Imiquimod

D06B - Chemotherapeutics for dermatological use ATC D06BB10 Small molecule approved 1997 Topical Natural product Black-box warning

JFDA label: Jedara Cream 5%

⚠ Black-Box Warning

Mechanism of Action

Agonist of Toll-like receptor 7 — Toll-like receptor 7 agonist

Target	Action	Gene / class
Toll-like receptor 7 efficacy	AGONIST	TLR7

Indications

Approved

Actinic keratosis (2.5%, 3.75% and 5% cream)
Genital and perianal warts (3.75% and 5% cream)
Superficial basal cell carcinoma (Aldara 5% cream)

Off-label

Cutaneous flat wart
Herpes simplex virus (HSV) infection, acyclovir-resistant

Contraindications

Source: Lexicomp

Hypersensitivity to imiquimod or any component of the formulation Absolute
There are no contraindications listed in the manufacturer's US labeling Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (2)

Common Chest pain · localized blanching

Nervous system disorders (3)

Common dizziness, skin hypertrophy, skin infection, eczema, cheilitis, alopecia, dermal hemorrhage (local), localized rash, papule (local), seborrhoeic keratosis, skin tenderness (local), stinging of the ski · fatigue · Headache

Renal and urinary disorders (2)

Common Bacterial vaginosis · urinary tract infection

Blood and lymphatic system disorders (2)

Common lymphadenopathy · Squamous cell carcinoma

Metabolism and nutrition disorders (1)

Common Increased serum glucose

Gastrointestinal disorders (5)

Common anorexia · diarrhea · dyspepsia · Nausea · vomiting

Skin and subcutaneous tissue disorders (7)

Very Common crusted skin · dermal ulcer · excoriation · Localized erythema · localized vesiculation · skin sclerosis · xeroderma

Musculoskeletal and connective tissue disorders (3)

Common Arthralgia · back pain · myalgia

Infections and infestations (2)

Very Common Fungal infection

Common Herpes simplex

General disorders and administration site conditions (5)

Very Common application site discharge · local pruritus · localized burning · Localized edema

Common Local irritation

Other (56)

Not Known Abdominal pain · acute exacerbations of multiple sclerosis · agitation · and individual sensitivity · anemia · angioedema · atrial fibrillation · capillary leak syndrome · cardiac failure · cardiomyopathy · cellulitis (local) · cerebrovascular accident · chills · depression · dermatitis · dyspnea · dysuria · erythema (scrotal) · erythema multiforme · exacerbation of psoriasis · exacerbation of ulcerative colitis · exfoliative dermatitis · febrile seizures · Frequency of reactions vary and are related to the degree of inflammation associated with the treated disease · Henoch-Schönlein purpura (IgA vasculitis) · hepatic insufficiency · herpes zoster · hyperpigmentation · immune thrombocytopenia (ITP) · insomnia · ischemia · lethargy · leukopenia · malignant lymphoma · myocardial infarction · number of weekly applications · pain (scrotal) · palpitations · pancytopenia · paresis · product formulation · proteinuria · psoriasis · pulmonary edema · scrotal edema · seizure · supraventricular tachycardia · syncope · tachycardia · thrombocytopenia · thyroiditis · ulcer (scrotal) · ulcerative colitis · urinary retention · urticaria · vertebral disk disease (spondylitis onset or exacerbated)

Respiratory, thoracic and mediastinal disorders (3)

Very Common Upper respiratory tract infection

Common flu-like symptoms · Sinusitis

Dosing

Source: Lexicomp

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). 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. 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. 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. Herpes simplex virus (HSV) infection, acyclovir-resistant (off-label use): Topical: Apply to lesions once daily for 5 consecutive days (CD

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

Refer to adult dosing.

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

Warnings & Precautions

Source: Lexicomp

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.

Pregnancy & Lactation

Pregnancy

FDA category C

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]).

Lactation

It is not known if imiquimod is present in breast milk. The manufacturer recommends that caution be exercised when administering imiquimod to breastfeeding women.

Monitoring

Clinical pearl	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.

Chemistry & Properties

Formula	C14H16N4
Molecular weight	240.31 g/mol
IUPAC name	1-(2-methylpropyl)imidazo[4,5-c]quinolin-4-amine
CAS	99011-02-6
PubChem CID	57469
InChIKey	`DOUYETYNHWVLEO-UHFFFAOYSA-N`
logP	2.82 (XLogP 2.6)
Polar surface area	56.73 Å²
H-bond acceptors / donors	4 / 1
Drug-likeness (QED)	0.75
Lipinski violations	0

SMILES

CC(C)Cn1cnc2c(N)nc3ccccc3c21

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2B6	Inhibitor	—
CYP2C19	Substrate	—
CYP2C8	Inhibitor	—
CYP2C9	Inhibitor	—
CYP2D6	Inhibitor	—
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MATE2 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Jedara Cream	Cream 5 %	12 sachet	JERASH PHARMACEUTICALS LTD.CO/JORDAN	38.470
Aldara	Sachet 5 %	12 sachet	Khoury Drug Store	55.520