- ERFA HYDROQUINONE
Gel, 4% w/w for topical use
FOR EXTERNAL USE ONLY
ERFA HYDROQUINONE is indicated for: the short-term treatment of hyperpigmented skin conditions such as chloasma, melasma, ‘liver spots’, ‘age spots’, freckles, senile/solar lentigines, and post-inflammatory hyperpigmentation.
- UV protection (sunscreen, and/ or protective clothing) should be used. See Warnings and Precautions.
- If reduction of pigmentation is not observed within 8-12 weeks of treatment (3 weeks for melasma), therapy should be discontinued and the hyperpigmented skin assessed for potentially more serious conditions. See Warnings and Precautions.
- Hyperpigmented skin should be thoroughly assessed for malignant lesions.
Pediatrics (<18 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
Geriatrics (≥65 years): No appropriate data are available to Health Canada; therefore, Health Canada has not authorized an indication for geriatric use.
ERFA HYDROQUINONE is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see Dosage Forms, Strengths, Composition and Packaging.
The safety of topical hydroquinone use during pregnancy or for children has not been studied.
- 3-Dosage and administration
3.1 Recommended Dose and Dosage Adjustment
Test for skin sensitivity before use:
Apply a small amount of gel on unbroken skin, and check for irritations within 24 hours. Minor redness is not necessarily a contraindication, but treatment should be discontinued if itching, excessive inflammation, or vesicle formation occurs.
ERFA HYDROQUINONE should be applied to affected areas and rubbed in well twice daily, in the morning and before bedtime, or as directed by a physician. If no improvement is seen after 2 months of treatment (within 3 weeks for melasma), ERFA HYDROQUINONE should be discontinued, and the skin reassessed for potentially more serious conditions.
Hydroquinone gel should not be used for maintenance therapy beyond 2 or 3 months. UV protection (sunscreen SPF > 30 (UVA and UVB), and/ or protective clothing) should be used. See Warnings and Precautions.
The use of hydroquinone products in paranasal and infraorbital areas increases the risk of irritation.
Discontinue use if mild irritation persists or if severe irritation or rash occurs.
Health Canada has not authorized an indication for pediatric use. (See 1.1 Pediatrics)
For topical use only. Not for oral, ophthalmic or intravaginal use.
Consumption of large acute doses of hydroquinone-containing mixtures, accidentally or with suicidal intent (≥ 1 g of hydroquinone), has been reported to produce signs of acute CNS disturbances such as tremor, dizziness, muscular twitching, headache, and delirium, in addition to tinnitus, nausea, respiratory difficulty, convulsions, and unconsciousness. If overdoses of hydroquinone are ingested, treat symptomatically.
For management of a suspected drug overdose, contact your regional poison control centre.
- 5-Dosage forms, strengths, composition and packaging
ERFA HYDROQUINONE is a clear, transparent gel with a characteristic odour. Each gram of ERFA HYDROQUINONE gel contains 40 mg of hydroquinone. The packaging unit (tube) contains 30 g of hydroquinone gel 4%. Excipients: Ethanol 96%, glycolic acid, propylene glycol, polyquaternium-10, ammonium hydroxide, citric acid anhydrous , sodium metabisulfite , sodium sulfite anhydrous , disodium edetate, butylhydroxytoluene and purified water.
Route of Administration Dosage Form / Strength/Composition Non-medicinal Ingredients Topical Hydroquinone gel 4% w/w Ammonium hydroxide, butylhydroxytoluene , citric acid anhydrous, disodium edetate, ethanol 96%, glycolic acid, propylene glycol, polyquaternium-10, sodium metabisulfite , sodium sulfite anhydrous, and purified water.
- 6-Warnings and precautions
Hydroquinone may produce exogenous ochronosis with continuous use (progressive asymptomatic hyperpigmentation of gray-blue or blue-black darkening of the skin, erythema, and papules on the sun exposed treated areas of the skin). In severe cases, ochronosis may cause disfiguring effects. If hyperpigmentation develops, treatment should immediately be discontinued. To reduce risk of exogenous ochronosis, hydroquinone should not be used with concomitant photosensitizing drugs (e.g. antimalarial drugs, resorcinol, phenol or injections of quinine).
Hydroquinone may produce leukoderma if used for a relatively long period of time. Leukoderma is mostly irreversible as melanocytes are destroyed leaving white patches on the skin. It may possibly mask other skin lesions, including malignant lesions.
Hydroquinone is a skin-bleaching agent, which may produce unwanted cosmetic effects. Use only as directed. The physician should be familiar with conditions of use of hydroquinone for skin application before prescribing. The skin lesions should be assessed by the physician before prescribing the drug in order to exclude malignant skin lesions.
UV protection (sunscreen, and/or protective clothing) should be used to avoid re-pigmentation. Hyperpigmentation or depigmentation during treatment should prompt discontinuation of therapy. Hydroquinone should only be applied to small areas of the body, and should not be applied on broken skin or mucous membranes. Avoid contact with eyes; in case of contact, the patient must rinse thoroughly with water.
If no improvement is seen after 2 or 3 months of treatment (within 3 weeks for melasma), ERFA HYDROQUINONE should be discontinued, and the skin reassessed for potentially more serious conditions.
ERFA HYDROQUINONE contains glycolic acid and citric acid, which are alpha-hydroxy acids (AHAs) which may increase the skin's sensitivity to the sun and particularly the possibility of sunburn. It is recommended that prior to exposure to the sun, users cover areas where AHAs have been applied with sunscreen. Contact of the product with the skin must be of limited frequency or duration. See Warnings and Precautions – Immune.
ERFA HYDROQUINONE contains sodium metabisulfite, which may cause allergic-type reactions including anaphylactic symptoms and life-threatening or asthmatic episodes. Sulfite sensitivity is more frequently reported among asthmatic subjects.
This medicinal product can cause local skin reactions (such as contact dermatitis) or irritation of
the eyes and mucous membranes as it contains butylhydroxytoluene. See Warnings and Precautions – Immune.
Carcinogenesis and Mutagenesis
Long term exposure to hydroquinone in animal carcinogenicity studies has shown some evidence of carcinogenicity. Published studies have demonstrated that hydroquinone is a mutagen and a clastogen. See NON-CLINICAL TOXICOLOGY.
Dermal application of hydroquinone was associated with cutaneous malignancy (spindle cell squamous cell carcinoma) in some cases reported in the literature. It is unknown whether hydroquinone was a pro-carcinogen or malignancy was due to suppression of natural photo-protection effect of melanin.
Caution should be exercised in patients who have a history of, or are at risk of developing cancer when using hydroquinone-containing products. Close monitoring should be considered.
Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.
Allergic contact dermatitis may occur. If contact dermatitis is reported or suspected, ERFA HYDROQUINONE should be discontinued immediately. (See ADVERSE REACTIONS - Adverse Reaction Overview.)
Reproduction and Fertility
Oral administration of hydroquinone did not produce embryotoxic, fetotoxic, or teratogenic effects in rats, nor did it produce significant adverse reproductive effects in a two-generation study. However in rabbits, various teratogenic/reproductive treatment-related effects were observed at high doses. (See NON-CLINICAL TOXICOLOGY). Animal reproduction studies have not been conducted with topical hydroquinone. It is also not known whether topical hydroquinone can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Topical hydroquinone should be given to a pregnant woman only if clearly needed.
This product contains glycolic acid and citric acid, which are alpha-hydroxy acids (AHAs) which may increase the skin's sensitivity to the sun and particularly the possibility of sunburn. It is recommended that prior to exposure to the sun, users cover areas where AHAs have been applied with sunscreen. Contact of the product with the skin must be of limited frequency or duration.
This medicinal product can cause skin irritation as it contains propylene glycol.
This medicinal product can cause local skin reactions (such as contact dermatitis) or irritation of the eyes and mucous membranes as it contains butylhydroxytoluene.
6.1 Special Populations
6.1.1 Pregnant Women
The safety of topical hydroquinone use during pregnancy has not been studied. Topical hydroquinone should be given to a pregnant woman only if the treatment benefit outweighs the perceived risks.
The safety of topical hydroquinone use during breast-feeding has not been studied. It is unknown if the drug is excreted in human milk. However, because many drugs are excreted in human milk, ERFA HYDROQUINONE should not be used during breast-feeding.
Pediatrics (<18 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
ERFA HYDROQUINONE has not been adequately studied in elderly patients Health Canada has not authorized an indication for geriatric use.
- 7-Adverse reactions
7.1 Adverse Reaction Overview
In published clinical trials of varying duration (most were of 12-week duration), the adverse effects reported in 559 patients treated with various formulations of hydroquinone cream (2% or 4%) mainly for melasma were local irritation, erythema, itchy eruptions, stinging, tingling, burning, pruritus at the application site. Most events were mild in intensity. Contact dermatitis was reported in three patients, one patient had a positive patch test for sensitization.
Spontaneous adverse event reports in Canada for hydroquinone topical skin products include the following events: contact dermatitis, burning sensation, skin discolouration/ hyperpigmentation, rash, serious rash, chemical burn, scarring, drug ineffective, serious erythema, and benign neoplasm of the skin.
Long term treatment with hydroquinone may result in ochronosis or leukoderma (see Warnings and Precautions).
Sulfite Sensitivity Reactions: Sulfite may cause allergic-type reactions (including anaphylaxis and life-threatening reactions and asthmatic episodes) in certain susceptible individuals. See Warnings and Precautions.
This product contains glycolic acid and citric acid, which are alpha-hydroxy acids (AHAs) which may increase the skin's sensitivity to the sun and particularly the possibility of sunburn.
This product can cause skin irritation as it contains propylene glycol.
This product can cause local skin reactions (such as contact dermatitis) or irritation of
the eyes and mucous membranes as it contains butylhydroxytoluene.
7.2 Clinical Trial Adverse Reactions
Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
In a study to demonstrate the efficacy and safety of a novel pharmaceutical formulation of hydroquinone 4%, in the gel form (HQ*-4% (02-0268)) there were no severe adverse reactions detected.
In the study, 48.3% of participants experienced adverse reactions out of which 43.3% were related to the product. There was only one adverse reaction which caused withdrawal in the control group (desquamation), 51.7% of the patients from the control group experienced no adverse reactions, 35 % experienced one adverse reaction, 6.7 % experienced two adverse reactions, 5.0% experienced three adverse reactions., and 1.7% experienced 4 adverse reactions.
(see pdf for table)
The most frequent adverse reactions reported in the clinical study were application site disorders with 46.43% of patients in the control group and 31.25% of patients in the placebo group. Skin and subcutaneous tissue disorders were the second most frequently reported adverse reaction with 14.29% of patients in the control group and 6.25% of patients in the placebo group. Two cases of respiratory, thoracic and mediastinal disorders were reported in the placebo group (nasal passage irritation and sneezing) resulting with 6.25% of the placebo group participants. Only one case of eye disorder (eye irritation) was reported in the study (3.57%)
7.3 Clinical Trial Adverse Reactions (Pediatrics)
ERFA HYDROQUINONE was not studied in pediatric populations.
7.4 Post-Market Adverse Reactions
The frequency is defined as: 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 unknown frequency (cannot be estimated from the data available).
Skin and subcutaneous tissue disorders
Uncommon: erythema and itching.
Rare: cutaneous sensitivity. In long-term treatment it can cause a cutaneous hyperpigmentation reaction.
The treatment should be discontinued if these disorders do not disappear after one week.
Very rare: leukoderma has been observed in isolated cases. Ochronosis has been observed in long-term treatments (more than 6 months), mainly in black people.
No systemic adverse effects have been described.
TREATMENT SHOULD BE STOPPED IF ADVERSE REACTIONS ARE OBSERVED.
- 8-Drug interactions
Peroxides: hydroquinone should not be used simultaneously with peroxides (for example: oxygenated water, benzoyl peroxide, etc.). (See Drug-Drug interactions).
Photosensitizing drugs: hydroquinone should not be used with concomitant photosensitizing drugs. (See Drug-Drug interactions).
8.2 Drug-Drug Interactions
The simultaneous use of hydroquinone with peroxides (for example: oxygenated water, benzoyl
peroxide, etc.) can cause temporary coloration of the skin, due to the oxidation of hydroquinone.
This temporary coloration is eradicated by stopping the use of one of these medicinal products and washing the area of application with mild soap.
To reduce risk of exogenous ochronosis, hydroquinone should not be used with concomitant photosensitizing drugs (e.g., antimalarial drugs, resorcinol, phenol or injections of quinine).
Many other commonly used medications may have photosensitizing properties to some degree.
- 9-Action and clinical pharmacology
9.1 Mechanism of Action
Topical application of hydroquinone produces a reversible depigmentation of the skin by inhibition of the enzymatic oxidation of tyrosine to 3, 4-dihydroxyphenylalanine (dopa) which is involved in the initial step of the melanin pigment biosynthesis pathway and suppression of other melanocyte metabolic processes. Exposure to sunlight or ultraviolet light will cause repigmentation of bleached areas.
Accumulation of melanin in the upper layer of the epidermis is the main cause for pigmentation disorders. Melanin is a durable polymer, and there is almost no available means of destroying its structure and lightening the skin. Thus, inhibition of synthesis of melanin is the approach most often used for reducing melanin content in the epidermis. Hydroquinone affects melanogenesis by competing with tyrosine for the enzyme tyrosinase for oxidation; in the presence of catalytic amounts of dopa, hydroquinone is oxidized to the toxic benzoquinone metabolite which could damage membranes; hydroquinone inhibits DNA and RNA synthesis and alters melanosome formation; histochemical and electron microscopy indicated that hydroquinone affects the membranous structures of melanocytes and eventually causes necrosis of whole melanocytes.
Absorption of orally administered or intratracheally instilled hydroquinone is rapid and extensive (Garton & Williams, 1949; Divincenzo et al., 1984; English et al., 1988). However, the rate of hydroquinone absorption through the skin is low. Marty et al. (1981) reported that the in vitro permeability constants for rat and human skin were 28 x 10-6 and 4 x 10-6 cm/hr, respectively. Based on the data of Bucks et al. (1988), an in vivo human dermal absorption rate of 3 µg/cm2/hr and a permeability constant of 2.25 x 10-6 cm/hr can be calculated. The actual amount of hydroquinone absorbed following dermal exposure depends on the exposure concentrations, length of exposure and vehicle, as well as other factors. When Bucks et al. (1988) applied 14C-labelled hydroquinone in an alcoholic vehicle to the foreheads of human volunteers for 24 hours, 57% of the total 14C label was excreted in the urine after 5 days. Addition of a sun screen to the hydroquinone solution reduced total excretion to 26%.
Following the oral administration of radiolabelled hydroquinone to F-344 rats, radioactivity was widely distributed throughout the animal tissues. The highest activity was localized in the kidney and liver (Divincenzo et al., 1984). However, on a quantitative basis, the amount retained within the animal was low, representing < 2% of the total dose 48 hours after exposure (Divincenzo et al., 1984; English et al., 1988). Widespread distribution and extensive elimination were also observed following intratracheal administration of hydroquinone to F-344 rats (Lockhart & Fox, 1985b). However, following the intravenous injection of radiolabelled hydroquinone to F-344 rats, radioactivity was shown, using whole body autoradiographic techniques, to concentrate in the bone marrow, thymus and white pulp of the spleen (Greenlee et al., 1981a). Subsequent experiments indicated that significant acid soluble and covalently bound radioactivity could be recovered in the thymus, bone marrow and white blood cells 24 hours after intravenous administration (Greenlee et al., 1981b). These results indicate that the route of administration may influence the profile of distribution and elimination observed following hydroquinone administration.
Hydroquinone is converted mainly by Phase II metabolism to water-soluble conjugates, as shown by the recovery of only little parent compound and p-benzoquinone (0.25-7%) but large amounts of hydroquinone-monoglucuronide and hydroquinone-monosulfate (>90%) in the urine (Divincenzo et al. 1984; English et al. 1988). A small percentage of the dose was recovered as the mercapturic acid conjugate of hydroquinone, suggesting the intermediate formation of a glutathione conjugate of hydroquinone.
Divincenzo et al. (1984) demonstrated that repeated dosing with 200 mg hydroquinone/kg did not alter the relative or absolute rat liver weight or induce the hepatic mixed-function oxidase system, nor did hydroquinone undergo Phase I oxidation to other metabolites such as 1,2,4-trihydroxybenzene. In addition, the formation of 1, 2, 4-trihydroxybenzene was not observed in the urine after oral administration of hydroquinone to rabbits (Garton & Williams, 1949). However, following intraperitoneal injection of hydroquinone (50 mg/kg) in Wistar rats and Japanese white rabbits, 1, 2, 4-trihydroxybenzene represented a significant proportion (approximately 12%) of the metabolites recovered in the urine (Inoue et al., 1989a, b). This apparent difference in the metabolic profile observed when hydroquinone is administered by the intraperitoneal route rather than the oral route is probably related to the ability of the gastrointestinal system to conjugate phenolic compounds absorbed in the intestine, thus reducing the amount of free hydroquinone available for Phase I metabolism in the liver (Powell et al., 1974; Cassidy & Houston, 1980a, b; Cassidy & Houston, 1984).
Hydroquinone is excreted mainly in the form of water-soluble metabolites via the urine (about 90%). Dose-related differences have been observed for rats receiving 25 or 350 mg/kg, which suggests that elimination processes are saturated at high-dose levels (English et al., 1988). The area under the curve (AUC) values for plasma concentration, which provide an index of bioavailability, also showed that saturation of elimination had occurred at high-dose levels, particularly for females. The fact that most of the radioactivity excreted is associated with the alpha-elimination phase suggests that this may be due to conjugation of hydroquinone to readily excreted metabolites. The appearance of a double peak in the blood concentration versus time curve indicates that enterohepatic recycling of hydroquinone may have occurred.
Permeation study (UIBF 03.09.60 (V)):
Transdermal permeability of hydroquinone in two semisolid (gel) formulations and a semisolid reference formulation using FRANZ type diffusion cells was studied. The capacity of hydroquinone to permeate the skin was established by determining the quantities of the agent that had crossed it at each of the prefixed time interval. No significant differences were seen between the three formulations in terms of the permeation variables studied (transdermal flow rate, latency and quantity permeated per unit time) (p=>0.1).
- 10-Storage, stability and disposal
Store at room temperature between 15 -30 o C. Do not freeze. Keep the tube totally sealed to protect it from light. Keep out of the sight and reach of children. Do not use the product if dark coloration is observed, even if it is within the expiry period.
- 11-Special handling instructions
Wash hands with soap after the application of the product, as hydroquinone can cause reversible brown spots on the fingernails.