to 2 packets or 2 full actuations of pump once daily at bedtime to affected area on either face or balding scalp (but not both concurrently); leave on skin for ~8 hours. Remove with mild soap and water. Patient should not receive more than 56 packets or 2 x 7.5 g pumps or 1 x 15 g pump per 2 cycles of treatment.

Superficial basal cell carcinoma: Topical: Aldara: Apply once daily prior to bedtime, 5 days/week for 6 weeks. No more than 36 packets should be used during the 6-week treatment period. 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. Leave on skin for ~8 hours. Remove with mild soap and water. Safety and efficacy of repeated use in a previously treated area have not been established.

Canadian labeling:

Actinic keratosis: Topical: Note: Prescribed course of therapy should be completed even if all lesions appear to be gone; safety and efficacy of repeated use in a previously treated area have not been established.

Aldara: Treatment should be limited to areas ≤25 cm2; apply 2 times/week for 16 weeks to a treatment area on face or scalp (but not both concurrently); no more than 1 packet should be applied at each application; apply prior to bedtime and leave on skin for ~8 hours. Remove with mild soap and water.

Zyclara: Treatment should be limited to an area <200 cm2 on the face or scalp and consists of 2 cycles (14 days each) separated by 1 rest period (14 days) with no treatment. Apply up to 2 packets or 2 full actuations of pump once daily at bedtime to affected area on either face or balding scalp (but not both concurrently). Leave on skin for ~8 hours. Remove with mild soap and water. Patient should not receive more than 56 packets or 2 x 7.5 g pumps or 1 x 15 g pump per 2 cycles of treatment.

External genital and/or perianal warts/condyloma acuminata: Topical:

Aldara: Apply a thin layer 3 times/week prior to bedtime and leave on skin for 6-10 hours. Remove with mild soap and water. Examples of 3 times/week application schedules are: Monday, Wednesday, Friday; or Tuesday, Thursday, Saturday. Continue treatment until there is total clearance of the warts or a maximum duration of therapy of 16 weeks.

Vyloma: Apply a thin layer once daily prior to bedtime and leave on skin for ~8 hours. Remove with mild soap and water. Continue treatment until there is total clearance of the warts or maximum duration of therapy of 8 weeks.

Superficial basal cell carcinoma: Topical: Aldara: Apply once daily prior to bedtime, 5 days/week for 6 weeks. 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. Leave on skin for ~8 hours. Remove with mild soap and water. Safety and efficacy of repeated use in a previously treated area have not been established.

Common warts (off-label use): Topical (5% cream): Apply once daily prior to bedtime for 5 days/week for up to 16 weeks (Hengge, 2000) or apply twice daily for up to 24 weeks (Grussendorf-Conen, 2002)

Herpes simplex virus (HSV) infection, acyclovir-resistant (off-label use): Apply to lesions once daily for 5 consecutive days (CDC [Workowski 2015])

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

External genital and perianal warts/condyloma acuminata: Topical: Aldara: Children ≥12 years: Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Adjustment for Toxicity

Local skin reactions (eg, erythema, edema, scabbing, etc): 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, etc): Consider temporary interruption of therapy.

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

Administration

Topical: For all products, wash hands prior to and following application. Zyclara pump 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. Zyclara pump should be discarded after a full course of therapy has been completed. Partially used packets of imiquimod cream should be discarded and not reused. Do not occlude the application site.

Actinic keratosis: The treatment area should be washed and thoroughly dried prior to application. Apply Aldara over a single contiguous area (approximately 25 cm2) on the face or scalp or Zyclara over an area <200 cm2 on the face or scalp. Both areas should not be treated concurrently. Apply a thin layer to the affected area and rub in until the cream is no longer visible. Avoid contact with the eyes, lips, and nostrils.

External anogenital warts: Instruct patients to apply to external or perianal warts; not for vaginal use. Apply a thin layer to the 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. Avoid contact with the eyes, lips, and nostrils.

Storage

Aldara: Store at 4°C to 25°C (39°F to 77°F); do not freeze.

Vyloma (Canadian availability; not available in U.S.): Store at 15°C to 25°C (59°F to 77°F); do not freeze.

Zyclara: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); do not freeze.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

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 (Limited to important or life-threatening): Acute exacerbations of multiple sclerosis, anemia, angioedema, atrial fibrillation, capillary leak syndrome, cardiac failure, cardiomyopathy, cerebrovascular accident, depression, erythema multiforme, erythema (scrotal), exacerbation of ulcerative colitis, exfoliative dermatitis, febrile seizures, hepatic insufficiency, Henoch-Schönlein purpura (IgA vasculitis), herpes zoster, hyperpigmentation, immune thrombocytopenia (ITP), ischemia, leukopenia, malignant lymphoma, myocardial infarction, pain (scrotal), palpitations, pancytopenia, paresis, proteinuria, psoriasis (onset or exacerbated), pulmonary edema, scrotal edema, seizure, squamous cell carcinoma, supraventricular tachycardia, syncope, tachycardia, thrombocytopenia, thyroiditis, ulcerative colitis, ulcer (scrotal), urinary retention, vertebral disk disease (spondylitis onset or exacerbated)

Warnings/Precautions

Concerns related to adverse effects:

• Local inflammatory reactions: Intense local inflammatory reactions may occur after a few applications and may be accompanied by systemic symptoms (fever, malaise, myalgia); reactions may extend beyond the application site. Interruption of therapy may be necessary.

• Photosensitivity: May increase sunburn susceptibility; in an animal study, topical imiquimod administration and concurrent ultraviolet radiation decreased the median time to skin tumor formation. Patients should protect themselves from the sun and artificial forms of sunlight.

• Vulvar swelling: Severe inflammation of female external genitalia following topical application may lead to severe vulvar swelling and urinary retention; interruption or discontinuation of therapy may be necessary.

Disease related concerns:

• Autoimmune disorders: Use caution in patients with pre-existing autoimmune disorders (onset or exacerbation of disease has been reported rarely with imiquimod).

• Basal cell carcinoma: Appropriate use: Should be limited to superficial carcinomas with a maximum diameter of 2 cm. Safety and efficacy in treatment of sBCC lesions of the face, head, and anogenital area, or other subtypes of basal cell carcinoma (including nodular and morpheaform), have not been established.

• Basal cell nevus syndrome: Safety and efficacy have not been established for basal cell nevus syndrome.

• Genital warts: 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.

• Skin inflammatory conditions: Has the potential to exacerbate inflammatory conditions of the skin (including chronic graft-versus-host disease).

• Xeroderma pigmentosum: Safety and efficacy have not been established for xeroderma pigmentosum.

Special populations:

• Immunocompromised patients: Safety and efficacy have not been established in immunosuppressed patients.

• Pediatric: Following 2 randomized, double-blind, placebo-controlled trials, efficacy of imiquimod was not established for molluscum contagiosum in children 2-12 years of age.

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.

• Zyclara 2.5%: Appropriate use: Safety and efficacy in the treatment of external genital warts have not been established.

Monitoring Parameters

Reduction in lesion size is indicative of a therapeutic response; signs and symptoms of hypersensitivity to imiquimod

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

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience scleroderma, skin scabbing and crusting, skin sores, skin discoloration, edema, headache, or nausea. Have patient report immediately to prescriber flu-like symptoms, severe skin irritation, skin ulcers, oozing, hemorrhaging, enlarged lymph nodes, or vaginal irritation or edema (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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