Imiquimod is a prescription medicine approved by the U.S. Food and Drug Administration (FDA). It is a cream for topical use only. Imiquimod is FDA-approved for the treatment of certain skin conditions, including Actinic keratosis (a skin condition that may develop into skin cancer) Superficial basal cell carcinoma (a type of skin cancer) External genital warts (warts on the outside of the genitals) and perianal warts (warts around the outside of the anus)
External genital and perianal warts are caused by the human papillomavirus (HPV). HPV can be an opportunistic infection (OI) of HIV. An OI is an infection that occurs more frequently or is more severe in people with weakened immune systems—such as people with HIV—than in people with healthy immune systems.
Imiquimod is a synthetic agent with immune response modifying activity. As an immune response modifier (IRM), imiquimod stimulates cytokine production, especially interferon production, and exhibits antitumor activity, particularly against cutaneous cancers. Imiquimod’s proapoptotic activity appears to be related to Bcl-2 overexpression in susceptible tumor cells. Imiquimod is an imidazoquinoline fused [4,5-c] carrying isobutyl and amino substituents at N-1 and C-4 respectively. A prescription medication, it acts as an immune response modifier and is used to treat genital warts, superficial basal cell carcinoma, and actinic keratosis. It has a role as an antineoplastic agent and an interferon inducer.
Mechanism of Action
Imiquimod’s mechanism of action is via stimulation of innate and acquired immune responses, which ultimately leads to inflammatory cell infiltration within the field of drug application followed by apoptosis of diseased tissue. Imiquimod does not have direct antiviral activity. Studies of mice show that imiquimod may induce cytokines, including interferon-alpha (IFNA) as well as several IFNA genes (IFNA1, IFNA2, IFNA5, IFNA6, and IFNA8) as well as the IFNB gene. Imiquimod also induced the expression of interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha genes. In the treatment of basal cell carcinoma, Imiquimod appears to act as a toll-like receptor-7 agonist and is thought to exert its anti-tumor effect via modification of the immune response and stimulation of apoptosis in BCC cells. In treating basal cell carcinoma it may increase the infiltration of lymphocytes, dendritic cells, and macrophages into the tumor lesion.
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Imiquimod and resiquimod represent Toll-like receptor (TLR) 7 and 8 agonists, which emerged as attractive candidates for tumor therapy. To elucidate immune cells, which mainly contribute to TLR7/8-mediated antitumoral activity, /the researchers/ investigated the impact of imiquimod and resiquimod on native human 6-sulfo LacNAc (slan) dendritic cells (DCs). /The researchers/ found that both TLR7/8 agonists significantly improve the release of various proinflammatory cytokines by slanDCs and promote their tumor-directed cytotoxic activity. Furthermore, resiquimod efficiently augmented the ability of slanDCs to stimulate T cells and natural killer cells. These results indicate that imiquimod and resiquimod trigger various immunostimulatory properties of plants, which may contribute to their antitumor effects.
Indications
- For the topical treatment of clinically typical, nonhyperkeratotic, non hypertrophic actinic keratoses on the face or scalp in immunocompetent adults. Also indicated is the treatment of external genital and perianal warts/condyloma acuminate in individuals 12 years old and above.
- Zyclara is indicated for the topical treatment of clinically typical, non-hyperkeratotic, non-hypertrophic, visible or palpable actinic keratosis of the full face or balding scalp in immunocompetent adults when other topical treatment options are contraindicated or less appropriate.
- Imiquimod cream is indicated for the topical treatment of external genital and perianal warts (condylomata acuminate) in adults; small superficial basal-cell carcinomas (sBCCs) in adults; clinically typical, non-hyperkeratotic, non-hypertrophic actinic keratoses (AKs) on the face or scalp in immunocompetent adult patients when size or number of lesions limit the efficacy and/or acceptability of cryotherapy and other topical treatment options are contraindicated or less appropriate.
- Imiquimod cream is indicated for the topical treatment of external genital and perianal warts (condyloma acuminata) in adult patients.
- Imiquimod is used topically for the treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratosis on the face or scalp in immunocompetent adults; treatment of biopsy-confirmed, primary superficial basal cell carcinoma in immunocompetent adults; and treatment of external genital and perianal exophytic warts (condylomata acuminate) caused by human papillomavirus (HPV).
- Topical imiquimod has been effective when used in a limited number of adults and children for the treatment of molluscum contagiosum.
- Imiquimod 5% cream has been used for the topical treatment of external genital and perianal HPV warts in a limited number of adults with human immunodeficiency virus (HIV) infection; however, the response rate appears to be lower in these individuals than in those who are not HIV infected.
- For the topical treatment of clinically typical, nonhyperkeratotic, non hypertrophic actinic keratoses on the face or scalp in immunocompetent adults. Also indicated for the treatment of external genital and perianal warts/condyloma acuminate in individuals 12 years old and above.
- Actinic Keratoses of the face
- Actinic Keratoses of the scalp
- Condylomata Acuminata
- Herpes Simplex Infections
- Molluscum Contagiosum
- Superficial Basal Cell Carcinoma
Use in Cancer
Imiquimod is approved to treat:
- Actinic keratosis in immunocompetent adults. This use is approved for the Aldara and Zyclara brands of imiquimod.
- Basal cell carcinoma is superficial. It is used in immunocompetent adults. This use is approved for the Aldara brand of imiquimod.
- Genital warts or perianal warts in adults and in children aged 12 years and older. This use is approved for the Aldara and Zyclara brands of imiquimod.
Imiquimod is also being studied in the treatment of other conditions and types of cancer.
Contraindications
- a reduction in the body’s resistance to infection
- disease in which body has an immune response against itself
- sunburn
- increased sensitivity of the skin to the sun
- graft-versus-host disease
Dosage
Strengths: 5%; 3.75%; 2.5%
Keratosis
- 2.5% and 3.75% cream: Apply a thin film once a day before bedtime to the affected area (either the entire face or balding scalp)
- Treatment should continue for two 2-week treatment cycles separated by a 2-week no-treatment period.
- The cream should be applied as a thin film to the entire treatment area and rubbed in until it is no longer visible.
- Up to 2 packets or 2 pumps, actuation may be applied per application.
- To be left on the skin for about 8 hours, after which, it to be removed with mild soap and water.
- 5% cream: Apply topically to the affected area on the face or scalp (but not both concurrently) 2 times per week for a full 16 weeks
- The treatment area is defined as one contiguous area of about 5 cm by 5 cm on the face (e.g., forehead or 1 cheek) or on the scalp.
- Examples of a schedule of 2 times per week are Monday and Thursday, or Tuesday and Friday.
- The cream should be applied to the entire treatment area and rubbed in until it is no longer visible.
- Not more than 1 packet should be applied to the contiguous treatment are at each application.
- To be applied prior to normal sleeping hours and left on the skin for about 8 hours, after which, to be removed with mild soap and water.
- For the topical treatment of clinically typical visible or palpable actinic keratoses of the full face or balding scalp in immunocompetent patients
Condylomata Acuminata
- 3.75% cream: Apply a thin layer once a day to the external genital/perianal warts until total clearance or up to 8 weeks
- Up to 1 packet or 1 full actuation of the pump of cream may be used at the treatment site for each application.
- To be applied prior to normal sleeping hours and left on the skin for about 8 hours, then removed by washing the area with mild soap and water.
- Nonocclusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reaction
- 5% cream: Apply topically to external genital/perianal warts 3 times per week
- Treatment should continue until there is total clearance of warts or up to a maximum of 16 weeks.
- Examples of 3 times per week application schedules are Monday, Wednesday, Friday or Tuesday, Thursday, and Saturday.
- To be applied prior to normal sleeping hours and left on the skin for 6 to 10 hours, then removed by washing the area with mild soap and water.
- For the treatment of external genital and perianal warts (EGW)/condyloma acuminate
Basal Cell Carcinoma
- 5% cream: Apply topically to a biopsy-confirmed superficial basal cell carcinoma 5 times per week for a full 6 weeks
- To be applied prior to normal sleeping hours and left on the skin for about 8 hours, then removed by washing the area with mild soap and water.
- The treatment area should include a 1 cm margin of skin around the tumor.
- Sufficient cream should be used to cover the treatment area and rubbed in until it is no longer visible.
- For the topical treatment of biopsy-confirmed, primary superficial basal cell carcinoma (sBCC) 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
Condylomata Acuminata
12 years or older:
- 3.75% cream: Apply a thin layer once a day to the external genital/perianal warts until total clearance or up to 8 weeks
- Up to 1 packet of cream may be used at the treatment site for each application.
- To be applied prior to normal sleeping hours and left on the skin for about 8 hours, then removed by washing the area with mild soap and water.
12 years or older:
- 5% cream: Apply topically to external genital/perianal warts 3 times per week
- Treatment should continue until there is total clearance of warts or up to a maximum of 16 weeks.
- Examples of 3 times per week application schedules are Monday, Wednesday, Friday or Tuesday, Thursday, and Saturday.
- To be applied prior to normal sleeping hours and left on the skin for 6 to 10 hours, then removed by washing the area with mild soap and water.
Administration advice:
- For topical use only; not for oral, ophthalmic, intra-anal, or intravaginal use.
- Wash hands before and after use.
- Avoid use in or on lips and nostrils; do not use in or near the eyes.
- Use of excessive amounts of cream should be avoided and partially used packets discarded and not reused.
- The pump should be primed before first-time use by repeatedly depressing the actuator until the cream is dispensed; it is not necessary to repeat the priming process.
- Local skin reactions are common in all treatment areas; a rest period of several days may be taken if required by the patient’s discomfort or severity of the reaction; however, neither 2-week treatment cycle when treating actinic keratosis should be extended due to missed doses or rest periods.
- A transient increase in lesion counts may be observed during the treatment of actinic keratosis; response to treatment cannot be adequately assessed until the resolution of local skin reactions.
- Treatment should continue for the full treatment course even if all actinic keratoses appear to be gone; carefully re-evaluate the patient if lesions do not respond to treatment.
Side Effects
The most common
- redness, itching, burning, or bleeding of the treated area
- flaking, scaling, dryness, or thickening of the skin
- swelling, stinging, or pain in the treated area
- blisters, scabs, or bumps on the skin
- headache
- diarrhea
- back pain
- tiredness
- skin breakdown or sores that may have drainage, especially during the first week of treatment
- flu-like symptoms such as nausea, fever, chills, tiredness, and muscle weakness or pain
- weight gain
- Confusion
- dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
- blisters, a burning sensation, skin redness, dry skin, itching, skin breakdown, skin crusting or scabbing, skin drainage, skin flaking or scaling, skin ulceration, sores, swelling, as well as systemic reactions, such as fever, “flu-like” symptoms, headache, and tiredness.
More Common
- Blisters on the skin
- body aches or pain
- chills
- cough
- difficulty with breathing
- ear congestion
- itching in the genital or other skin areas
- loss of voice
- open sores or scabs on the skin
- pain or tenderness around the eyes and cheekbones
- redness of the skin (severe)
- scaling
- shortness of breath or troubled breathing
- skin rash
- sneezing
- sore throat
- stuffy or runny nose
- tightness of the chest or wheezing
- unusual tiredness or weakness
Rare
- Abdominal or stomach pain
- ankle, knee, or great toe joint pain
- bladder pain
- bloody or cloudy urine
- blurred vision
- chest pain
- cold flu-like symptoms
- difficult, burning, or painful urination
- dizziness
- fainting
- fast or irregular heartbeat
- frequent urge to urinate
- hoarseness
- joint stiffness or swelling
- lower back or side pain
- lump in the abdomen or stomach
- nervousness
- persistent non-healing sore
- pink growth on the skin
- pounding in the ears
- a reddish patch or irritated area
- severe headache
- shiny bump on the skin
- slow or fast heartbeat
- swollen, painful, or tender lymph glands in the neck, armpit, or groin
- a white, yellow, or waxy scar-like area
- Blue lips and fingernails
- convulsions
- coughing that sometimes produces a pink frothy sputum
- dilated neck veins
- extreme fatigue
- fast, irregular, or pounding heartbeat
- headache
- irregular breathing
- nausea or vomiting
- pain in the shoulders, arms, jaw, or neck
- slurred speech
- sudden and severe inability to speak
- suicide
- sweating
- swelling of the face, fingers, feet, or lower legs
- temporary blindness
- weakness in the arm or leg on one side of the body
Drug Interactions
| DRUG | INTERACTION |
|---|---|
| Abametapir | The serum concentration of Imiquimod can be increased when it is combined with Abametapir. |
| Allogeneic processed | The therapeutic efficacy of Allogeneic processed thymus tissue can be decreased when used in combination with Imiquimod. |
| Avanafil | The serum concentration of Avanafil can be increased when it is combined with Imiquimod. |
| Cenobamate | The serum concentration of Imiquimod can be decreased when it is combined with Cenobamate. |
| Dabrafenib | The serum concentration of Imiquimod can be decreased when it is combined with Dabrafenib. |
| Enzalutamide | The serum concentration of Imiquimod can be decreased when it is combined with Enzalutamide. |
| Haloperidol | The serum concentration of Haloperidol can be increased when it is combined with Imiquimod. |
| Inebilizumab | The risk or severity of infection can be increased when Imiquimod is combined with Inebilizumab. |
| Ivosidenib | The metabolism of Imiquimod can be increased when combined with Ivosidenib. |
| Lopinavir | The serum concentration of Imiquimod can be increased when it is combined with Lopinavir. |
| Magnesium | The serum concentration of Magnesium can be decreased when it is combined with Imiquimod. |
| Mavacamten | The serum concentration of Imiquimod can be decreased when it is combined with Mavacamten. |
| Meningococcal | The therapeutic efficacy of Meningococcal (groups A, C, Y and W-135) oligosaccharide diphtheria CRM197 conjugate vaccine can be decreased when used in combination with Imiquimod. |
| Ritonavir | The serum concentration of Imiquimod can be increased when it is combined with Ritonavir. |
| Satralizumab | The serum concentration of Imiquimod can be decreased when it is combined with Satralizumab. |
| Somatrogon | The metabolism of Imiquimod can be increased when combined with Somatrogon. |
| Sotorasib | The serum concentration of Imiquimod can be decreased when it is combined with Sotorasib. |
| Stiripentol | The metabolism of Imiquimod can be decreased when combined with Stiripentol. |
| Tacrolimus | Tacrolimus may increase the immunosuppressive activities of Imiquimod. |
| Telotristat ethyl | The serum concentration of Imiquimod can be decreased when it is combined with Telotristat ethyl. |
| Trastuzumab | Trastuzumab may increase the neutropenic activities of Imiquimod. |
| Tucatinib | The metabolism of Tucatinib can be decreased when combined with Imiquimod. |
| Ublituximab | The risk or severity of infection can be increased when Ublituximab is combined with Imiquimod. |
| Vibrio cholerae | The therapeutic efficacy of Vibrio cholerae CVD 103-HgR strain live antigen can be decreased when used in combination with Imiquimod. |
| Viloxazine | The metabolism of Imiquimod can be decreased when combined with Viloxazine. |
Pregnancy and Lactation
US FDA pregnancy category C
Pregnancy
Drugs that have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.
Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant the use of the drug in pregnant women despite potential risks.
Use with caution; benefits should outweigh risks. According to some authorities: Use is not recommended.
Lactation
Caution is recommended. According to some authorities: Use is not recommended. Excreted into human milk: Unknown Excreted into animal milk: Unknown.m No adverse effects were demonstrated in animal studies with rats treated with this drug during gestation and lactation at doses up to 8 times the maximum human dose on an mg/m2 basis.
How should this medicine be used?
Imiquimod comes as a cream to apply to the skin.
If you are using imiquimod cream to treat actinic keratoses, you will probably apply it once a day for 2 days a week, 3 to 4 days apart (e.g., Monday and Thursday or Tuesday and Friday). Do not apply the cream to an area larger than your forehead or cheek (about 2 inches by 2 inches). Imiquimod cream should be left on the skin for approximately 8 hours. Continue using imiquimod cream for a full 16 weeks, even if all the actinic keratoses are gone, unless you are told otherwise by your doctor.
If you are using imiquimod cream to treat superficial basal cell carcinoma, you will probably apply it once a day for 5 days a week (e.g., Monday through Friday). Apply the cream to the basal cell carcinoma and the immediate surrounding area. Imiquimod cream should be left on the skin for approximately 8 hours. Continue using imiquimod for a full 6 weeks, even if the superficial basal cell carcinoma appears to be gone, unless you are told otherwise by your doctor.
If you are using imiquimod cream to treat genital and anal warts, you will probably apply it once a day for 3 days a week (e.g., Monday, Wednesday, and Friday or Tuesday, Thursday, and Saturday). Imiquimod cream should be left on the skin for 6 to 10 hours. Continue using imiquimod until all of the warts are healed, up to a maximum of 16 weeks.
Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Use imiquimod exactly as directed. Do not use more or less of it or use it more often than prescribed by your doctor.
Do not cover the treated area with a tight bandage or dressing unless told to do so by your doctor. Cotton gauze dressings may be used if needed. Cotton underwear may be worn after treating the genital or anal areas.
If you are using imiquimod cream to treat genital or anal warts, you should avoid sexual (oral, anal, genital) contact while the cream is on your skin. Imiquimod cream may weaken condoms and vaginal diaphragms.
Uncircumcised men who are treating warts under the penis foreskin should pull the foreskin back and clean daily and before each treatment.
Imiquimod cream is only for use on the skin. Do not apply imiquimod cream in or near your eyes, lips, nostrils, vagina, or anus. If you get imiquimod cream in your mouth or eyes, rinse well with water right away.
Imiquimod cream comes in single-use packets. Dispose of any open packets if you do not use all of the cream.
To use the cream, follow these steps:
- Wash your hands.
- Wash the area to be treated with mild soap and water and allow it to dry.
- Apply a thin layer of cream to the area to be treated, just before going to sleep.
- Rub the cream into the skin until it disappears.
- Wash your hands.
- Leave the cream on the area for the amount of time your doctor has told you to do so. Do not bathe, shower, or swim during this time.
- After the treatment time is over, wash the area with mild soap and water to remove any cream.
Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.
What special precautions should I follow?
Before using imiquimod,
- tell your doctor and pharmacist if you are allergic to imiquimod, any of the ingredients in imiquimod cream, or any other medications. Ask your pharmacist for a list of the ingredients.
- tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any other treatments for genital or anal warts, actinic keratoses, or superficial basal cell carcinoma.
- tell your doctor if you have a sunburn or if you have or have ever had unusual sensitivity to sunlight, any skin disease such as psoriasis, graft vs. host disease, recent surgery to the affected area or any condition that affects the immune system (such as human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS).
- tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while using imiquimod, call your doctor.
- plan to avoid exposure to sunlight as much as possible and to wear protective clothing (such as a hat), sunglasses, and sunscreen if you go outside during daylight hours. Do not use tanning beds or sunlamps. Imiquimod cream may make your skin sensitive to sunlight.
- you should know that imiquimod cream may cause changes in your skin color. These changes may not go away after you finish treatment with imiquimod cream. Tell your doctor if you notice any changes in your skin color.
References
