Aceoto Plus

Ciprofloxacin Hydrochloride:

• Pharmacological action
• Pharmacokinetics
• Why is Aceoto Plus prescribed?
• Dosage and administration
• Aceoto Plus (Ciprofloxacin Hydrochloride) side effects, adverse reactions
• Contraindications
• Aceoto Plus (Ciprofloxacin Hydrochloride) Cipla: restrictions to using
• Using during pregnancy and breastfeeding
• Special instructions
• Precautionary measures
• Aceoto Plus (Ciprofloxacin Hydrochloride) drug interactions
• Aceoto Plus in case of emergency / overdose
• Aceoto Plus (Ciprofloxacin Hydrochloride) reviews

Pharmacological action

Aceoto Plus is a broad-spectrum antimicrobial drug of fluoroquinolone group with bactericidal action. Inhibits DNA gyrase and inhibits the synthesis of bacterial DNA. Highly active against most gram-negative bacteria: Pseudomonas aeruginosa, Haemophilus influenzae, Escherichia coli, Shigella spp., Salmonella spp., Neisseria meningitidis, Neisseria gonorrhoeae.

Aceoto Plus (Ciprofloxacin Hydrochloride) is active against Staphylococcus spp. (including strains producing and not producing penicillinase, methicillin-resistant strains), some strains of Enterococcus spp., Campylobacter spp., Legionella spp., Mycoplasma spp., Chlamydia spp., Mycobacterium spp.

Aceoto Plus (Ciprofloxacin Hydrochloride) is active against bacteria producing beta-lactamases.

Ureaplasma urealyticum, Clostridium difficile, Nocardia asteroides resistant to Aceoto Plus (Ciprofloxacin Hydrochloride). The effect on Treponema pallidum is studied not enough.

Pharmacokinetics

Aceoto Plus (Ciprofloxacin Hydrochloride) rapidly absorbed from the gastrointestinal tract. Bioavailability after oral administration of 70%. Eating has a little effect on the absorption of Aceoto Plus (Ciprofloxacin Hydrochloride). Plasma protein binding is 20-40%. Distributed in tissues and body fluids. It penetrates the cerebrospinal fluid: the concentration of Aceoto Plus (Ciprofloxacin Hydrochloride) for not inflamed meninges reach 10% with inflammation - up to 37%. High concentrations are achieved in bile. Excreted in the urine and bile.

Why is Aceoto Plus prescribed?

Infectious-inflammatory diseases caused by microorganisms susceptible to Aceoto Plus (Ciprofloxacin Hydrochloride), including respiratory diseases, diseases of abdominal and pelvic organs, bones, joints, skin, septicemia; severe infections of ENT organs. Treatment of postoperative infections. Prevention and treatment of infections in patients with reduced immunity.

For Aceoto Plus (Ciprofloxacin Hydrochloride) local use: acute and subacute conjunctivitis, blepharoconjunctivitis, blepharitis, bacterial corneal ulcers, keratitis, keratoconjunctivitis, chronic dacryocystitis, meybomity. Infectious lesions in the eyes from injury or contact with foreign bodies. Preoperative prophylaxis in ophthalmic surgery.

Dosage and administration

Individual. For oral administration dose of Aceoto Plus is 250-750 mg 2 times / day. Treatment duration is from 7-10 days to 4 weeks.

For IV administration a single dose is 200-400 mg, the multiplicity of the introduction is 2 times / day, duration of treatment - 1-2 weeks and more if necessary. May be IV injected as jet but more preferably a drip for 30 minutes.

When Aceoto Plus (Ciprofloxacin Hydrochloride) applied topically instilled 1-2 drops into the lower conjunctival sac of the affected eye every 1-4 hours. After improving the intervals between instillation can be increased. The maximum oral daily dose for adults is 1.5 g.

Aceoto Plus (Ciprofloxacin Hydrochloride) side effects, adverse reactions

Digestive system: nausea, vomiting, diarrhea, abdominal pain, increase in liver transaminases, alkaline phosphatase, LDH, bilirubin, pseudomembranous colitis.

CNS: headache, dizziness, fatigue, insomnia, nightmares, hallucinations, fainting, disorders of vision.

Urinary system: crystalluria, glomerulonephritis, dysuria, polyuria, albuminuria, hematuria, transient increase of serum creatinine.

Hemopoietic system: eosinophilia, leukopenia, neutropenia, changes in the number of platelets.

Cardiovascular system: tachycardia, cardiac arrhythmias, hypotension.

Allergic reactions: itching, urticaria, Quincke's edema, Stevens-Johnson syndrome, arthralgia.

Adverse reactions associated with the chemotherapeutic effect: candidiasis.

Local reactions: pain, phlebitis (for IV injections). When applying eye drops in some cases may be mild pain and conjunctival hyperemia.

Other: vasculitis.

Contraindications

Pregnancy, lactation, childhood and adolescence to 15 years, increased sensitivity to Aceoto Plus (Ciprofloxacin Hydrochloride) and other drugs hinolonovogo series; deficiency of glucose-6-phosphate dehydrogenase; in ophthalmology: viral keratitis.

Aceoto Plus (Ciprofloxacin Hydrochloride) Cipla: restrictions to using

Pronounced cerebral arteriosclerosis, cerebral circulatory disorder, mental illness, epilepsy, epileptic syndrome, marked renal and / or hepatic insufficiency.

Using during pregnancy and breastfeeding

Contraindicated in pregnancy ; Aceoto Plus (Ciprofloxacin Hydrochloride) crosses the placenta, excreted in breast milk.

In experimental studies found that it causes arthropathy. In experiments on rats and mice treated with Aceoto Plus (Ciprofloxacin Hydrochloride) in doses exceeding the usual daily dose for a person 6 times, adverse effects on the fetus is not revealed. In experiments on rabbits treated with oral dose of Aceoto Plus (Ciprofloxacin Hydrochloride) 30 and 100 mg / kg, it is shown that the drug causes disruption of the gastrointestinal tract, leading to loss of body weight in females and increase the number of miscarriages but teratogenicity not found. When IV introduction to the doses of 20 mg / kg Aceoto Plus (Ciprofloxacin Hydrochloride) did not exert toxic effects on the mother and embryo, showed no teratogenicity. The use of local forms of Aceoto Plus (Ciprofloxacin Hydrochloride) in pregnancy is possible if the anticipated benefits exceed the potential risk to the fetus.

Category of the fetus by FDA - C.

Aceoto Plus (Ciprofloxacin Hydrochloride) is excreted in breast milk, so the period of lactation should decide, stop taking Aceoto Plus (Ciprofloxacin Hydrochloride) or breastfeeding based on the degree of importance of the use of drugs for the mother.

With careful use of local forms of Aceoto Plus (Ciprofloxacin Hydrochloride) in breast-feeding (not known whether Aceoto Plus (Ciprofloxacin Hydrochloride) is excreted in breast milk when applied topically).

Special instructions

Patients with impaired renal function requires correction dosing regimen. With caution used in elderly patients, with cerebral arteriosclerosis, cerebral circulatory disorders, epilepsy, convulsive syndrome of unknown etiology.

During treatment patients with Aceoto Plus (Ciprofloxacin Hydrochloride) should receive enough amounts of liquids.

In the case of persistent diarrhea Aceoto Plus (Ciprofloxacin Hydrochloride) should not be taken.

At the same time of Aceoto Plus (Ciprofloxacin Hydrochloride) IV introduction and barbiturates is necessary to monitor heart rate, blood pressure, ECG. In the course of treatment is necessary to monitor blood concentrations of urea, creatinine, hepatic transaminases.

In the period of treatment may decrease the reactivity (especially when used with alcohol).

Not allowed the introduction of Aceoto Plus (Ciprofloxacin Hydrochloride) subconjunctival or directly into the anterior chamber of the eye.

Precautionary measures

Due to the threat of adverse reactions from the CNS Aceoto Plus should be used only according to the life in the pathology of the CNS in history: organic brain lesions, epilepsy, lowering the convulsive threshold, severe atherosclerosis of the brain (risk of circulatory disorders, stroke), the elderly, with severely impaired renal function and liver (requires monitoring concentrations in blood plasma).

Patients with allergic reactions to fluoroquinolone derivatives in history may develop reactions to Aceoto Plus (Ciprofloxacin Hydrochloride). During the period of treatment should avoid sunlight and UV radiation, intense physical exercise, control of drinking mode, pH of urine.

Reported cases of crystalluria, particularly in patients with alkaline reaction of urine (pH 7 or more). In order to avoid the development of crystalluria unacceptable excess of the recommended daily dose, should also be adequate fluid intake and maintaining acidic urine.

If you have pain in the tendons or the first signs tendovaginitah treatment should be discontinued (described isolated cases of inflammation or tendon rupture during fluoroquinolone treatment).

It can reduce the speed of psychomotor reactions, especially against the backdrop of alcohol, that should be considered for patients who work with potentially dangerous machinery or drive vehicles.

If you have severe diarrhea, pseudomembranous colitis should be excluded (for which Aceoto Plus (Ciprofloxacin Hydrochloride) is contraindicated). At the same time of barbiturates IV injections requires monitoring function of the cardiovascular system (heart rate, BP, ECG). Teenagers under 18 years shall be appointed only if the pathogen resistance to other chemotherapeutic drugs. The solution in the form of eye drops are not designed for intraocular injections. The use of other ophthalmic means the interval between injections should be at least 5 minutes.

Aceoto Plus (Ciprofloxacin Hydrochloride) drug interactions

Activity increases when combined with beta-lactam antibiotics, aminoglycosides, vancomycin, clindamycin, metronidazole. Sukralfat, bismuth preparations, antacids containing aluminum ions, magnesium or calcium, cimetidine, ranitidine, vitamin and mineral supplement, iron sulfate, zinc, didanosine (recommended for 2 hours before or 4 hours after these drugs) reduce the suction. Probenecid, azlocillin increase the concentration in the blood. Decreases clearance and increases in plasma caffeine, aminophylline and theophylline (increased likelihood of side effects). Aceoto Plus (Ciprofloxacin Hydrochloride) enhances the effect of warfarin and other oral anticoagulants (prolongs bleeding time). Increases nephrotoxicity of cyclosporine, increase the risk of CNS excitability and convulsive reactions against the background of NSAIDs. Medicines alkalinizing the urine (citrates, sodium bicarbonate, carbonic anhydrase inhibitors) reduce the solubility (increases the probability of crystalluria). Infusion solutions of Aceoto Plus (Ciprofloxacin Hydrochloride) ready to use can be combined with infusion solutions: 0.9% sodium chloride solution, Ringer's solution, Ringer lactate, 5 and 10% dextrose, 10% solution of fructose, and a solution containing 5% dextrose with 0,225 or 0.45% sodium chloride. Incompatible with solutions having a pH > 7.

Aceoto Plus in case of emergency / overdose

May occur after receiving a single large dose or prolonged use. If a single dose of less than 150 mg / kg, acute poisoning feel light, 150-300 mg / kg - moderate, when using higher doses - heavy.

Symptoms: No specific symptoms.

Treatment: gastric lavage, the use of emetic drugs, the introduction of large quantities of liquid, the creation of acidic urine, in addition - hemodialysis and peritoneal dialysis (can be derived only 10% of the drug), all events are held on the background to maintain vital functions. The specific antidote is unknown.

Fluocinolone Acetonide:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Aceoto Plus (Fluocinolone Acetonide) reviews

1 INDICATIONS AND USAGE

Aceoto Plus Cream is a combination of Aceoto Plus (Fluocinolone Acetonide) acetonide (a corticosteroid), hydroquinone (a melanin synthesis inhibitor), and tretinoin (a retinoid) that is indicated for the short-term treatment of moderate to severe melasma of the face, in the presence of measures for sun avoidance, including the use of sunscreens.

1.1 Indication

Aceoto Plus (Fluocinolone Acetonide) Cream is a combination of Aceoto Plus (Fluocinolone Acetonide) acetonide (a corticosteroid), hydroquinone (a melanin synthesis inhibitor), and tretinoin (a retinoid) that is indicated for the short-term treatment of moderate to severe melasma of the face, in the presence of measures for sun avoidance, including the use of sunscreens.

1.2 Limitations of Use

Aceoto Plus (Fluocinolone Acetonide) Cream is NOT indicated for the maintenance treatment of melasma. After achieving control with Aceoto Plus (Fluocinolone Acetonide) Cream, some patients may be managed with other treatments instead of triple therapy with Aceoto Plus (Fluocinolone Acetonide) Cream. Melasma usually recurs upon discontinuation of Aceoto Plus (Fluocinolone Acetonide) Cream.

The safety and efficacy of Aceoto Plus (Fluocinolone Acetonide) Cream in patients of Fitzpatrick Skin Types V and VI have not been studied. Excessive bleaching resulting in undesirable cosmetic effect in patients with darker skin cannot be excluded.

The safety and efficacy of Aceoto Plus (Fluocinolone Acetonide) Cream in the treatment of hyperpigmentation conditions other than melasma of the face have not been studied.

Because pregnant and lactating women were excluded from, and women of childbearing potential had to use birth control measures in the clinical trials, the safety and efficacy of Aceoto Plus (Fluocinolone Acetonide) Cream in pregnant women and nursing mothers have not been established [see Use in Specific Populations (8.1, 8.3)].

2 DOSAGE AND ADMINISTRATION

Apply a thin film of Aceoto Plus (Fluocinolone Acetonide) Cream to the effected area once daily, at least 30 minutes before bedtime.

Gently wash the face and neck with a mild cleanser. Rinse and pat the skin dry. Apply Aceoto Plus (Fluocinolone Acetonide) Cream to the hyperpigmented areas of melasma including about 1/2 inch of normal appearing skin surrounding each lesion. Rub lightly and uniformly into the skin.

Therapy should be discontinued when control is achieved.

During the day, use a sunscreen of SPF 30, and wear protective clothing. Avoid sunlight exposure. Patients may use moisturizers and/or cosmetics during the day.

Aceoto Plus (Fluocinolone Acetonide) Cream is for topical use only. It is not for oral, ophthalmic, or intravaginal use.

• Apply a thin film to the affected area once daily, at least 30 minutes before bedtime. (2)
• During the day, use a sunscreen of SPF 30, and wear protective clothing. Avoid sunlight exposure. (2)

3 DOSAGE FORMS AND STRENGTHS

Cream, 0.01%/4%/0.05%.

Each gram of Aceoto Plus (Fluocinolone Acetonide) Cream contains 0.1 mg of Aceoto Plus (Fluocinolone Acetonide) acetonide, 40 mg of hydroquinone, and 0.5 mg of tretinoin in a light yellow, hydrophilic cream base.

• Cream, 0.01%/4%/0.05%. Each gram of Aceoto Plus (Fluocinolone Acetonide) Cream contains 0.1 mg of Aceoto Plus (Fluocinolone Acetonide) acetonide, 40 mg of hydroquinone, and 0.5 mg of tretinoin. (3)

4 CONTRAINDICATIONS

Aceoto Plus (Fluocinolone Acetonide) Cream is contraindicated in individuals with a history of hypersensitivity to this product or any of its components.

• Aceoto Plus (Fluocinolone Acetonide) Cream is contraindicated in individuals with a history of hypersensitivity to this product or any of its components. (4)

5 WARNINGS AND PRECAUTIONS

• Aceoto Plus Cream contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening asthmatic episodes in susceptible people. If anaphylaxis, asthma or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue Aceoto Plus (Fluocinolone Acetonide). (5.1)
• Aceoto Plus (Fluocinolone Acetonide) Cream contains hydroquinone, which may produce exogenous ochronosis, a gradual blue-black darkening of the skin, the occurrence of which should prompt discontinuation of therapy. (5.2)

5.1 Hypersensitivity

Aceoto Plus (Fluocinolone Acetonide) Cream contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening asthmatic episodes in susceptible individuals. If anaphylaxis, asthma or other clinically significant hypersensitivity reactions occur, institute appropriate therapy and discontinue Aceoto Plus (Fluocinolone Acetonide). Allergic contact dermatitis may also occur [see Warnings and Precautions 5.4].

5.2 Exogenous Ochronosis

Aceoto Plus Cream contains hydroquinone, which may produce exogenous ochronosis, a gradual blue-black darkening of the skin, the occurrence of which should prompt discontinuation of therapy. The majority of patients developing this condition are Black, but it may also occur in Caucasians and Hispanics.

5.3 Effects on Endocrine System

Aceoto Plus (Fluocinolone Acetonide) Cream contains the corticosteroid Aceoto Plus (Fluocinolone Acetonide) acetonide. Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria can also be produced by systemic absorption of topical corticosteroid while on treatment. If HPA axis suppression is noted, the use of Aceoto Plus (Fluocinolone Acetonide) Cream should be discontinued. Recovery of HPA axis function generally occurs upon discontinuation of topical corticosteroids.

The ACTH or cosyntropin stimulation test may be helpful in evaluating patients for HPA axis suppression.

5.4 Cutaneous Reactions

Cutaneous hypersensitivity to the active ingredients of Aceoto Plus (Fluocinolone Acetonide) Cream has been reported in the literature. In a patch test study to determine sensitization potential in 221 healthy volunteers, three volunteers developed sensitivity reactions to Aceoto Plus (Fluocinolone Acetonide) Cream or its components.

Aceoto Plus (Fluocinolone Acetonide) Cream contains hydroquinone and tretinoin that may cause mild to moderate irritation. Local irritation, such as skin reddening, peeling, mild burning sensation, dryness, and pruritus may be expected at the site of application. Transient skin reddening or mild burning sensation does not preclude treatment. If a reaction suggests hypersensitivity or chemical irritation, the use of the medication should be discontinued.

Patients should avoid medicated or abrasive soaps and cleansers, soaps and cosmetics with drying effects, products with high concentrations of alcohol and astringents, and other irritants or keratolytic drugs while on Aceoto Plus (Fluocinolone Acetonide) Cream treatment. Patients are cautioned on concomitant use of medications that are known to be photosensitizing.

6 ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In the controlled clinical trials, adverse events were monitored in the 161 subjects who used Aceoto Plus (Fluocinolone Acetonide) Cream once daily during an 8-week treatment period. There were 102 (63%) subjects who experienced at least one treatment-related adverse event during these trials. The most frequently reported events were erythema, desquamation, burning, dryness, and pruritus at the site of application. The majority of these events were mild to moderate in severity. Adverse events reported by at least 1% of patients and judged by the investigators to be reasonably related to treatment with Aceoto Plus (Fluocinolone Acetonide) Cream from the controlled clinical trials are summarized (in decreasing order of frequency) as follows:

In an open-label trial, subjects who had cumulative treatment of melasma with Aceoto Plus (Fluocinolone Acetonide) Cream for 6 months showed a similar pattern of adverse events as in the 8-week studies.

The following local adverse reactions have been reported with topical corticosteroids. They may occur more frequently with the use of occlusive dressings, especially with higher potency corticosteroids. These reactions are listed in an approximate decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, and miliaria.

Most common adverse reactions (incidence > 5%) are erythema, desquamation, burning, dryness, pruritus, and acne. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Galderma Laboratories, L.P. at 1-866-735-4137 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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8 USE IN SPECIFIC POPULATIONS

Aceoto Plus Cream contains the teratogen, tretinoin, which may cause embryofetal death, altered fetal growth, congenital malformations, and potential neurologic deficits. Aceoto Plus (Fluocinolone Acetonide) Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (8.1)

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Aceoto Plus (Fluocinolone Acetonide) Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Aceoto Plus (Fluocinolone Acetonide) Cream contains the teratogen, tretinoin, which may cause embryo-fetal death, altered fetal growth, congenital malformations, and potential neurologic deficits.

In clinical trials involving Aceoto Plus (Fluocinolone Acetonide) Cream in the treatment of facial melasma, women of child-bearing potential initiated treatment only after having had a negative pregnancy test and used effective birth control measures during therapy. However, 13 women became pregnant during treatment with Aceoto Plus (Fluocinolone Acetonide) Cream. Most of the pregnancy outcomes are unknown. Three women gave birth to apparently healthy babies. One pregnancy was terminated prematurely, and another ended in miscarriage.

In general, use of drugs should be reduced to a minimum in pregnancy. If a patient has been inadvertently exposed to Aceoto Plus (Fluocinolone Acetonide) Cream in pregnancy, she should be counseled on the risk of teratogenesis due to this exposure. The risk of teratogenesis due to topical exposure to Aceoto Plus (Fluocinolone Acetonide) Cream may be considered low. However, exposure during the period of organogenesis in the first trimester is theoretically more likely to produce adverse outcome than in later pregnancy.

Tretinoin is considered to be highly teratogenic upon systemic administration. Animal reproductive studies are not available with topical hydroquinone. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals.

- In a dermal application study using Aceoto Plus (Fluocinolone Acetonide) Cream in pregnant rabbits, there was an increase in the number of in utero deaths and a decrease in fetal weights in litters from dams treated topically with the drug product.

- In a dermal application study in pregnant rats treated with Aceoto Plus (Fluocinolone Acetonide) Cream during organogenesis there was evidence of teratogenicity of the type expected with tretinoin. These morphological alterations included cleft palate, protruding tongue, open eyes, umbilical hernia, and retinal folding or dysplasia.

- In a dermal application study on the gestational and postnatal effects of a 10-fold dilution of Aceoto Plus (Fluocinolone Acetonide) Cream in rats, an increase in the number of stillborn pups, lower pup body weights, and delay in preputial separation were observed. An increase in overall activity was seen in some treated litters at postnatal day 22 and in all treated litters at five weeks, a pattern consistent with effects previously noted in animals exposed in utero with retinoic acids. No adequate study of the late gestational and postnatal effects of the full-strength Aceoto Plus (Fluocinolone Acetonide) Cream has been performed.

- It is difficult to interpret these animal studies on teratogenicity with Aceoto Plus (Fluocinolone Acetonide) Cream, because the availability of the dermal applications in these studies could not be assured, and comparison with clinical dosing is not possible.

8.3 Nursing Mothers

Corticosteroids, when systemically administered, appear in human milk. It is not known whether topical application of Aceoto Plus Cream could result in sufficient systemic absorption to produce detectable quantities of Aceoto Plus (Fluocinolone Acetonide) acetonide, hydroquinone, or tretinoin in human milk. Because many drugs are secreted in human milk, caution should be exercised when Aceoto Plus (Fluocinolone Acetonide) Cream is administered to a nursing woman. Care should be taken to avoid contact between the infant being nursed and Aceoto Plus (Fluocinolone Acetonide) Cream.

8.4 Pediatric use

Safety and effectiveness of Aceoto Plus (Fluocinolone Acetonide) Cream in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Aceoto Plus (Fluocinolone Acetonide) Cream did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

11 DESCRIPTION

Aceoto Plus (Fluocinolone Acetonide) (fluocinolone acetonide, hydroquinone, and tretinoin) Cream, 0.01%/4%/0.05% contains Aceoto Plus (Fluocinolone Acetonide) acetonide, USP, hydroquinone, USP, and tretinoin, USP, in a light yellow, hydrophilic cream base for topical application.

Aceoto Plus (Fluocinolone Acetonide) acetonide is a synthetic fluorinated corticosteroid. It is a white crystalline powder that is odorless and stable in light.

The chemical name for Aceoto Plus (Fluocinolone Acetonide) acetonide is: (6α,11β,16α)-6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]-pregna-1,-4-diene-3,20-dione.

The molecular formula is C₂₄H₃₀F₂O₆ and molecular weight is 452.50.

Aceoto Plus (Fluocinolone Acetonide) acetonide has the following structural formula:

Hydroquinone is a melanin synthesis inhibitor. It is prepared from the reduction of p-benzoquinone with sodium bisulfite. It occurs as fine white needles that darken on exposure to air.

The chemical name for hydroquinone is: 1,4-benzenediol.

The molecular formula is C₆H₆O₂ and molecular weight is 110.11.

Hydroquinone has the following structural formula:

Tretinoin, a retinoid, is all-trans-retinoic acid formed from the oxidation of the aldehyde group of retinene to a carboxyl group. It occurs as yellow to light-orange crystals or crystalline powder with a characteristic odor of ensilage. It is highly reactive to light and moisture.

The chemical name for tretinoin is: (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid.

The molecular formula is C₂₀H₂₈O₂ and molecular weight is 300.44.

Tretinoin has the following structural formula:

Each gram of Aceoto Plus (Fluocinolone Acetonide) Cream contains Active: Aceoto Plus (Fluocinolone Acetonide) acetonide 0.01% (0.1 mg), hydroquinone 4% (40 mg), and tretinoin 0.05% (0.5 mg). Inactive: butylated hydroxytoluene, cetyl alcohol, citric acid anhydrous, glycerin, glyceryl stearate, magnesium aluminum silicate, methyl gluceth-10, methylparaben, PEG-100 stearate, propylparaben, purified water, sodium metabisulfite, stearic acid, and stearyl alcohol.

fluocinolone-mol hydro-mol tretinoin

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of the active ingredients in Aceoto Plus Cream in the treatment of melasma is unknown.

12.3 Pharmacokinetics

Percutaneous absorption of unchanged tretinoin, hydroquinone and Aceoto Plus (Fluocinolone Acetonide) acetonide into the systemic circulation of two groups of healthy volunteers (Total N=59) was found to be minimal following 8 weeks of daily application of 1g (Group I, n=45) or 6g (Group II, n=14) of Aceoto Plus (Fluocinolone Acetonide) Cream.

For tretinoin quantifiable plasma concentrations were obtained in 57.78% (26 out of 45) of Group I and 57.14% (8 out of 14) of Group II subjects. The exposure to tretinoin as reflected by the C_max values ranged from 2.01 to 5.34 ng/mL (Group I) and 2.0 to 4.99 ng/mL (Group II). Thus, daily application of Aceoto Plus (Fluocinolone Acetonide) Cream resulted in a minimal increase of normal endogenous levels of tretinoin. The circulating tretinoin levels represent only a portion of total tretinoin-associated retinoids, which would include metabolites of tretinoin and that sequestered into peripheral tissues.

For hydroquinone, quantifiable plasma concentrations were obtained in 18% (8 out of 44) Group I subjects. The exposure to hydroquinone, as reflected by the C_max values, ranged from 25.55 to 86.52 ng/mL. All Group II subjects (6g dose) had post-dose plasma hydroquinone concentrations below the quantitation limit. For Aceoto Plus (Fluocinolone Acetonide) acetonide, Groups I and II subjects had all post-dose plasma concentrations below quantitation limit.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

When Aceoto Plus (Fluocinolone Acetonide) acetonide, hydroquinone, and tretinoin in fixed combinations equivalent to 10%, 50%, 100%, and 150% of the concentrations in the clinical formulation of Aceoto Plus (Fluocinolone Acetonide) Cream were applied topically to male and female CD-1 mice for up to 24 months at dosages approximating up to 50, 19,000, and 250 µg/kg/day, respectively (corresponding to dosages of 150, 57,000, and 750 μg/m²/day, respectively), no statistically significant changes in tumor incidence were observed.

When Aceoto Plus (Fluocinolone Acetonide) acetonide, hydroquinone, and tretinoin in fixed combinations equivalent to 10%, 25%, 50%, and 100% of the concentrations in the clinical formulation of Aceoto Plus (Fluocinolone Acetonide) Cream were applied topically to male and female SD rats for up to 24 months at dosages approximating up to 10, 4000, and 50 µg/kg/day, respectively (corresponding to dosages of 60, 24,000, and 300 μg/m²/day, respectively), statistically significant increases in the incidences of islet cell adenomas and combined islet cell adenomas and carcinomas of the pancreas in both males and females were observed. The clinical relevance of these findings is unknown.

Studies of hydroquinone in animals have demonstrated some evidence of carcinogenicity. The carcinogenic potential of hydroquinone in humans is unknown.

Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources.

Mutagenicity studies were not conducted with this combination of active ingredients. Published studies have demonstrated that hydroquinone is a mutagen and a clastogen. Treatment with hydroquinone has resulted in positive findings for genetic toxicity in the Ames assay in bacterial strains sensitive to oxidizing mutagens, in in vitro studies in mammalian cells, and in the in vivo mouse micronucleus assay. Tretinoin has been shown to be negative for mutagenesis in the Ames assay. Additional information regarding the genetic toxicity potential of tretinoin and of Aceoto Plus (Fluocinolone Acetonide) acetonide is not available.

A dermal reproductive fertility study was conducted in SD rats using a 10-fold dilution of the clinical formulation. No effect was seen on the traditional parameters used to assess fertility, although prolongation of estrus was observed in some females, and there was a trend towards an increase in pre-and post-implantation loss that was not statistically significant. No adequate study of fertility and early embryonic toxicity of the full-strength drug product has been performed. In a six-month study in minipigs, small testes and severe hypospermia were found when males were treated topically with the full strength drug product.

14 CLINICAL STUDIES

Two adequate and well-controlled efficacy and safety trials were conducted in 641 subjects between the ages of 21 to 75 years, having Fitzpatrick Skin types I-IV and moderate to severe melasma of the face. Aceoto Plus (Fluocinolone Acetonide) Cream was compared with 3 possible combinations of 2 of the 3 active ingredients [(1) hydroquinone 4% (HQ) + tretinoin 0.05% (RA); (2) Aceoto Plus (Fluocinolone Acetonide) acetonide 0.01% (FA) + tretinoin 0.05% (RA); (3) Aceoto Plus (Fluocinolone Acetonide) acetonide 0.01% (FA) + hydroquinone 4% (HQ)], contained in the same vehicle as Aceoto Plus (Fluocinolone Acetonide) Cream. Subjects were instructed to apply their study medication each night, after washing their face with a mild soapless cleanser, for 8 weeks. Instructions were given to apply a thin layer of study medication to the hyperpigmented lesion, making sure to cover the entire lesion including the outside borders extending to the normal pigmented skin. Subjects were provided a mild moisturizer for use as needed. A sunscreen with SPF 30 was also provided with instructions for daily use. Protective clothing and avoidance of sunlight exposure to the face was recommended.

Subjects were evaluated for melasma severity at Baseline and at Weeks 1, 2, 4, and 8 of treatment. Primary efficacy was based on the proportion of subjects who had an investigators’ assessment of treatment success, defined as the clearing of melasma at the end of the eight-week treatment period. The majority of subjects enrolled in the two trials were white (approximately 66%) and female (approximately 98%). Aceoto Plus (Fluocinolone Acetonide) Cream was demonstrated to be significantly more effective than any of the other combinations of the active ingredients.

PRIMARY EFFICACY ANALYSIS:

p-value is from Cochran-Mantel-Haenszel chi-square statistics controlling for pooled investigator and comparing Aceoto Plus (Fluocinolone Acetonide) Cream to the other treatment groups.

In the Investigators’ assessment of melasma severity at Day 56 of treatment, the following table shows the clinical improvement profile for all subjects treated with Aceoto Plus (Fluocinolone Acetonide) Cream based on severity of their melasma at the start of treatment.

Assessment Scale: Cleared (melasma lesions approximately equivalent to surrounding normal skin or with minimal residual hyperpigmentation); Mild (slightly darker than the surrounding normal skin); Moderate (moderately darker than the surrounding normal skin); Severe (markedly darker than the surrounding normal skin).

Subjects experienced improvement of their melasma with the use of Aceoto Plus (Fluocinolone Acetonide) Cream as early as 4 weeks. However, among 7 subjects who had clearing at the end of 4 weeks of treatment with Aceoto Plus (Fluocinolone Acetonide) Cream, 4 of them did not maintain the remission after an additional 4 weeks of treatment.

After 8 weeks of treatment with the trial drug, subjects entered into an open-label extension period in which Aceoto Plus (Fluocinolone Acetonide) Cream was given on an as-needed basis for the treatment of melasma. The remission periods appeared to shorten between progressive courses of treatment. Additionally, few subjects maintained complete clearing of melasma (approximately 1 to 2%).

table-2 table-3

16 HOW SUPPLIED/STORAGE AND HANDLING

Aceoto Plus (Fluocinolone Acetonide) Cream is light yellow in color, and supplied in 30 g aluminum tubes, NDC 0299-5950-30.

Storage: Keep tightly closed. Store in a refrigerator, 2° - 8°C (36° - 46°F). Protect from freezing.

See FDA-approved patient labeling (Patient Information)

Inform patients of the following:

• Advise patients to change to non-hormonal forms of birth control, if hormonal methods are used.
• Use Aceoto Plus (Fluocinolone Acetonide) Cream as directed by the health care provider and do not use Aceoto Plus (Fluocinolone Acetonide) Cream for any disorder other than that for which it is prescribed.
• Avoid exposure to sunlight, sunlamp, or ultraviolet light. Patients who are consistently exposed to sunlight or skin irritants either through their work environment or habits should exercise particular caution. Use sunscreen and protective covering (such as the use of a hat) over the treated areas. Sunscreen use is an essential aspect of melasma therapy, as even minimal sunlight sustains melanocytic activity.
• Weather extremes, such as heat or cold, may be irritating to patients treated with Aceoto Plus (Fluocinolone Acetonide) Cream. Because of the drying effect of this medication, a moisturizer may be applied to the face in the morning after washing.
• Keep Aceoto Plus (Fluocinolone Acetonide) Cream away from the eyes, nose, angles of the mouth, or open wounds because these areas are more sensitive to the irritant effect. If local irritation persists or becomes severe, discontinue application of the medication and consult your health care provider. Seek medical attention if you experience allergic contact dermatitis, blistering, crusting, and severe burning or swelling of the skin and irritation of the mucous membranes of the eyes, nose, and mouth.
• If the medication is applied excessively, marked redness, peeling, or discomfort may occur.
• Wash your hands after each application.

Marketed by:

GALDERMA LABORATORIES, L.P.

Fort Worth, TX 76177 USA

Manufactured by:

Hill Dermaceuticals, Inc.

Sanford, FL 32773 USA

P51400-1

or

Manufactured by:

G Production Inc.

Baie d’Urfé, QC, H9X 3S4 Canada

Made in Canada

P52091-2

PATIENT INFORMATION

Aceoto Plus (Fluocinolone Acetonide)^® (try-LOOM-ah)

(fluocinolone acetonide 0.01%, hydroquinone 4%, and tretinoin 0.05%)

Cream

Important information: Aceoto Plus (Fluocinolone Acetonide) Cream is for use on skin only. Do not use Aceoto Plus (Fluocinolone Acetonide) Cream in your mouth, eyes, or vagina.

What is the most important information I should know about Aceoto Plus (Fluocinolone Acetonide) Cream?

Aceoto Plus (Fluocinolone Acetonide) Cream may cause birth defects or death of the baby if used during pregnancy. The risk of birth defects or death of the baby may be greater if Aceoto Plus (Fluocinolone Acetonide) Cream is used during the first trimester of pregnancy. Tell your doctor if you are pregnant or plan to become pregnant.

If you become pregnant while using Aceoto Plus (Fluocinolone Acetonide) Cream, tell your doctor right away.

What is Aceoto Plus (Fluocinolone Acetonide) Cream?

Aceoto Plus (Fluocinolone Acetonide) Cream is a prescription medicine used for the short-term treatment of moderate to severe melasma of the face, in combination with sun avoidance and the use of sunscreens.

Aceoto Plus (Fluocinolone Acetonide) Cream is not for continuous treatment of melasma.

It is not known if Aceoto Plus (Fluocinolone Acetonide) Cream is safe and effective in children.

It is not known if Aceoto Plus (Fluocinolone Acetonide) Cream is safe and effective in people with dark brown to black skin color.

It is not known if Aceoto Plus (Fluocinolone Acetonide) Cream is safe and effective in the treatment of dark spots (hyperpigmentation) of the skin caused by conditions other than melasma of the face.

It is not known if Aceoto Plus (Fluocinolone Acetonide) Cream is safe and effective in females who are pregnant or who are breastfeeding. See "What is the most important information I should know about Aceoto Plus (Fluocinolone Acetonide) Cream? and What should I tell my doctor before using Aceoto Plus (Fluocinolone Acetonide) Cream?"

Who should not use Aceoto Plus (Fluocinolone Acetonide) Cream?

Do not use Aceoto Plus (Fluocinolone Acetonide) Cream if you are allergic to it or any of the ingredients in Aceoto Plus (Fluocinolone Acetonide) Cream. See the end of this leaflet for a complete list of ingredients in Aceoto Plus (Fluocinolone Acetonide) Cream.

What should I tell my doctor before using Aceoto Plus (Fluocinolone Acetonide) Cream?

Before you use Aceoto Plus (Fluocinolone Acetonide) Cream, tell your doctor if you:

• are allergic to sulfites
• have any other medical conditions
• are pregnant or plan to become pregnant. See " What is the most important information I should know about Aceoto Plus (Fluocinolone Acetonide) Cream?"
• are breastfeeding or plan to breastfeed. It is not known if Aceoto Plus (Fluocinolone Acetonide) Cream passes into your breast milk. You should avoid skin-to-skin contact between areas treated with Aceoto Plus (Fluocinolone Acetonide) Cream and your baby.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, herbal supplements and skin products that you use.

How should I use Aceoto Plus (Fluocinolone Acetonide) Cream?

• Use Aceoto Plus (Fluocinolone Acetonide) Cream exactly as your doctor tells you to use it.
• Before you apply Aceoto Plus (Fluocinolone Acetonide) Cream, gently wash your face with a mild cleanser. Rinse your face and pat your skin dry.
• Apply Aceoto Plus (Fluocinolone Acetonide) Cream 1 time a day, at least 30 minutes before bedtime.
• Apply a thin layer of Aceoto Plus (Fluocinolone Acetonide) Cream to the affected skin areas. Include about 1/2 inch of normal skin surrounding the affected area.
• Gently rub Aceoto Plus (Fluocinolone Acetonide) Cream evenly into your skin.
• Do not get Aceoto Plus (Fluocinolone Acetonide) Cream near the corners of your mouth, your nose, your eyes, or open wounds.
• Do not bandage or cover the treated skin after applying Aceoto Plus (Fluocinolone Acetonide) Cream.
• You may use moisturizers and cosmetics during the day.
• Wash your hands after applying Aceoto Plus (Fluocinolone Acetonide) Cream.

What should I avoid while using Aceoto Plus (Fluocinolone Acetonide) Cream?

• You should avoid sunlight, sunlamps, tanning beds, and ultraviolet light during treatment with Aceoto Plus (Fluocinolone Acetonide) Cream.
• Use sunscreen with an SPF (sun protection factor) of 30 or more. If you have to be in the sunlight, wear a wide-brimmed hat or other protective clothing to cover the treated areas.
• Melasma can get worse with even a small amont of sunlight. You should continue to avoid sunlight, use sunscreen, and wear protective clothing after treatment with Aceoto Plus (Fluocinolone Acetonide) Cream.
• Females should avoid the use of hormonal forms of birth control. Hormonal birth control methods can cause your melasma to become worse. Talk to your doctor about other birth control options.
• Heat and cold weather may irritate skin treated with Aceoto Plus (Fluocinolone Acetonide). Talk with your doctor about ways to manage skin irritation.

What are the possible side effects of Aceoto Plus (Fluocinolone Acetonide) Cream?

Aceoto Plus (Fluocinolone Acetonide) Cream may cause serious side effects, including:

- allergic reactions. Aceoto Plus (Fluocinolone Acetonide) Cream may cause allergic reactions that can be life threatening. Stop using Aceoto Plus (Fluocinolone Acetonide) Cream and call your doctor or get medical help right away if you get any of the following symptoms:

• swelling of your face, eyes, lips, tongue, or throat
• trouble breathing
• severe itching
• skin rash or hives

- change in skin color. One of the medicines in Aceoto Plus (Fluocinolone Acetonide) Cream can cause a blue-black darkening of your skin. Stop using Aceoto Plus (Fluocinolone Acetonide) Cream and tell you doctor if you develop a blue-black darkening of your skin.

- Aceoto Plus (Fluocinolone Acetonide) Cream can pass through your skin. Too much Aceoto Plus (Fluocinolone Acetonide) Cream passing through your skin can cause your adrenal glands to stop working. Your doctor may do blood tests to check for adrenal gland problems.

- skin irritation. Stop using Aceoto Plus (Fluocinolone Acetonide) Cream and call your doctor if you have:

• blistering or crusting of your skin
• severe burning
• swelling of your skin
• irritation of your eyes, nose, or mouth

The most common side effects of Aceoto Plus (Fluocinolone Acetonide) Cream include:

• redness
• peeling
• burning
• dryness
• itching
• acne

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

These are not all the possible side effects of Aceoto Plus (Fluocinolone Acetonide) Cream. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to Galderma Laboratories, L.P. at 1-866-735-4137.

How should I store Aceoto Plus (Fluocinolone Acetonide) Cream?

• Store Aceoto Plus (Fluocinolone Acetonide) Cream in a refrigerator, between 36°F to 46°F (2°C to 8 °C).
• Keep Aceoto Plus (Fluocinolone Acetonide) Cream tube tightly closed.
• Do not freeze Aceoto Plus (Fluocinolone Acetonide) Cream.

General information about the safe and effective use of Aceoto Plus (Fluocinolone Acetonide) Cream

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

If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Aceoto Plus (Fluocinolone Acetonide) Cream that is written for health professionals.

What are the ingredients in Aceoto Plus (Fluocinolone Acetonide) Cream?

Active ingredients: Aceoto Plus (Fluocinolone Acetonide) acetonide, hydroquinone, and tretinoin

Inactive ingredients: butylated hydroxytoluene, cetyl alcohol, citric acid anhydrous, glycerin, glyceryl stearate, magnesium aluminum silicate, methyl gluceth-10, methylparaben, PEG-100 stearate, propylparaben, purified water, sodium metabisulfite, stearic acid, and stearyl alcohol

This Patient Information has been approved by the U.S. Food and Drug Administration.

Marketed by:

GALDERMA LABORATORIES, L.P.

Fort Worth, TX 76177 USA

Manufactured by:

Hill Dermaceuticals, Inc.

Sanford, FL 32773 USA

or

Manufactured by:

G Production Inc.

Baie dUrfé, QC, H9X 3S4 Canada

Made in Canada

Revised: March 2014

Aceoto Plus (Fluocinolone Acetonide)^® (fluocinolone acetonide, hydroquinone, tretinoin) cream, 0.01%/4%/0.05%

MUST BE REFRIGERATED

NDC 0299-5950-30

Rx Only

NET WT. 30 g

GALDERMA

Lot No.: Exp. Date:

For Topical Use Only. Not for Ophthalmic Use.

Usual

Dosage: Apply a thin film to affected areas once daily at night. See package insert for complete prescribing information.

Each gram contains: Active: Aceoto Plus (Fluocinolone Acetonide) acetonide 0.01% (0.1 mg), hydroquinone 4% (40 mg), and tretinoin 0.05% (0.5 mg). Inactive: butylated hydroxytoluene, cetyl alcohol, citric acid anhydrous, glycerin, glyceryl stearate, magnesium aluminum silicate, methyl gluceth-10, methylparaben, PEG-100 stearate, propylparaben, purified water, sodium metabisulfite, stearic acid, and stearyl alcohol.

Storage: Store in a refrigerator, 2° to 8°C (36° to 46°F). Protect from freezing.

www.triluma.com

Marketed by:

GALDERMA LABORATORIES, L.P.

Fort Worth, Texas 76177 USA

Galderma is a registered trademark.

P51399-2

MUST BE REFRIGERATED

p51399-2-tri-luma-30g-crm-crtn