Zyclara

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZYCLARA (ZYCLARA)

Composition:

Active substance: imiquimod;

1 g of cream contains 37.5 mg of imiquimod;

Excipients: isostearic acid, cetyl alcohol, stearyl alcohol, white soft paraffin, polysorbate 60, sorbitan stearate, benzyl alcohol, methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), glycerol, xanthan gum, purified water.

Pharmaceutical form. Cream.

Main physicochemical properties: homogeneous cream, white to pale yellow in color.

Pharmacotherapeutic group. Dermatological agents. Antibiotics and chemotherapeutic agents for dermatological use. Chemotherapeutic agents for topical use. Antiviral agents. Imiquimod. ATC code D06B B10.

Pharmacological Properties

Pharmacodynamics

Imiquimod is an immune response modifier. It is the lead compound of the imidazoquinoline class.

Saturation binding studies suggest the presence of protein receptors on immune cell membranes that respond to imiquimod; these are known as Toll-like receptors 7 and 8. Imiquimod induces the release of interferon-alpha (IFN-α) and other cytokines from various human and animal cells (e.g., human monocytes/macrophages and keratinocytes). Topical application of imiquimod cream in vivo to animal skin resulted in increased concentrations of IFN and tumor necrosis factor (TNF) compared to skin from untreated animals. The panel of induced cytokines varies depending on the tissue source of the cells. Furthermore, cytokine release occurred following either topical application or oral administration of imiquimod in various laboratory animals and in human studies. In animal models, imiquimod is effective against viral infections and acts as an antitumor agent primarily by initiating the release of alpha-interferon and other cytokines. Additionally, data from human studies indicate that topical application of imiquimod leads to increased systemic levels of alpha-interferon and other cytokines.

Clinical Efficacy and Safety

The efficacy of the medicinal product Zyclara was evaluated in two double-blind, randomized, vehicle-controlled trials. Patients had 5–20 typical visible or palpable actinic keratosis (AK) lesions on an area exceeding 25 cm² on the face or balding scalp. A total of 319 patients with AK were treated with 3.75% imiquimod cream (up to 2 sachets once daily) or matching vehicle cream in two treatment cycles of 2 weeks each, separated by a 2-week treatment-free interval. In the combined studies, the complete clearance rate of the entire face or balding scalp area was 35.6% (57/160 patients, CI 28.2%, 43.6%) with 3.75% imiquimod cream versus 6.3% (10/159 patients, CI 3.1%, 11.3%) with vehicle cream at the 8-week post-treatment visit. No overall differences in safety or efficacy were observed between patients aged 65 years and older and younger patients. Squamous cell carcinoma was observed in 1.3% (2/160) of patients treated with 3.75% imiquimod and in 0.6% (1/159) of patients treated with vehicle cream. This difference was not statistically significant.

In a subsequent study, patients who achieved complete clearance of AK lesions after 3.75% imiquimod therapy remained free of AK treatment for at least 14 months, and 40.5% of these patients remained free of AK lesions on the entire treatment area (either face or balding scalp). There are no other data on long-term clearance of the treatment area following use of 3.75% imiquimod cream.

Two open-label, randomized, controlled trials evaluated the long-term effects of 5% imiquimod (but not 3.75%) compared to topical diclofenac (3% gel). In these studies, treatment of AK was performed on facial areas or balding scalp areas with a total surface area of approximately 40 cm². At baseline, the median number of clinically typical AK lesions was 7. Investigational treatment was applied according to official recommendations. These studies demonstrated that imiquimod was more effective than diclofenac in preventing progression of AK lesions to squamous cell carcinoma in situ or invasive squamous cell carcinoma. Additionally, data from these studies support the possibility of using one or two additional treatment cycles with imiquimod when AK lesions do not completely clear or recur after successful initial treatment with imiquimod.

Use in Children

The European Medicines Agency has deferred the obligation to submit the results of studies with Zyclara in all pediatric subgroups with actinic keratosis (see section "Dosage and Administration" for information on use in children).

Pharmacokinetics

Absorption

Less than 0.9% of a single topically applied dose of radiolabeled imiquimod was absorbed through the skin in humans.

Systemic exposure (transdermal penetration) was estimated based on the recovery of carbon-14 from [14C]imiquimod in urine and feces.

In a pharmacokinetic study of 3.75% imiquimod cream applied as 2 sachets once daily (18.75 mg imiquimod per day) for three weeks to the entire face and/or hairy scalp (approximately 200 cm²) in patients with AK, systemic absorption of imiquimod was low. Steady-state levels were reached within 2 weeks, and the time to maximum concentration (Tmax) ranged from 6 to 9 hours after the last application.

Distribution

The mean peak serum concentration of imiquimod at the end of the pharmacokinetic study was 0.323 ng/mL.

Biotransformation

When administered orally, imiquimod is rapidly and extensively metabolized, forming two major metabolites.

Elimination

A small amount of the drug absorbed into systemic circulation was rapidly excreted in urine and feces in an approximate ratio of 3 to 1.

Following topical application of 3.75% imiquimod cream, the observed elimination half-life in the pharmacokinetic study was approximately 29 hours.

Clinical characteristics.

Indications.

Topical treatment of typical, non-hyperkeratotic, non-hypertrophic actinic keratosis (AK), palpable or visible, on the entire face or balding scalp area in immunocompetent adults when other topical treatment options are contraindicated or less suitable.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have not been conducted, including studies with immunosuppressive agents. Since the transdermal absorption of imiquimod cream is minimal, interaction with systemic agents is limited.

Due to the immunostimulatory properties of imiquimod cream, it should be used with caution in patients receiving immunosuppressive medicinal products (see section "Special precautions").

Concomitant use of Zyclara medicinal product and other creams containing imiquimod on the same area should be avoided, as they contain the same active substance (imiquimod), which may increase the risk and severity of local skin reactions.

Special precautions for use.

General instructions for treatment.

Biopsy should be performed in clinically atypical actinic keratosis (AK) lesions or when malignancy is suspected in order to determine appropriate treatment.

Contact of the drug with the mucous membranes of the eyes, lips, and nose should be avoided, as studies on the use of imiquimod for actinic keratosis of the eyelids, inside the nose or ears, or beyond the vermilion border of the lips have not been conducted.

Initiating therapy with imiquimod cream is not recommended until the skin has healed following treatment with any other medicinal product or after surgical intervention. Application to damaged skin may lead to increased systemic absorption of imiquimod, thereby increasing the risk of adverse effects (see sections "Overdose" and "Adverse reactions").

Due to increased sensitivity to sunburn, patients should use sunscreen, and during treatment with Zyclara cream, patients should minimize exposure to natural or artificial light (solarium or UV therapy) or avoid it altogether. The treated area of skin should be protected from sunlight.

Imiquimod is not recommended for the treatment of AK lesions with marked hyperkeratosis or hypertrophy, as seen in cutaneous horn.

Local skin reactions.

During treatment and until regeneration, the treated skin may appear distinctly different from normal skin. Local skin reactions are common, but their intensity usually decreases during treatment or resolves after discontinuation of imiquimod cream. Occasionally, severe local inflammatory reactions, including weeping skin or erosion, may occur after only a few applications of imiquimod cream.

There is a correlation between the rate of complete clearance and the intensity of local skin reactions (e.g., erythema). These local skin reactions are likely related to stimulation of the local immune response. Furthermore, imiquimod has the potential to exacerbate inflammatory skin conditions. If necessary, due to patient discomfort or the intensity of the local skin reaction, a treatment break of several days may be considered. Treatment with imiquimod cream can be resumed once the skin reaction has subsided. The intensity of skin reactions tends to decrease during the second treatment cycle compared to the first cycle of Zyclara cream therapy.

Systemic reactions.

Influenza-like systemic signs and symptoms may accompany or even precede pronounced local skin reactions and may include increased fatigue, nausea, fever, myalgia, arthralgia, and chills. In such cases, treatment should be discontinued or the dose reduced (see section "Adverse reactions").

Imiquimod should be used with caution and under the supervision of an experienced physician in patients with impaired hematological reserve (see section "Adive reactions").

Use in specific patient populations.

Patients with impaired cardiac, hepatic, or renal function were not included in clinical trials. The drug should be used with caution and under the supervision of an experienced physician in such patients.

Use in immunocompromised patients and/or patients with autoimmune conditions.

The safety and efficacy of Zyclara cream in immunocompromised patients (e.g., organ transplant recipients) and/or patients with autoimmune conditions have not been established. Therefore, imiquimod cream should be used with caution in these patients (see section "Interaction with other medicinal products and other forms of interaction"). The benefit-risk balance of using imiquimod in such patients should be carefully considered, taking into account the potential risk of organ rejection or graft-versus-host reaction, or possible worsening of the patient's autoimmune condition.

Repeated treatment.

There are no data on retreatment of actinic keratosis that has cleared after two cycles of Zyclara cream treatment over 2 weeks and then recurred (see sections "Pharmacodynamics" and "Dosage and administration").

Excipients.

Cetyl alcohol and stearyl alcohol may cause local skin reactions (i.e., contact dermatitis). Benzyl alcohol may cause allergic reactions and mild local irritation.

Methylparahydroxybenzoate (E 218) and propylparahydroxybenzoate (E 216) may cause allergic reactions (possibly delayed-type).

Use during pregnancy or breastfeeding.

Pregnancy. There are no clinical data on the use of imiquimod in pregnant women. Animal studies have not shown any direct or indirect harmful effects on pregnancy, embryonal/fetal development, parturition, or postnatal development.

Zyclara should be prescribed to pregnant women with caution. Zyclara may be used during pregnancy only if the expected benefit outweighs the potential risk to the fetus.

Breastfeeding. It is unknown whether imiquimod/metabolites are excreted in human breast milk. Risk to the newborn/infant cannot be excluded. Considering the benefits of breastfeeding for the child and the benefits of therapy for the woman, a decision should be made whether to discontinue breastfeeding or to discontinue/forego treatment with Zyclara.

Fertility. There are no clinical data, and no information on potential risk in humans.

Ability to affect reaction speed when driving or operating machinery.

Zyclara usually has no or negligible influence on the ability to drive or operate machinery.

Method of Administration and Dosage

Treatment is prescribed and monitored by a physician.

One sachet contains 9.375 mg of imiquimod in 250 mg of cream (3.75%).

Dosage

Apply the cream once daily at bedtime to the affected skin area. Up to 2 sachets may be used per application (250 mg of imiquimod cream per sachet). Treatment consists of two 2-week cycles with a 2-week break between cycles, or as directed by the physician.

The cream should be applied to the skin of the face or to areas of the scalp affected by hair loss.

Local skin reactions at the application site are expected to some extent and occur frequently; these are related to the mechanism of action of the drug (see section "Special Warnings and Precautions for Use"). If necessary, due to patient discomfort or severe skin reaction, a treatment break of several days may be taken. However, the 2-week treatment cycle should not be extended to compensate for missed doses or treatment interruptions.

During treatment, transient worsening of actinic keratosis lesions may occur, likely due to imiquimod revealing and treating subclinical lesions. Response to treatment cannot be assessed until local skin reactions have resolved. The patient should continue treatment as prescribed. Treatment should be continued for the full course, even if all signs of actinic keratosis have disappeared.

The clinical outcome of treatment should be evaluated after the treated skin has regenerated, approximately 8 weeks after completion of treatment, and again after an appropriate interval, based on clinical judgment. Lesions that have not adequately responded 8 weeks after the second treatment course should be re-evaluated, and consideration may be given to one additional 2-week course of treatment with Zyclara.

Alternative therapy is recommended if lesions do not respond adequately to Zyclara.

If actinic keratosis lesions resolve after two 2-week treatment cycles with Zyclara and then recur, retreatment with one or two additional 2-week cycles of Zyclara may be considered after a minimum 12-week treatment-free interval.

Hepatic or Renal Impairment

Patients with hepatic or renal impairment were not included in clinical trials. Such patients should be closely monitored by an experienced physician.

Method of Administration

The product is for topical use only. Avoid contact with the mucous membranes of the eyes, lips, and nose.

The application site does not require bandaging or other covering.

The prescribing physician should instruct the patient on the correct technique for cream application to achieve optimal effect.

Apply the cream once daily at bedtime to the affected skin area and leave it on the skin for approximately 8 hours. During this time, avoid showering or bathing. Before application, the patient should wash the affected skin area with water and mild soap and allow the skin to dry completely. Apply a thin layer of cream to the entire affected area and rub in gently until no longer visible. Up to 2 sachets of cream may be applied per daily dose (to the entire face or scalp area, but not both areas simultaneously). Partially used sachets should be discarded and not reused. The cream should remain on the skin for about 8 hours; after this time, remove the cream by washing the treated area and hands with water and mild soap.

Hands should be thoroughly washed before and after applying the cream.

Missed Dose

If a dose is missed, the patient should wait until the next evening to apply the cream and then continue treatment as prescribed. Do not apply the cream more than once daily. Each treatment cycle must not exceed 2 weeks, even if doses have been missed or treatment interruptions occurred.

Children

The safety and efficacy of imiquimod in children (under 18 years of age) for the treatment of actinic keratosis have not been established. Data are lacking.

Overdose

Due to minimal transdermal absorption, systemic overdose following topical application of imiquimod cream is unlikely. Animal studies have shown that the dermal lethal dose of imiquimod is greater than 5 g/kg. Prolonged local overdose of imiquimod may result in severe local skin reactions and may increase the risk of systemic reactions.

Following accidental ingestion of a single 200 mg dose of imiquimod—equivalent to the contents of more than 21 sachets of Zyclara cream—nausea, vomiting, headache, myalgia, and fever may occur. The most serious adverse reaction was observed after repeated oral doses of ≥ 200 mg and was characterized by hypotension, which resolved following administration of fluids orally or as intravenous infusions.

Management of overdose should include symptomatic treatment of clinical manifestations.

Side effects.

Summary of safety profile

The data below describe the effects of Zyclara cream or the cream base in 319 patients who participated in two double-blind studies. Patients applied up to two sachets of 3.75% Zyclara cream or cream base per day to the affected skin area (either the entire face or the balding scalp area, but not both areas simultaneously) over two two-week treatment cycles with a two-week break between cycles.

Most patients (159/160) who used Zyclara cream to treat actinic keratosis experienced local skin reactions (most commonly erythema, crusting, and flaking/dryness at the application site) at the site of application. However, only 11% (17/160) of patients in clinical trials with Zyclara cream required treatment interruption due to local adverse reactions. Some systemic adverse reactions were observed in patients receiving imiquimod during clinical trials, such as headache – 6% (10/160), and increased fatigue – 4% (7/160).

Adverse effects

The data below reflect:

• the use of Zyclara cream or cream base in the aforementioned studies (with frequencies ranging from "very common" to "uncommon" and more frequent after cream base);
• clinical experience with 5% imiquimod cream.

Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (<1/10,000); and frequency not known (cannot be estimated based on available data).

Infections and infestations: common – herpes simplex; uncommon – infections, pustules; frequency not known – skin infections.

Blood and lymphatic system disorders: common – lymphadenopathy; frequency not known – decreased hemoglobin, decreased white blood cell count, decreased neutrophil count, decreased platelet count.

Immune system disorders: rare – exacerbation of autoimmune conditions.

Metabolism and nutrition disorders: common – anorexia, increased blood glucose.

Psychiatric disorders: common – insomnia; uncommon – depression, irritability.

Nervous system disorders: common – headache, dizziness.

Eye disorders: uncommon – conjunctival irritation, eyelid edema.

Respiratory, thoracic and mediastinal disorders: uncommon – nasal congestion, pharyngolaryngeal pain.

Hepatobiliary disorders: frequency not known – increased liver enzyme levels.

Gastrointestinal disorders: common – nausea, diarrhea, vomiting; uncommon – dry mouth, abdominal pain.

Skin and subcutaneous tissue disorders: very common – erythema, crusting, skin flaking, skin edema, skin ulceration, hypopigmentation of the skin; common – dermatitis; uncommon – facial edema; rare – dermatological reactions at distant skin sites; frequency not known – alopecia, erythema multiforme, Stevens-Johnson syndrome, cutaneous lupus erythematosus, hyperpigmentation of the skin.

Musculoskeletal and connective tissue disorders: common – myalgia, arthralgia; uncommon – back pain, limb pain.

General disorders and administration site conditions: very common – erythema at application site, crusting at application site, flaking at application site, skin dryness at application site, swelling at application site, ulceration at application site, discharge at application site; common – application site reactions, itching at application site, pain at application site, swelling at application site, burning sensation at application site, irritation at application site, rash at application site, fatigue, hyperthermia, influenza-like illness, pain, chest pain; uncommon – dermatitis at application site, bleeding at application site, papules at application site, paresthesia at application site, hyperesthesia at application site, inflammation at application site, scarring at application site, skin fissures at application site, vesicles at application site, sensation of warmth at application site, asthenia, chills, lethargy, discomfort, inflammation.

Description of selected adverse reactions

Blood system disorders. During clinical trials with 5% imiquimod cream, decreases in hemoglobin, white blood cell count, absolute neutrophil count, and platelet count were observed. These decreases are not considered clinically significant in patients with normal hematological reserve. Patients with impaired hematological reserve were not included in clinical trials. Post-marketing reports have described decreases in hematological parameters requiring clinical intervention.

Skin infections. Skin infections have been observed during imiquimod treatment. Although no serious consequences have been reported, the possibility of infection development should always be considered in the presence of skin lesions.

Hypopigmentation and hyperpigmentation. Cases of localized hypopigmentation and hyperpigmentation have been reported following the use of 5% imiquimod cream. Subsequent information indicates that such skin color changes may be permanent in some patients.

Dermatological reactions at distant skin sites. Rare cases of dermatological reactions at distant skin sites, including erythema multiforme, were observed during clinical trials with 5% imiquimod cream.

Alopecia. During clinical trials of 5% imiquimod cream for the treatment of actinic keratosis, alopecia occurred with a frequency of 0.4% (5/1214) at the treatment site or adjacent areas.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life. 18 months.

Storage conditions. For single use only. Do not reuse opened sachets. Store at temperatures not exceeding 25°C.

Keep out of reach of children.

Packaging. 250 mg of cream in a sachet; 14 or 28 sachets per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Swiss Caps GmbH.

Manufacturer's address.

Grassinger Strasse 9, Bad Aibling, Bavaria, 83043, Germany.