Imiquimod Cream

ZYCLARA (imiquimod) Cream, 2.5% or 3.75% is intended for topical administration. Each gram contains 25 mg or 37.5 mg of imiquimod, respectively, in a white to faintly yellow oil-in-water cream base consisting of isostearic acid, cetyl alcohol, stearyl alcohol, white petrolatum, polysorbate 60, sorbitan monostearate, glycerin, xanthan gum, purified water, benzyl alcohol, methylparaben, and propylparaben.

Chemically, imiquimod is 1-(2-methylpropyl)-1H-imidazol[4,5-c]quinolin-4-amine. Imiquimod has a molecular formula of C14H16N4 and a molecular weight of 240.3. Its structural formula is:

ZYCLARA (imiquimod) Cream, 3.75% comes as a premeasured packet containing 9.4 mg of imiquimod in 0.25 g of cream. ZYCLARA (imiquimod) Cream, 2.5% and 3.75% also come in pumps which dispense 5.9 mg or 8.8 mg of imiquimod, respectively, in 0.235 g of cream per full actuation of the pump after priming.

Skip the missed dose and wait until the next time you are getting ready for bed to use the medicine. Do not use extra medicine to make up the missed dose.

The application frequency for Imiquimod Cream is different for each indication.

Imiquimod is not for oral, ophthalmic, or intravaginal use.

Actinic Keratosis

Imiquimod Cream should be applied 2 times per week for a full 16 weeks to a defined treatment area on the face or scalp (but not both concurrently). The treatment area is defined as one contiguous area of approximately 25 cm2 (e.g., 5 cm x 5 cm) on the face (e.g. forehead or one cheek) or on the scalp. Examples of 2 times per week application schedules are Monday and Thursday, or Tuesday and Friday. Imiquimod Cream should be applied to the entire treatment area and rubbed in until the cream is no longer visible. No more than one packet of Imiquimod Cream should be applied to the contiguous treatment area at each application. Imiquimod Cream should be applied prior to normal sleeping hours and left on the skin for approximately 8 hours, after which time the cream should be removed by washing the area with mild soap and water. The prescriber should demonstrate the proper application technique to maximize the benefit of Imiquimod Cream therapy.           

It is recommended that patients wash their hands before and after applying Imiquimod Cream. Before applying the cream, the patient should wash the treatment area with mild soap and water and allow the area to dry thoroughly (at least 10 minutes).

Contact with the eyes, lips and nostrils should be avoided.

Local skin reactions in the treatment area are common. [see Adverse Reactions (6.1, 6.5)] A rest period of several days may be taken if required by the patient's discomfort or severity of the local skin reaction. However, the treatment period should not be extended beyond 16 weeks due to missed doses or rest periods. Response to treatment cannot be adequately assessed until resolution of local skin reactions. Lesions that do not respond to treatment should be carefully re-evaluated and management reconsidered.

Imiquimod Cream is packaged in single-use packets, with 12 packets or 24 packets supplied per box. Patients should be prescribed no more than 36 packets for the 16-week treatment period. Unused packets should be discarded. Partially-used packets should be discarded and not reused.

External Genital Warts

Imiquimod Cream should be applied 3 times per week to external genital/perianal warts. Imiquimod Cream treatment should continue until there is total clearance of the genital/perianal warts or for a maximum of 16 weeks. Examples of 3 times per week application schedules are: Monday, Wednesday, Friday or Tuesday, Thursday, Saturday. Imiquimod Cream should be applied prior to normal sleeping hours and left on the skin for 6 -10 hours, after which time the cream should be removed by washing the area with mild soap and water. The prescriber should demonstrate the proper application technique to maximize the benefit of Imiquimod Cream therapy.

It is recommended that patients wash their hands before and after applying Imiquimod Cream.

A thin layer of Imiquimod Cream should be applied to the wart area and rubbed in until the cream is no longer visible. The application site should not be occluded. Following the treatment period the cream should be removed by washing the treated area with mild soap and water.

Local skin reactions at the treatment site are common. [see Adverse Reactions (6.3, 6.5)]. A rest period of several days may be taken if required by the patient's discomfort or severity of the local skin reaction. Treatment may resume once the reaction subsides. Non-occlusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions.

Imiquimod Cream is packaged in single-use packets which contain sufficient cream to cover a wart area of up to 20 cm2; use of excessive amounts of cream should be avoided.

Pregnancy

Pregnancy Category C:

Note: The Maximum Recommended Human Dose (MRHD) was set at 2 packets per treatment of Imiquimod Cream (25 mg imiquimod) for the animal multiple of human exposure ratios presented in this label. If higher doses than 2 packets of Imiquimod Cream are used clinically, then the animal multiple of human exposure would be reduced for that dose. A non-proportional increase in systemic exposure with increased dose of Imiquimod Cream was noted in the clinical pharmacokinetic study conducted in actinic keratosis subjects [see Clinical Pharmacology (12.3)]. The AUC after topical application of 6 packets of Imiquimod Cream was 8 fold greater than the AUC after topical application of 2 packets of Imiquimod Cream in actinic keratosis subjects. Therefore, if a dose of 6 packets per treatment of Imiquimod Cream was topically administered to an individual, then the animal multiple of human exposure would be either 1/3 of the value provided in the label (based on body surface area comparisons) or 1/8 of the value provided in the label (based on AUC comparisons). The animal multiples of human exposure calculations were based on weekly dose comparisons for the carcinogenicity studies described in this label. The animal multiples of human exposure calculations were based on daily dose comparisons for the reproductive toxicology studies described 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 (gestational days 6 to 15) to pregnant female rats. In the presence of maternal toxicity, fetal effects noted at 20 mg/kg/day (577X MRHD based on AUC comparisons) 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 teratogenicity were noted at 5 mg/kg/day (98X MRHD based on AUC comparisons).

Intravenous doses of 0.5, 1 and 2 mg/kg/day imiquimod were administered during the period of organogenesis (gestational days 6 to 18) to pregnant female rabbits. No treatment related effects on embryofetal toxicity or teratogenicity were noted at 2 mg/kg/day (1.5X MRHD based on BSA comparisons), the highest dose evaluated in this study, or 1 mg/kg/day (407X MRHD based on AUC comparisons).

A combined fertility and peri- and post-natal 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 post-natal development were noted at doses up to 6 mg/kg/day (87X MRHD based on AUC comparisons), 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 (87X MRHD based on AUC comparisons). This fetal effect was also noted in the oral rat embryofetal development study conducted with imiquimod. No treatment related effects on teratogenicity were noted at 3 mg/kg/day (41X MRHD based on AUC comparisons).

There are no adequate and well-controlled studies in pregnant women. Imiquimod Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether imiquimod is excreted in human milk following use of Imiquimod Cream. Because many drugs are excreted in human milk, caution should be exercised when Imiquimod Cream is administered to nursing women.

Padiatric Use

AK is not a condition generally seen within the pediatric population. The safety and efficacy of Imiquimod Cream for AK in patients less than 18 years of age have not been established.

Safety and efficacy in patients with external genital/perianal warts below the age of 12 years have not been established.

Imiquimod Cream was evaluated in two randomized, vehicle-controlled, double-blind trials involving 702 pediatric subjects with molluscum contagiosum (MC) (470 exposed to imiquimod; median age 5 years, range 2 to12 years). Subjects applied Imiquimod Cream or vehicle 3 times weekly for up to 16 weeks. Complete clearance (no MC lesions) was assessed at Week 18. In Study 1, the complete clearance rate was 24% (52/217) in the Imiquimod Cream group compared with 26% (28/106) in the vehicle group. In Study 2, the clearance rates were 24% (60/253) in the Imiquimod Cream group compared with 28% (35/126) in the vehicle group. These studies failed to demonstrate efficacy.

Similar to the studies conducted in adults, the most frequently reported adverse reaction from 2 studies in children with molluscum contagiosum was application site reaction. Adverse events which occurred more frequently in imiquimod-treated subjects compared with vehicle-treated subjects generally resembled those seen in studies in indications approved for adults and also included otitis media (5% imiquimod vs. 3% vehicle) and conjunctivitis (3% imiquimod vs. 2% vehicle).

Erythema was the most frequently reported local skin reaction. Severe local skin reactions reported by imiquimod -treated subjects in the pediatric studies included erythema (28%), edema (8%), scabbing/crusting (5%), flaking/scaling (5%), erosion (2%) and weeping/exudate (2%).

Systemic absorption of imiquimod across the affected skin of 22 subjects aged 2 to 12 years with extensive MC involving at least 10% of the total body surface area was observed after single and multiple doses at a dosing frequency of 3 applications per week for 4 weeks. The investigator determined the dose applied, either 1, 2 or 3 packets per dose, based on the size of the treatment area and the subject's weight. The overall median peak serum drug concentrations at the end of week 4 was between 0.26 and 1.06 ng/mL except in a 2-year old female who was administered 2 packets of study drug per dose, had a Cmax of 9.66 ng/mL after multiple dosing. Children aged 2 to 5 years received doses of 12.5 mg (one packet) or 25 mg (two packets) of imiquimod and had median multiple-dose peak serum drug levels of approximately 0.2 or 0.5 ng/mL, respectively. Children aged 6 to12 years received doses of 12.5 mg, 25 mg, or 37.5 mg (three packets) and had median multiple dose serum drug levels of approximately 0.1, 0.15, or 0.3 ng/mL, respectively. Among the 20 subjects with evaluable laboratory assessments, the median WBC count decreased by 1.4*109/L and the median absolute neutrophil count decreased by 1.42*109/L.

Geriatric Use

Of the 215 subjects treated with Imiquimod Cream in the AK clinical studies, 127 subjects (59%) were 65 years and older, while 60 subjects (28%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. No other clinical experience has identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Topical overdosing of Imiquimod Cream could result in an increased incidence of severe local skin reactions and may increase the risk for systemic reactions.

The most clinically serious adverse event reported following multiple oral imiquimod doses of >200 mg (equivalent to imiquimod content of >16 packets) was hypotension, which resolved following oral or intravenous fluid administration.

See FDA-Approved Patient Labeling

General Information: All Indications

Imiquimod Cream should be used as directed by a physician. [see Dosage and Administration (2)]. Imiquimod Cream is for external use only. Contact with the eyes, lips and nostrils should be avoided. [see Indications and Usage (1) and Dosage and Administration (2)]

The treatment area should not be bandaged or otherwise occluded. Partially-used packets should be discarded and not reused. The prescriber should demonstrate the proper application technique to maximize the benefit of Imiquimod Cream therapy.

It is recommended that patients wash their hands before and after applying Imiquimod Cream.

Local Skin Reactions: All Indications

Patients may experience local skin reactions during treatment with Imiquimod Cream (even with normal dosing). Potential local skin reactions include erythema, edema, vesicles, erosions/ulcerations, weeping/exudate, flaking/scaling/dryness, and scabbing/crusting. These reactions can range from mild to severe in intensity and may extend beyond the application site onto the surrounding skin. Patients may also experience application site reactions such as itching and/or burning. [see Adverse Reactions (6)]

Local skin reactions may be of such intensity that patients may require rest periods from treatment. Treatment with Imiquimod Cream can be resumed after the skin reaction has subsided, as determined by the physician. Patients should contact their physician promptly if they experience any sign or symptom at the application site that restricts or prohibits their daily activity or makes continued application of the cream difficult.

Because of local skin reactions, during treatment and until healed, the treatment area is likely to appear noticeably different from normal skin. Localized hypopigmentation and hyperpigmentation have been reported following use of Imiquimod Cream. These skin color changes may be permanent in some patients.

Systemic Reactions: All Indications

Patients may experience flu-like systemic signs and symptoms during treatment with Imiquimod Cream (even with normal dosing). Systemic signs and symptoms may include malaise, fever, nausea, myalgias and rigors [see Adverse Reactions (6)]. An interruption of dosing should be considered.

Patients Being Treated for Actinic Keratosis (AK)

Dosing is 2 times per week for a full 16 weeks, unless otherwise directed by the physician. However, the treatment period should not be extended beyond 16 weeks due to missed doses or rest periods. [see Dosage and Administration (2.1)]

It is recommended that the treatment area be washed with mild soap and water 8 hours following Imiquimod Cream application.

Most patients using Imiquimod Cream for the treatment of AK experience erythema, flaking/scaling/dryness and scabbing/crusting at the application site with normal dosing [see Adverse Reactions (6.1)].

Use of sunscreen is encouraged, and patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using Imiquimod Cream. [see Warnings and Precautions (5.3)]

Sub-clinical AK lesions may become apparent in the treatment area during treatment and may subsequently resolve. [see Clinical Studies (14.1)]

Patients Being Treated for External Genital Warts

Dosing is 3 times per week to external genital/perianal warts. Imiquimod Cream treatment should continue until there is total clearance of the genital/perianal warts or for a maximum of 16 weeks.

It is recommended that the treatment area be washed with mild soap and water 6 to 10 hours following Imiquimod Cream application.

It is common for patients to experience local skin reactions such as erythema, erosion, excoriation/flaking, and edema at the site of application or surrounding areas. Most skin reactions are mild to moderate.

Sexual (genital, anal, oral) contact should be avoided while Imiquimod Cream is on the skin. Application of Imiquimod Cream in the vagina is considered internal and should be avoided. Female patients should take special care if applying the cream at the opening of the vagina because local skin reactions on the delicate moist surfaces can result in pain or severe swelling, and may cause difficulty in passing urine or inability to urinate.

Uncircumcised males treating warts under the foreskin should retract the foreskin and clean the area daily.

New warts may develop during therapy, as Imiquimod Cream is not a cure.

The effect of Imiquimod Cream on the transmission of genital/perianal warts is unknown.

Imiquimod Cream may weaken condoms and vaginal diaphragms, therefore concurrent use is not recommended.

Should severe local skin reaction occur, the cream should be removed by washing the treatment area with mild soap and water.

Rx Only

Manufactured for:

Strides Shasun Limited

Made in Italy

Distributed by:

Strides Pharma Inc.

East Brunswick, NJ 08816

Revised: 07/2016

Patient Information

Imiquimod Cream, 5%

Read the Patient Information that comes with Imiquimod Cream before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or treatment.  

If you do not understand the information, or have any questions about Imiquimod Cream, talk with your healthcare provider or pharmacist.

What is Imiquimod Cream?

Imiquimod Cream is a prescription medicine for use on the skin only (topical) to treat:

•   actinic keratosis on the face or scalp in adults with a normal immune system. Actinic keratosis is caused by too much sun exposure.
•   warts on or around the genitals or anus in people 12 years and older.

Imiquimod Cream will not cure your genital or perianal warts. New warts may develop during treatment with Imiquimod Cream. It is not known if Imiquimod Cream can stop you from spreading genital or perianal warts to other people.

It is not known if Imiquimod Cream is safe and effective in:

•   people who do not have a normal immune system.
•   the treatment of basal cell nervus syndrome.
•   the treatment of xeroderma pigmentosum.
•   the treatment of actinic keratosis with more than one treatment course in the same affect area. 

It is not known if Imiquimod Cream is safe and effective in children younger than 18 years of age for the treatment of actinic keratosis. Children usually do not get actinic keratosis.

It is not known if Imiquimod Cream is safe and effective in children younger than 12 years of age for the treatment of genital and perianal warts.

What should I tell my healthcare provider before using Imiquimod Cream? Before using Imiquimod Cream, tell your healthcare provider if you:

•   have problems with your immune system.
•   are being treated or have been treated for actinic keratosis with other medicines or surgery. You should not use Imiquimod Cream until you have healed from other treatments.
•   have any other skin problems.
•   have any other medical conditions. 
•   are pregnant or planning to become pregnant. It is not known if Imiquimod Cream can harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
•   are breastfeeding or plan to breastfeed. It is not known if Imiquimod Cream passes into your breast milk and if it can harm your baby. Talk to your healthcare provider about the best way to feed your baby if you use Imiquimod Cream.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.  

Especially tell your healthcare provider if you have had other treatments for genital warts or warts around your anus, or actinic keratosis. Imiquimod Cream should not be used until your skin has healed from other treatments.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. 

How should I use Imiquimod Cream?

•   Do not get Imiquimod Cream in or near your mouth, eyes, nose or vagina.
•   Use Imiquimod Cream exactly as your healthcare provider tells you to use it. Your healthcare provider will tell you where to apply Imiquimod Cream and how often and for how long to apply it for your condition.
•   Imiquimod Cream is used for different skin conditions. Use Imiquimod Cream only on the area of your body to be treated. Do not apply Imiquimod Cream to other areas.
•   Do not use Imiquimod Cream longer than prescribed. Using too much Imiquimod Cream, or using it too often, or for too long can increase your chances for having a severe skin reaction or other side effect.  
•   You should follow-up with your healthcare provider regularly for check-ups while using Imiquimod Cream.
•   Talk to your healthcare provider if you think Imiquimod Cream is not working for you.

Applying Imiquimod Cream

Imiquimod Cream should be applied just before your bedtime.

•   Wash the area where the cream will be applied with mild soap and water. Uncircumcised males treating warts under their penis foreskin must pull their foreskin back and clean the area before treatment, and clean the area daily during treatment.
•   Allow the area to dry for at least 10 minutes.
•   Wash your hands.
•   Open a new packet of Imiquimod Cream.
•   Apply a thin layer of Imiquimod Cream only to the affected area. Do not use more Imiquimod Cream than is needed to cover the affected area.
•   Rub the cream into your skin until you can not see the Imiquimod Cream. After applying Imiquimod Cream, wash your hands well.
•   Leave the cream on the treated area for the amount of time your healthcare provider tells you.  The length of time that Imiquimod Cream is left on the skin is different for each skin condition that Imiquimod Cream is used to treat. Do not take a bath or get the treated area wet during this time.
•   After the right amount of time has passed, wash the treated area with mild soap and water.
•   If you get Imiquimod Cream in your mouth or in your eyes, rinse well with water right away.

What should I avoid while using Imiquimod Cream?

•   Do not cover the treated area with bandages or other closed dressings. 
•   Do not use sunlamps or tanning beds, and avoid sunlight as much as possible during treatment with Imiquimod Cream. Use sunscreen and wear protective clothing if you go outside during daylight.
•   Do not have sexual contact including genital, anal, or oral sex when Imiquimod Cream is on your genital or the skin around your anus. Imiquimod Cream may weaken condoms and vaginal diaphragms. This means they may not work as well to prevent pregnancy. 

What are the possible side effects of Imiquimod Cream?

Imiquimod Cream may cause serious side effects including:

•   Local skin reactions , including:
•   skin drainage (weeping)
•   ulcers
•   severe swelling near the vagina. This may lead to pain or trouble passing urine or cause you not to be able to urinate.  Female patients should take special care when applying Imiquimod Cream at the opening of the vagina.
•   Flu-like symptoms: tiredness, fever, nausea, muscle pain and chills. 

Tell your healthcare provider right away if you have any of the symptoms listed above.

The most common side effects of Imiquimod Cream include:

•   itching
•   burning
•   redness
•   flaking and scaling
•   dryness
•   scabbing and crusting
•   swelling
•   skin that becomes hard or thickened
•   sores, blisters, or ulcers
•   changes in skin color that do not always go away

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Imiquimod Cream. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to Strides Shasun Limited at 1-877-244-9825 or go to www.stridesshasun.com or contact FDA at 1-800- FDA-1088 or www.fda.gov/medwatch.

How do I store Imiquimod Cream?

•   Store Imiquimod Cream at 39°F to 77°F (4°C to 25°C).
•   Do not freeze.
•   Safely throw away unused Imiquimod Cream or partially used Imiquimod Cream packets that you do not need.

Keep Imiquimod Cream and all medicines out of the reach of children.

General information about the safe and effective use of Imiquimod Cream

Medicines are sometimes prescribed for purposes other than those listed in this Patient Information leaflet. Do not use Imiquimod Cream for a condition for which it was not prescribed. Do not give Imiquimod Cream to other people, even if they have the same symptoms you have. It may harm them.

This Patient Information leaflet summarizes the most important information about Imiquimod Cream. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Imiquimod Cream that is written for the healthcare professionals.

What are the ingredients in Imiquimod Cream?

Active ingredient: imiquimod

Inactive ingredients: isostearic acid, cetyl alcohol, stearyl alcohol, white petrolatum, polysorbate 60, sorbitan monostearate, glycerin, xanthan gum, purified water, benzyl alcohol, methylparaben, and propylparaben.

Manufactured for:

Strides Shasun Limited

Made in Italy

Distributed by:

Strides Pharma Inc.

East Brunswick, NJ 08816

Revised: 07/2016

Imiquimod Cream

Rx only

Net wet - 0.25g 

NDC 64380-773-00

Imiquimod Cream 5% 

Contains 1 Application

Discard Unused Portion

For Dermatological Use Only

Not for Ophthalmic Use

Imiquimod Cream 5%

12 single use packets

Net wt. per packet - 0.25g

Net wt. per box - 3g

NDC – 64380-773-02

Rx only  

Store at 4 - 25°C (39 - 77°F). Do not freeze.

Imiquimod Cream 5%

Contains 1 Application

Discard Unused Portion

For Dermatological Use Only

Not for Ophthalmic Use

Imiquimod Cream 5%

24 single use packets

Net wt. per packet - 0.25g

Net wt. per box - 6g

NDC – 64380-773-19

Rx only  

Store at 4 - 25°C (39 - 77°F). Do not freeze.

Imiquimod Cream 5%

Contains 1 Application

Discard Unused Portion

For Dermatological Use Only

Not for Ophthalmic Use