Tri-Luma

fluocinolone acetonide, hydroquinone, and tretinoin

Dosage Form: cream
Tri-Luma® Cream

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

For External Use Only

Not for Ophthalmic Use

Rx only

Tri-Luma Description

Tri-Luma® Cream (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) contains fluocinolone acetonide, USP, hydroquinone, USP, and tretinoin, USP, in a hydrophilic cream base for topical application.

Fluocinolone acetonide is a synthetic fluorinated corticosteroid for topical dermatological use and is classified therapeutically as an anti-inflammatory. It is a white crystalline powder that is odorless and stable in light.

The chemical name for fluocinolone 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. Fluocinolone acetonide has the following structural formula:

Hydroquinone is classified therapeutically as a depigmenting agent. 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 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. Tretinoin is classified therapeutically as a keratolytic.

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 Tri-Luma® Cream contains Active: fluocinolone acetonide 0.01% (0.1 mg), hydroquinone 4% (40 mg), and tretinoin 0.05% (0.5 mg). Inactive: butylated hydroxytoluene, cetyl alcohol, citric acid, glycerin, glyceryl stearate, magnesium aluminum silicate, methyl gluceth-10, methylparaben, PEG-100 stearate, propylparaben, purified water, sodium metabisulfite, stearic acid, and stearyl alcohol.

Tri-Luma - Clinical Pharmacology

One of the components in Tri-Luma Cream, hydroquinone, is a depigmenting agent, and may interrupt one or more steps in the tyrosine-tyrosinase pathway of melanin synthesis. However, the mechanism of action of the active ingredients in Tri-Luma Cream in the treatment of melasma is unknown.

Pharmacokinetics: Percutaneous absorption of unchanged tretinoin, hydroquinone and fluocinolone 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 Tri-Luma 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 Cmax 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 Tri-Luma 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 Cmax 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 fluocinolone acetonide, Groups I and II subjects had all post-dose plasma concentrations below quantitation limit.

Clinical Studies: Two adequate and well-controlled efficacy and safety studies were conducted in 641 patients between the ages of 21 to 75 years, having skin phototypes I-IV and moderate to severe melasma of the face. Tri-Luma Cream was compared with 3 possible combinations of 2 of the 3 active ingredients [(1) hydroquinone 4% (HQ) + tretinoin 0.05% (RA); (2) fluocinolone acetonide 0.01% (FA) + tretinoin 0.05% (RA); (3) fluocinolone acetonide 0.01% (FA) + hydroquinone 4% (HQ)], contained in the same vehicle as Tri-Luma Cream. Patients 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. Patients 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.

Patients 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 patients 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 patients enrolled in the two studies were white (approximately 66%) and female (approximately 98%). Tri-Luma Cream was demonstrated to be significantly more effective than any of the other combinations of the active ingredients.

PRIMARY EFFICACY ANALYSIS:

Investigators’ Assessment of Treatment Success* At the End of 8 Weeks of Treatment

		Tri-Luma	HQ+RA	FA+RA	FA+HQ
*Treatment success was defined as melasma severity score of zero (melasma lesions cleared of hyperpigmentation).
p-value is from Cochran-Mantel-Haenszel chi-square statistics controlling for pooled investigator and comparing Tri-Luma
Cream to the other treatment groups.
Study No. 1	Number of Patients	85	83	85	85
	No. of Successes	32	12	0	3
	Proportion of Successes	38%	15%	0	4%
	p-value		<0.001	<0.001	<0.001
Study No. 2	Number of Patients	76	75	76	76
	No. of Successes	10	3	3	1
	Proportion of Successes	13%	4%	4%	1%
	p-value		0.045	0.042	0.005

In the Investigators’ assessment of melasma severity at Day 56 of treatment, the following table shows the clinical improvement profile for all patients treated with Tri-Luma Cream based on severity of their melasma at the start of treatment.

Investigators’ Assessment of Change in Melasma Severity from Baseline to Day 56 of Treatment (combined results from studies 1 and 2)

			Number (%) of Patients at Day 56a
	Baseline		Clearedb	Mildb	Moderateb	Severeb	Missingb
	Severity Rating	N	N (%)	N (%)	N (%)	N (%)	N (%)
a Assessment based on patients with severity scores at Day 56. Percentages are based on the total number in the treatment group population.
b Does not include patients who cleared before Day 56 or were missing from the Day 56 assessment.
Tri-Luma Cream N=161	Moderate	124	36 (29)	63 (51)	18 (15)	0 (0)	7 (6%)
	Severe	37	6 (16)	19 (51)	9 (24)	2 (5)	1 (3%)

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).

Patients experienced improvement of their melasma with the use of Tri-Luma Cream as early as 4 weeks. However, among 7 patients who had clearing at the end of 4 weeks of treatment with Tri-Luma Cream, 4 of them did not maintain the remission after an additional 4 weeks of treatment.

After 8 weeks of treatment with the study drug, patients entered into an open-label extension period in which Tri-Luma 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 patients maintained complete clearing of melasma (approximately 1 to 2%).

Indications and Usage for Tri-Luma

Tri-Luma Cream 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.

The following are important statements relating to the indication and usage of Tri-Luma Cream:

• 
  

  Tri-Luma Cream, a combination drug product containing corticosteroid, retinoid, and bleaching agent, is NOT indicated for the maintenance treatment of melasma. After achieving control with Tri-Luma Cream, some patients may be managed with other treatments instead of triple therapy with Tri-Luma Cream. Because melasma usually recurs upon discontinuation of Tri-Luma Cream, patients need to avoid sunlight exposure, use sunscreen with appropriate SPF, wear protective clothing, and change to non-hormonal forms of birth control, if hormonal methods are used.

  
  


• 
  

  In clinical trials used to support the use of Tri-Luma Cream in the treatment of melasma, patients were instructed to avoid sunlight exposure to the face, wear protective clothing and use a sunscreen with SPF 30 each day. They were to apply the study medication each night, after washing their face with a mild soapless cleanser.

  
  


• 
  

  The safety and efficacy of Tri-Luma Cream in patients of 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 Tri-Luma 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 child-bearing potential had to use birth control measures in the clinical trials, the safety and efficacy of Tri-Luma Cream in pregnant women and nursing mothers have not been established (See PRECAUTIONS, Pregnancy).

  
  

Contraindications

Tri-Luma Cream is contraindicated in individuals with a history of hypersensitivity, allergy, or intolerance to this product or any of its components.

Warnings

Tri-Luma Cream contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening asthmatic episodes in susceptible people.

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

Cutaneous hypersensitivity to the active ingredients of Tri-Luma 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 Tri-Luma Cream or its components.

Precautions

General

Tri-Luma 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.

Tri-Luma Cream also contains the corticosteroid fluocinolone 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 Tri-Luma Cream should be discontinued. Recovery of HPA axis function generally occurs upon discontinuation of topical corticosteroids.

Information for Patients

Exposure to sunlight, sunlamp, or ultraviolet light should be avoided. Patients who are consistently exposed to sunlight or skin irritants either through their work environment or habits should exercise particular caution. Sunscreen and protective covering (such as the use of a hat) over the treated areas should be used. 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 Tri-Luma Cream. Because of the drying effect of this medication, a moisturizer may be applied to the face in the morning after washing.

Application of Tri-Luma Cream should be kept away from the eyes, nose, or angles of the mouth, because the mucosa is much more sensitive than the skin to the irritant effect. If local irritation persists or becomes severe, application of the medication should be discontinued, and the health care provider consulted. 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 require medical attention.

If the medication is applied excessively, marked redness, peeling, or discomfort may occur.

This medication is to be used as directed by the health care provider and should not be used for any disorder other than that for which it is prescribed.

Laboratory Tests

The following tests may be helpful in evaluating patients for HPA axis suppression:

          ACTH or cosyntropin stimulation test

          A.M. plasma cortisol test

          Urinary free cortisol test

Drug Interactions

Patients should avoid medicated or abrasive soaps and cleansers, soaps and cosmetics with drying effects, products with high concentration of alcohol and astringent, and other irritants or keratolytic drugs while on Tri-Luma Cream treatment. Patients are cautioned on concomitant use of medications that are known to be photosensitizing.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies to determine the carcinogenic potential of Tri-Luma Cream have not been conducted.

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 fluocinolone 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.

Pregnancy

Teratogenic Effects: Pregnancy Category C: Tri-Luma Cream contains the teratogen, tretinoin, which may cause embryo fetal death, altered fetal growth, congenital malformations, and potential neurologic deficits. It is difficult to interpret the animal studies on teratogenicity with Tri-Luma Cream, because the availability of the dermal applications in these studies cannot be assured, and comparison with clinical dosing is not possible. There are no adequate and well-controlled studies in pregnant women. Tri-Luma Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Summary Statement on Teratogenic Risk

Tri-Luma Cream contains the teratogen, tretinoin, which may cause embryo-fetal death, altered fetal growth, congenital malformations, and potential neurologic deficits. However, human data have not confirmed an increased risk of these developmental abnormalities when tretinoin is administered by the topical route.

Clinical considerations relevant to actual or potential inadvertent exposure during pregnancy:

In clinical trials involving Tri-Luma 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. Thus, safety and efficacy of Tri-Luma Cream in pregnancy has not been established. In general, use of drugs should be reduced to a minimum in pregnancy. If a patient has been inadvertently exposed to Tri-Luma 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 Tri-Luma 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.

The prescriber should have the following clinical considerations in making prescribing decisions:

• 
  

  The potential developmental effects of tretinoin are serious but the risk from topical administration is small.

  
  


• 
  

  Exposure during the period for organogenesis in the first trimester is theoretically more likely to produce adverse outcome than in later pregnancy.

  
  


• 
  

  The risk to the mother for not treating melasma should be determined by the physician with the patient. Mild forms of melasma may not necessarily require drug treatment. Tri-Luma Cream is indicated for the treatment of moderate to severe melasma. Melasma may also be managed with other forms of therapy such as topical hydroquinone in the presence of sunlight avoidance, or stopping the use of hormonal birth control methods. If possible, delaying treatment with Tri-Luma Cream until after delivery should be considered.

  
  


• 
  

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

  
  

Data Discussion: 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.

1. Human Data.

• 
  

  In clinical trials involving Tri-Luma 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 Tri-Luma Cream. Most of the pregnancy outcomes have not been known. Three women gave birth to apparently healthy babies. One pregnancy was terminated prematurely, and another ended in miscarriage.

  
  


• 
  

  Epidemiologic studies have not confirmed an increase in birth defects associated with the use of topical tretinoin. However, there may be limitations to the sensitivity of epidemiologic studies in the detection of certain forms of fetal injury, such as subtle neurologic or intelligence deficits.

  
  

2. Animal Data.

• 
  

  In a dermal application study using Tri-Luma 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 Tri-Luma 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 Tri-Luma 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 Tri-Luma Cream has been performed.


• 
  

  It is difficult to interpret these animal studies on teratogenicity with Tri-Luma Cream, because the availability of the dermal applications in these studies could not be assured, and comparison with clinical dosing is not possible.

  
  

All pregnancies have a risk of birth defect, loss, or other adverse event regardless of drug exposure. Typically, estimates of increased fetal risk from drug exposure rely heavily on animal data. However, animal studies do not always predict effects in humans. Even if human data are available, such data may not be sufficient to determine whether there is an increased risk to the fetus. Drug effects on behavior, cognitive function, and fertility in the offspring are particularly difficult to assess.

Nursing Mothers

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

Pediatric Use

Safety and effectiveness of Tri-Luma Cream in pediatric patients have not been established.

Geriatric Use

Clinical studies of Tri-Luma Cream did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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.

Adverse Reactions

In the controlled clinical trials, adverse events were monitored in the 161 patients who used Tri-Luma Cream once daily during an 8-week treatment period. There were 102 (63%) patients who experienced at least one treatment-related adverse event during these studies. 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 Tri-Luma Cream from the controlled clinical studies are summarized (in decreasing order of frequency) as follows:

Incidence and Frequency of Treatment-related Adverse Events with Tri-Luma Cream in at least 1% or more of Patients (N=161)

Adverse Event	Number (%) of Patients
Erythema	66 (41%)
Desquamation	61 (38%)
Burning	29 (18%)
Dryness	23 (14%)
Pruritus	18 (11%)
Acne	8 (5%)
Paresthesia	5 (3%)
Telangiectasia	5 (3%)
Hyperesthesia	3 (2%)
Pigmentary changes	3 (2%)
Irritation	3 (2%)
Papules	2 (1%)
Acne-like rash	1 (1%)
Rosacea	1 (1%)
Dry mouth	1 (1%)
Rash	1 (1%)
Vesicles	1 (1%)

In an open-label long-term safety study, patients who have had cumulative treatment of melasma with Tri-Luma 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 infrequently 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.

Tri-Luma Cream contains hydroquinone, which may produce exogenous ochronosis, a gradual blue-black darkening of the skin, whose occurrence should prompt discontinuation of therapy.

Cutaneous hypersensitivity to the active ingredients of Tri-Luma 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 Tri-Luma Cream or its components.

Tri-Luma Dosage and Administration

Tri-Luma Cream should be applied once daily at night. It should be applied at least 30 minutes before bedtime.

Gently wash the face and neck with a mild cleanser. Rinse and pat the skin dry. Apply a thin film of the 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. Do not use occlusive dressing.

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.

How is Tri-Luma Supplied

Tri-Luma Cream is supplied in 30 g aluminum tubes, NDC 0299-5950-30.

Storage: Keep tightly closed. Store at controlled room temperature 68° to 77°F (20°-25°C). Protect from freezing.

Marketed by:

GALDERMA LABORATORIES, L.P.

Fort Worth, TX 76177 USA

Manufactured by:

Hill Dermaceuticals, Inc.

Sanford, FL 32773 USA

20071-0210 Revised: February 2010

PATIENT INFORMATION

For External Use Only.

Not for Ophthalmic Use.

Tri-Luma®Cream

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

Read this information carefully before you begin treatment. Read the information you get whenever you get more medicine. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about Tri-Luma (try-LOOM-ah), ask your doctor. Only your doctor can determine if Tri-Luma is right for you.

What is the most important information I should know about Tri-Luma Cream?

Use of Tri-Luma Cream in pregnant women may carry the chance of having birth defects in the baby. Tell your doctor if you are pregnant, may be pregnant, or plan to become pregnant. Your doctor will talk with you about the benefits and risks of using Tri-Luma during pregnancy to help decide if the benefits for you are greater than the risks. You may decide to delay treatment until after your baby is born.

If you become pregnant while taking Tri-Luma Cream, tell your doctor right away. You should discuss the chances that your baby may be harmed. Using Tri-Luma Cream early in pregnancy may be more likely to produce birth defects than using it later in pregnancy.

What is Tri-Luma Cream?

Tri-Luma (try-LOOM-ah) Cream is a medicine with three active components. You put Tri-Luma Cream on your face to treat a skin condition called melasma. Melasma consists of dark (hyperpigmented) spots on facial skin, especially on the cheeks and forehead. This condition usually happens with hormone changes.

Tri-Luma Cream is for SHORT-TERM (up to 8 weeks) treatment of moderate to severe melasma of the face. It is NOT FOR LONG-TERM (more than 8 weeks) or maintenance (continuous) treatment of melasma. Milder forms of melasma may not need treatment with medicine. Melasma can also be managed by staying out of the sun or by stopping the use of birth control methods that involve hormones.

In studies, after 8 weeks of treatment with Tri-Luma Cream, most patients had at least some improvement. Some had their dark spots clear up completely (38% in one study and 13% in another). In most patients treated with Tri-Luma Cream, their melasma came back after treatment. If the underlying cause of melasma, such as the use of certain birth control pills or too much exposure to sunlight, are not removed, melasma will come back when you stop treatment. Tri-Luma Cream may improve your melasma, but it is NOT a cure.

Who should not use Tri-Luma Cream?

Do not use Tri-Luma if you are allergic to the medicine or any of its ingredients. See the end of this leaflet for a list of ingredients.

What should I tell my doctor before taking Tri-Luma?

If you are pregnant, think you are pregnant, plan to be pregnant or are nursing an infant, tell your doctor. Your doctor will decide with you whether the benefits in using Tri-Luma Cream will be greater than the risks. If possible, delay treatment with Tri-Luma Cream until after the baby is born.

Tell your doctor about all the other medicines and skin products you use, including prescription and nonprescription medicines, cosmetics, and supplements. They may make your skin more sensitive to sunlight.

How should I use Tri-Luma Cream?

Tri-Luma Cream should be used as instructed by your doctor.

To help you use the medicine correctly, follow these steps:

• 
  

  Gently wash your face with a mild cleanser. Don’t use a wash cloth to apply the cleanser, just your fingers. Rinse and pat your skin dry.

  
  


• 
  

  Apply Tri-Luma Cream at night, at least 30 minutes before bedtime.

  
  


• 
  

  Put a small amount (pea sized or 1/2 inch or less) of Tri-Luma Cream on your fingertip. Apply a thin coat onto the discolored spot(s). Include about 1/2 inch of normal skin surrounding the affected area. After you have used the medicine for a while, you may find that you need slightly less to do the job.

  
  


• 
  

  Rub the medicine lightly and uniformly into your skin. The medicine should become invisible almost at once. If you can still see it, you are using too much.

  
  


• 
  

  Keep the medicine away from the corners of your nose, your mouth, eyes and open wounds. Spread it away from those areas when applying it.

  
  


• 
  

  Do not use more Tri-Luma Cream or apply it more often than recommended by your doctor. Too much Tri-Luma Cream may irritate your skin, waste medicine, and won’t give you faster or better results.

  
  


• 
  

  Do not cover the treated area with anything after applying Tri-Luma Cream.

  
  


• 
  

  If your skin gets too irritated, stop using Tri-Luma Cream, and let your doctor know.

  
  


• 
  

  To help avoid skin dryness, you may use a moisturizer in the morning after you wash your face.

  
  


• 
  

  You may also use a moisturizer and cosmetics during the day.

  
  

Use a sunscreen of at least SPF 30 and a wide-brimmed hat over the treated areas. It requires only a small amount of sunlight to worsen melasma. Melasma can get worse even if you don’t get sunburn.

Only your doctor knows which other medicines may be helpful during treatment, and will tell you about them if needed. Do not use other medicines unless your doctor approves them.

If you get sunburned, stop using Tri-Luma Cream until your skin is healed.

After stopping Tri-Luma treatment, continue to protect your skin from sunlight.

What should I avoid while using Tri-Luma Cream?

Sunlight or ultraviolet light. Too much natural sunlight or artificial sunlight from a sunlamp can cause sunburn. Dark skin patches may become darker when the skin is exposed to sunlight. You don’t have to have a sunburn to make your melasma worse.

Tri-Luma can make your skin more likely to get sunburn or develop other unwanted effects from the sun. Protect your skin from natural sunlight as much as possible to help prevent further darkening of existing dark patches and formation of new ones. Staying out of the sun is especially important for women who take birth control pills or hormone replacement therapy, and for people who have had dark patches in the past.

Use an effective sunscreen any time you are outside, even on hazy days. The sunscreen should have SPF (sun protection factor) of 30 or more. Use sunscreen year-round on areas of the skin that are regularly exposed to sunlight, such as your face and hands. If possible, protect the treated area from sunlight exposure.

If you spend a lot of time outside, be especially careful of sunlight. Ask your doctor what SPF level will give you the needed high level of protection. If you will be outside, wear protective clothing, including a hat.

Do not use sunlamps while you use Tri-Luma Cream.

Heat, wind and cold. Heat and cold tend to dry or irritate normal skin. Skin treated with Tri-Luma Cream may be more likely to react to heat and cold. Your doctor can recommend ways to manage your melasma under these conditions.

Other skin products and medicines. Avoid products that may dry or irritate your skin. These may include soaps and cleansers that are rough or cause drying; certain astringents, such as alcohol-containing products, soaps and toiletries containing alcohol, spices, or lime; or certain medicated soaps, shampoos, and hair permanent products. Do not use any other medicines with Tri-Luma Cream unless you have consulted your doctor. The medicines and product you have used in the past may cause redness or peeling when used with Tri-Luma.

What are the possible side effects of Tri-Luma Cream?

A very few patients may get severe allergic reactions from Tri-Luma. This includes people allergic to sulfites. They may have trouble breathing or severe asthma attacks, which can be life-threatening.

While you use Tri-Luma Cream, your skin may develop mild to moderate redness, peeling, burning, dryness, or itching.

Tri-Luma Cream contains a corticosteroid medicine as one of its active components. The following side effects have been reported with application of corticosteroid medicines to the skin: itching, irritation, dryness, infection of the hair follicles, acne, change in skin color, inflammation around the mouth, allergic skin reaction, skin infection, skin thinning, stretch marks, and sweat problems.

Stop using Tri-Luma Cream and contact your doctor if you have

• 
  

  severe or continued irritation, blistering, oozing, scaling, or crusting

  
  


• 
  

  severe burning or swelling of your skin

  
  


• 
  

  irritation of your eyes, nose, and mouth

  
  

Some patients using Tri-Luma Cream develop dark spots on their skin (hyperpigmentation), tingling, increased skin sensitivity, rash, acne, skin redness caused by a condition called rosacea, skin bumps, blisters, or tiny red lines or blood vessels showing through the skin (telangiectasia).

If you are concerned about how your skin is reacting to the medicine, call your doctor.

General information about prescription medicines

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Tri-Luma for a condition for which it was not prescribed. Do not give Tri-Luma to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about Tri-Luma. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Tri-Luma that is written for health professionals.

Ingredients: Tri-Luma Cream contains fluocinolone acetonide, hydroquinone, and tretinoin as active ingredients, as well as the following in the cream base: butylated hydroxytoluene, cetyl alcohol, citric acid, glycerin, glyceryl stearate, magnesium aluminum silicate, methyl gluceth-10, methylparaben, PEG-100 stearate, propylparaben, purified water, sodium metabisulfite, stearic acid, and stearyl alcohol.

Marketed by:

GALDERMA LABORATORIES, L.P.

Fort Worth, TX 76177 USA

Manufactured by:

Hill Dermaceuticals, Inc.

Sanford, FL 32773 USA

20071-0210 Revised February 2010

PACKAGE LABEL

Tri-Luma® Cream

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

Rx Only

NDC 0299-5950-30

NET WT. 30 g

GALDERMA

For External 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: fluocinolone acetonide 0.01% (0.1 mg), hydroquinone 4% (40 mg), and tretinoin 0.05% (0.5mg). Inactive: butylated hydroxytouluene, cetyl alcohol, citric acid, glycerin, glyceryl stearate, magnesium aluminum silicate, methyl gluceth-10, methylparaben, PEG-100 stearate, propylparaben, purified water, sodium metabisulfite, stearic acid, and stearyl alcohol.

Storage: Keep tightly closed. Store at controlled room temperature 68° to 77°F (20°-25°C), excursions permitted between 59° and 86°F (15°-30°C). Protect from freezing.

US Patent Pending   www.triluma.com

Marketed by:

GALDERMA LABORATORIES, L.P.

Fort Worth, Texas 76177 USA

Manufactured by:

Hill Dermaceuticals, Inc.

Sanford, Florida 32773 USA

GALDERMA is a registered trademark.

10084-0507

Lot No:




Exp.Date:

Tri-Luma   fluocinolone acetonide, hydroquinone, and tretinoin  cream

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0299-5950 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength fluocinolone acetonide (Fluocinolone Acetonide) Fluocinolone Acetonide 0.1 mg  in 1 g hydroquinone (hydroquinone) hydroquinone 40 mg  in 1 g tretinoin (tretinoin) tretinoin 0.5 mg  in 1 g

Inactive Ingredients Ingredient Name Strength butylated hydroxytoluene   cetyl alcohol   citric acid   glycerin   Glyceryl Monostearate   magnesium aluminum silicate   methyl gluceth-10   methylparaben   Polyoxyl 100 Stearate   propylparaben   water   sodium metabisulfite   stearic acid   stearyl alcohol

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packa

Carvedilol

Pronunciation: kar-VE-dil-ol
Generic Name: Carvedilol
Brand Name: Coreg

Carvedilol is used for:

Treating high blood pressure or certain types of heart failure. It may also be used after a heart attack to improve survival in certain patients. It may be used along with other medicines. It may also be used for other conditions as determined by your doctor.

Carvedilol is an alpha- and beta-blocker. It works by relaxing the blood vessels, slowing down the heart, and decreasing the amount of blood it pumps out. This decreases blood pressure, helps the heart pump more efficiently, and reduces the workload on the heart.

Do NOT use Carvedilol if:

• you are allergic to any ingredient in Carvedilol


• you have certain types of irregular heartbeat (eg, moderate to severe heart block, sick sinus syndrome), very severe heart failure (eg, requires treatment in a hospital), or shock caused by severe heart problems


• you have a very slow heartbeat and you do not have a permanent pacemaker


• you have asthma or other severe breathing problems


• you have severe liver problems


• you are taking mibefradil

Contact your doctor or health care provider right away if any of these apply to you.

Before using Carvedilol:

Some medical conditions may interact with Carvedilol. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances or are taking medicine for allergies


• if you have a history of other heart problems (eg, heart failure, slow or irregular heartbeat, angina) or low blood pressure


• if you have a history of liver or kidney problems, blood vessel disease, blood flow problems (eg, in the legs or feet), lung or breathing problems (eg, chronic bronchitis emphysema, chronic obstructive pulmonary disease), diabetes, low blood sugar, thyroid problems, or glaucoma


• if you have an adrenal gland tumor (pheochromocytoma)


• if you will be having surgery

Some MEDICINES MAY INTERACT with Carvedilol. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Mibefradil because the risk of serious heart side effects may be increased


• Many prescription and nonprescription medicines (eg, used for infections, inflammation, aches and pains, high blood pressure, heart problems, irregular heartbeat, cancer, diabetes, depression, mental or mood problems, multiple sclerosis [MS], prostate problems, immune system suppression, allergic reactions, asthma, high cholesterol, seizures, thyroid problems), multivitamin products, and herbal or dietary supplements (eg, herbal teas, coenzyme Q10, garlic, ginseng, ginkgo, St. John's wort) may interact with Carvedilol, increasing the risk of side effects

This may not be a complete list of all interactions that may occur. Ask your health care provider if Carvedilol may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Carvedilol:

Use Carvedilol as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Carvedilol. Talk to your pharmacist if you have questions about this information.


• Take Carvedilol by mouth with food.


• Take Carvedilol on a regular schedule to get the most benefit from it. Taking Carvedilol at the same time each day will help you remember to take it.


• Continue to take Carvedilol even if you feel well. Do not miss any doses.


• Do not suddenly stop taking Carvedilol. You may have an increased risk of side effects. If you need to stop Carvedilol or add a new medicine, your doctor will gradually lower your dose.


• If you miss a dose of Carvedilol, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Carvedilol.

Important safety information:

• Carvedilol may cause dizziness, fainting, or blurred vision. These effects may be worse if you take it with alcohol or certain medicines. Use Carvedilol with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Carvedilol may cause dizziness, light-headedness, or fainting. These effects may occur within the first hour after you take your dose. They may be more likely when you start taking Carvedilol or if your dose is increased. Alcohol, hot weather, exercise, or fever may increase these effects. To prevent them, sit up or stand slowly, especially in the morning. Sit or lie down at the first sign of any of these effects. Tell your doctor if these effects occur.


• Do NOT take more than the recommended dose without checking with your doctor.


• Do not suddenly stop taking Carvedilol. Sharp chest pain, irregular heartbeat, and sometimes heart attack may occur if you suddenly stop Carvedilol. The risk may be greater if you have certain types of heart disease. Your doctor should slowly lower your dose over several weeks if you need to stop taking it. This should be done even if you only take Carvedilol for high blood pressure. Heart disease is common and you may not know you have it. Limit physical activity while you are lowering your dose. If new or worsened chest pain or other heart problems occur, contact your doctor right away. You may need to start taking Carvedilol again.


• Patients who take medicine for high blood pressure often feel tired or run down for a few weeks after starting treatment. Be sure to take your medicine even if you may not feel "normal." Tell your doctor if you develop any new symptoms.


• Tell your doctor or dentist that you take Carvedilol before you receive any medical or dental care, emergency care, or surgery.


• If you have a history of any severe allergic reaction, talk with your doctor. You may be at risk for an even more severe allergic reaction if you come into contact with the substance that caused your allergy. Some medicines used to treat severe allergies may also not work as well while you are using Carvedilol.


• Diabetes patients - Carvedilol may affect your blood sugar. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.


• Diabetes patients - Carvedilol may hide signs of low blood sugar, such as a rapid heartbeat. Be sure to watch for other signs of low blood sugar. Low blood sugar may make you anxious, sweaty, weak, dizzy, drowsy, or faint. It may also make your vision change; give you a headache, chills, or tremors; or make you more hungry. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.


• Lab tests, including blood pressure and heart function, may be performed while you use Carvedilol. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Carvedilol with caution in the ELDERLY; they may be more sensitive to its effects, especially dizziness.


• Carvedilol should be used with extreme caution in CHILDREN younger than 18 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Carvedilol while you are pregnant. It is not known if Carvedilol is found in breast milk. Do not breast-feed while taking Carvedilol.

Possible side effects of Carvedilol:

All medicines may cause side effects, but many people have no, or minor side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Diarrhea; dizziness; dry eyes; fatigue; light-headedness; weakness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); change in the amount of urine produced; chest pain; cold or numb legs or feet; fainting; irregular or unusually slow heartbeat; persistent or severe vision changes; red, swollen, blistered, or peeling skin; severe dizziness; shortness of breath; sudden, unusual weight gain; swelling of the hands, ankles, or feet; unusual bruising or bleeding; unusual leg pain; very cold or blue fingers or toes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Carvedilol side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include chest pain; fainting; seizures; severe dizziness; slow heartbeat; slow, shallow, or difficult breathing.

Proper storage of Carvedilol:

Store Carvedilol below 86 degrees F (30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Carvedilol out of the reach of children and away from pets.

General information:

• If you have any questions about Carvedilol, please talk with your doctor, pharmacist, or other health care provider.


• Carvedilol is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Carvedilol. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Carvedilol resources

• Carvedilol Side Effects (in more detail)
• Carvedilol Dosage
• Carvedilol Use in Pregnancy & Breastfeeding
• Drug Images
• Carvedilol Drug Interactions
• Carvedilol Support Group
• 36 Reviews for Carvedilol - Add your own review/rating

• Carvedilol Prescribing Information (FDA)


• Carvedilol Monograph (AHFS DI)


• Carvedilol Professional Patient Advice (Wolters Kluwer)


• carvedilol Advanced Consumer (Micromedex) - Includes Dosage Information


• Coreg Consumer Overview


• Coreg Prescribing Information (FDA)


• Coreg CR Prescribing Information (FDA)

Compare Carvedilol with other medications

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Aminosyn-PF Injection

Dosage Form: injection, solution
Aminosyn® -PF 10%

Sulfite-Free

AN AMINO ACID INJECTION - PEDIATRIC FORMULA

Pharmacy Bulk Package − Not for Direct Infusion.

Flexible Plastic Container

Rx only

Aminosyn-PF Injection Description

Aminosyn®-PF 10%, Sulfite-Free, (an amino acid injection — pediatric formula) is a sterile, nonpyrogenic solution for intravenous infusion. Aminosyn-PF 10% is oxygen sensitive. The Pharmacy Bulk Package is a sterile dosage form which contains multiple single doses for use only in a pharmacy bulk admixture program. The formulation is described below:

Aminosyn-PF 10%
An Amino Acid Injection — Pediatric Formula
Essential Amino Acids (mg/100 mL)
Isoleucine	760
Leucine	1200
Lysine (acetate)*	677
Methionine	180
Phenylalanine	427
Threonine	512
Tryptophan	180
Valine	673
* Amount cited is for lysine alone and does not include the acetate salt.

Nonessential Amino Acids (mg/100 mL)
Alanine	698
Arginine	1227
Aspartic Acid	527
Glutamic Acid	820
Glycine	385
Histidine	312
Proline	812
Serine	495
Taurine	70
Tyrosine	44

Electrolytes (mEq/L)
Sodium (Na+)	None
Potassium (K+)	None
Chloride (Cl−)	None
Acetate (C2H3O2−) a	46

Product Characteristics
Protein Equivalent (Approx. grams/L)	100
Total Nitrogen (grams/L)	15.2
Osmolarity (mOsmol/L)	788
pH (range)	5.5 (5.0 to 6.5)
Specific Gravity	1.03
a From lysine acetate.

The formulas for the individual amino acids present in Aminosyn-PF 10% are as follows:

Essential Amino Acids
Isoleucine	CH3CH2CH(CH3)CH(NH2)COOH
Leucine	(CH3)2CHCH2CH(NH2)COOH
Lysine Acetate	H2N(CH2)4CH(NH2)COOH • CH3COOH
Methionine	CH3S(CH2)2CH(NH2)COOH
Phenylalanine
Threonine	CH3CH(OH)CH(NH2)COOH
Tryptophan
Valine	(CH3)2CHCH(NH2)COOH

Nonessential Amino Acids
Alanine	CH3CH(NH2)COOH
Arginine	H2NC(NH)NH(CH2)3CH(NH2)COOH
L-Aspartic Acid	HOOCCH2CH(NH2)COOH
L-Glutamic Acid	HOOC(CH2)2CH(NH2)COOH
Glycine	H2NCH2COOH
Histidine
Proline
Serine	HOCH2CH(NH2)COOH
Taurine	H2N − CH2CH2− SO3H
Tyrosine

The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly.

Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials.

Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period.

The Pharmacy Bulk Package is designed for use with manual, gravity flow operations and automated compounding devices for preparing sterile parenteral nutrient admixtures; it contains no bacteriostat. Multiple single doses may be dispensed during continual aliquoting operations. Withdrawal of container contents should be promptly completed within 4 hours after initial closure puncture.

Aminosyn-PF Injection - Clinical Pharmacology

Aminosyn-PF 10%, Sulfite-Free, (an amino acid injection — pediatric formula) contains a mixture of essential and nonessential amino acids as well as taurine. The amino acid composition has been specifically formulated to provide a well-tolerated nitrogen source for nutritional support and therapy for infants and young children. When administered in conjunction with a cysteine hydrochloride additive, Aminosyn-PF 10% results in plasma amino acid concentrations approximating a profile consistent with that of a breast-fed infant.

The rationale for Aminosyn-PF 10% is based on the observation of inadequate levels of essential amino acids in the plasma of infants receiving total parenteral nutrition (TPN) using conventional amino acid solutions.

Clinical studies in infants who required TPN therapy showed that infusion of Aminosyn-PF 10% resulted in plasma amino acid concentrations approximating those of normal breast or formula fed infants. In addition, weight gains, nitrogen balance, and serum protein concentrations were consistent with an improving nutritional status.

When infused with hypertonic dextrose as a calorie source, supplemented with cysteine hydrochloride, electrolytes, vitamins, and minerals, Aminosyn-PF 10% provides TPN for infants and young children, with the exception of essential fatty acids.

It is thought that the acetate from lysine acetate under the conditions of parenteral nutrition, does not impact net acid-base balance when renal and respiratory functions are normal. Clinical evidence seems to support this thinking; however, confirmatory experimental evidence is not available. The amounts of sodium and acetate in Aminosyn-PF 10% are not of clinical significance.

The addition of a cysteine hydrochloride additive will contribute to the chloride load.

The electrolyte content of any additives that are introduced should be carefully considered and included in input computations.

The human newborn conjugates bile with taurine which becomes the primary method of biliary excretion. Taurine deficiency because of its effect on bile salt conjugation and, therefore, on bile salt flow may be of major importance in the genesis of cholestasis. Taurine has also been shown to play a role in central nervous system development.

Indications and Usage for Aminosyn-PF Injection

Aminosyn-PF 10%, Sulfite-Free, (an amino acid injection — pediatric formula) is indicated for the nutritional support of infants (including those of low birth weight) and young children requiring TPN via either central or peripheral infusion routes. Parenteral nutrition with Aminosyn-PF 10% is indicated to prevent nitrogen and weight loss or treat negative nitrogen balance in infants and young children where (1) the alimentary tract by the oral gastrostomy, or jejunostomy route, cannot or should not be used or adequate protein intake is not feasible by these routes; (2) gastrointestinal absorption of protein is impaired; or (3) protein requirements are substantially increased as with extensive burns. Dosage, route of administration, and concomitant infusion of non-protein calories are dependent on various factors, such as nutritional and metabolic status of the patient, anticipated duration of parenteral nutrition support, and vein tolerance. See DOSAGE AND ADMINISTRATION for additional information.

Central Venous Infusion

Central venous infusion should be considered when amino acid solutions are to be admixed with hypertonic dextrose to promote protein synthesis in hypercatabolic or severely depleted infants or those requiring long-term parenteral nutrition.

Peripheral Parenteral Nutrition

For moderately catabolic or depleted patients in whom the central venous route is not indicated, diluted amino acid solutions mixed with 5 to 10% dextrose solutions may be infused by peripheral vein, supplemented, if desired, with fat emulsion.

Contraindications

Aminosyn-PF 10%, Sulfite-Free, (an amino acid injection — pediatric formula) is contraindicated in patients with untreated anuria, hepatic coma, inborn errors of amino acid metabolism (including those involving branched chain amino acid metabolism such as maple syrup urine disease and isovaleric acidemia), or hypersensitivity to one or more amino acids present in the solution.

Warnings

Safe, effective use of parenteral nutrition requires a knowledge of nutrition as well as clinical expertise in recognition and treatment of the complications which can occur. FREQUENT EVALUATION AND LABORATORY DETERMINATIONS ARE NECESSARY FOR PROPER MONITORING OF PARENTERAL NUTRITION. Studies should include blood sugar, serum proteins, kidney and liver function tests, electrolytes, hemogram, carbon dioxide content, serum osmolalities, blood cultures, and blood ammonia levels.

Administration of amino acids in the presence of impaired renal function or gastrointestinal bleeding may augment an already elevated blood urea nitrogen. Patients with azotemia from any cause should not be infused with amino acids without regard to total nitrogen intake.

Administration of intravenous solutions can cause fluid and/or solute overload resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the solutions.

Administration of amino acid solutions to a patient with hepatic insufficiency may result in plasma amino acid imbalances, hyperammonemia, prerenal azotemia, stupor and coma.

Hyperammonemia is of special significance in infants, as its occurrence in the syndrome caused by genetic metabolic defects is sometimes associated, although not necessarily in a causal relationship, with mental retardation. This reaction appears to be dose-related and is more likely to develop during prolonged therapy. It is essential that blood ammonia levels be measured frequently in infants.

Conservative doses of amino acids should be given, dictated by the nutritional status of the patient. Should symptoms of hyperammonemia develop, amino acid dosage levels should be reduced and titrated against serum ammonia levels.

WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Precautions

Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Significant deviations from normal concentrations may require the use of additional electrolyte supplements.

Strongly hypertonic nutrient solutions should be administered via an intravenous catheter placed in a central vein, preferably the superior vena cava.

Care should be taken to avoid circulatory overload, particularly in patients with cardiac insufficiency.

Special care must be taken when giving hypertonic dextrose to a diabetic or pre-diabetic patient. To prevent severe hyperglycemia in such patients, insulin may be required.

Administration of glucose at a rate exceeding the patient’s utilization rate may lead to hyperglycemia, coma, and death.

The effect of infusion of amino acids, without dextrose, upon carbohydrate metabolism of children is not known at this time. It is essential to provide adequate exogenous dextrose calories concurrently with amino acids. Administration of amino acids without carbohydrates may result in the accumulation of ketone bodies in the blood. Correction of this ketonemia may be achieved by the administration of carbohydrate.

Essential fatty acid deficiency (EFAD) is becoming increasingly recognized in patients on long term TPN (more than 5 days). The use of fat emulsion to provide 4 — 10% of total caloric intake as linoleic acid may prevent EFAD.

Peripheral administration of Aminosyn-PF 10%, Sulfite-Free, (an amino acid injection — pediatric formula) requires appropriate dilution and provision of adequate calories. Care should be taken to assure proper placement of the needle within the lumen of the vein. The venipuncture site should be inspected frequently for signs of infiltration. If venous thrombosis or phlebitis occurs, discontinue infusion or change infusion site and initiate appropriate treatment.

Extraordinary electrolyte losses such as may occur during protracted nasogastric suction, vomiting, diarrhea, or gastrointestinal fistula drainage may necessitate additional electrolyte supplementation.

Metabolic acidosis can be prevented or readily controlled by adding a portion of the cations in the electrolyte mixture as acetate salts and in the case of hyperchloremic acidosis, by keeping the total chloride content of the infusate to a minimum.

Aminosyn-PF 10% contains no chloride.

Aminosyn-PF 10% contains no added phosphorus. Patients, especially those with hypophosphatemia, may require the addition of phosphate. To prevent hypocalcemia, calcium supplementation should always accompany phosphate administration. To assure adequate intake, serum levels should be monitored frequently.

Aminosyn-PF 10% contains no more than 25 mcg/L of aluminum.

To minimize the risk of possible incompatibilities arising from mixing this solution with other additives that may be prescribed, the final infusate should be inspected for cloudiness or precipitation immediately after mixing, prior to administration, and periodically during administration.

SPECIAL PRECAUTIONS FOR

CENTRAL INFUSIONS

ADMINISTRATION BY CENTRAL VENOUS CATHETER SHOULD BE

USED ONLY BY THOSE FAMILIAR WITH THIS TECHNIQUE

AND ITS COMPLICATIONS.

Central vein infusion (with added concentrated carbohydrate solutions) of amino acid solutions requires a knowledge of nutrition as well as clinical expertise in recognition and treatment of complications. Attention must be given to solution preparation, administration and patient monitoring. IT IS ESSENTIAL THAT A CAREFULLY PREPARED PROTOCOL, BASED ON CURRENT MEDICAL PRACTICES, BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM.

SUMMARY HIGHLIGHTS OF COMPLICATIONS (See also Current Medical Literature).

1. 
   

   Technical

   
   
   

   The placement of a central venous catheter should be regarded as a surgical procedure. One should be fully acquainted with various techniques of catheter insertion. For details of technique and placement sites, consult the medical literature. X-ray is the best means of verifying catheter placement. Complications known to occur from the placement of central venous catheters are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arteriovenous fistula, phlebitis, thrombosis and air and catheter emboli.

   
   


2. 
   

   Septic

   
   
   

   The constant risk of sepsis is present during administration of total parenteral nutrition. It is imperative that the preparation of the solution and the placement and care of catheters be accomplished under strict aseptic conditions.

   
   
   

   Solutions should ideally be prepared in the hospital pharmacy under a laminar flow hood using careful aseptic technique to avoid inadvertent touch contamination. Solutions should be used promptly after mixing. Storage should be under refrigeration and limited to a brief period of time, preferably less than 24 hours.

   
   
   

   Administration time for a single container and set should never exceed 24 hours.

   
   


3. 
   

   Metabolic

   
   
   

   The following metabolic complications have been reported with TPN administration: Metabolic acidosis and alkalosis, hypophosphatemia, hypocalcemia, osteoporosis, hyperglycemia and glycosuria, rebound hypoglycemia, osmotic diuresis and dehydration, elevated liver enzymes, hypo- and hypervitaminosis, electrolyte imbalances and hyperammonemia in children. Frequent evaluations are necessary especially during the first few days of therapy to prevent or minimize these complications.

   
   
   

   Administration of glucose at a rate exceeding the patient’s utilization rate may lead to hyperglycemia, coma and death. CLINICAL EVALUATION AND LABORATORY DETERMINATIONS, AT THE DISCRETION OF THE ATTENDING PHYSICIAN ARE NECESSARY FOR PROPER MONITORING DURING ADMINISTRATION. Do not withdraw venous blood for blood chemistries through the peripheral infusion site, as interference with estimations of nitrogen-containing substances may occur. Blood studies should include glucose, urea nitrogen, serum electrolytes, ammonia, cholesterol, acid-base balance, serum proteins, kidney and liver function tests, osmolarity and hemogram. White blood count and blood cultures are to be determined if indicated. Urinary osmolality and glucose should be determined as necessary.

   
   

Pregnancy Category C

Animal reproduction studies have not been conducted with Aminosyn-PF 10%. It is also not known whether Aminosyn-PF 10% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Aminosyn-PF 10% should be given to a pregnant woman only if clearly needed.

Adverse Reactions

Local reactions consisting of erythema, phlebitis and thrombosis at the infusion site have occurred with peripheral intravenous infusion of amino acids particularly if other substances, such as antibiotics, are also administered through the same site. In such cases the infusion site should be changed promptly to another vein. Use of large peripheral veins, inline filters, and slowing the rate of infusion may reduce the incidence of local venous irritation. Electrolyte additives should be spread throughout the day. Irritating additive medications may need to be injected at another venous site.

Generalized flushing, fever and nausea also have been reported during peripheral infusions of amino acid solutions.

If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.

Overdosage

In the event of overhydration or solute overload, re-evaluate the patient and institute appropriate corrective measures. See WARNINGS and PRECAUTIONS.

Aminosyn-PF Injection Dosage and Administration

Aminosyn-PF 10%, Sulfite-Free, is an amino acid injection-pediatric formula not intended for direct infusion. Admixtures should be made by or under the direction of a pharmacist using strict aseptic technique under a laminar flow hood. Admixtures must be stored under refrigeration and used within 24 hours of admixing.

The total daily dose of the solution depends on the daily protein requirements and on the patient’s metabolic and clinical response.

Pediatric requirements for parenteral nutrition are constrained by the greater relative fluid requirements of the infant and greater caloric requirements per kilogram than in the adult.

The recommended intravenous dose of Aminosyn-PF 10% is up to 2.5 g amino acid/kg/day for infants up to 10 kg. For infants and children larger than 10 kg, the total daily dose of amino acids should be up to 25 g amino acids/day for the first 10 kg of body weight plus 1.0 to 1.25 g amino acid for each kg of body weight over 10 kg. Initial amino acid dosage levels of 1.0 g/kg/day may be increased gradually in increments of 0.5 g/kg/day to approximate desired intake levels.

Aminosyn-PF 10% should be diluted with dextrose prior to use. Nonprotein calories should constitute approximately 100 to 130 kcal/kg/day. Part of the nonprotein caloric requirement may be provided as lipid emulsion administered concurrently to provide up to 60% of daily calories at a dose not to exceed 4 g fat/kg/day. Fluid intake for the infant receiving central venous TPN should be approximately 125 mL/kg/day (range: 100 to 175 mL/kg/day), depending on the clinical condition of the patient. Fat emulsion coadministration should be considered when prolonged (more than 5 days) parenteral nutrition is required in order to prevent essential fatty acid deficiency (EFAD). Serum lipids should be monitored for evidence of EFAD in patients maintained on fat-free TPN. Premature infants with respiratory distress syndrome suspected of having a patent ductus arteriosus should be given fluids more cautiously.

Cysteine is considered to be an essential amino acid for infants, especially preterm infants with potentially immature enzyme pathways. Therefore, addition of a cysteine supplement to the TPN admixture is recommended. The intake of cysteine by the preterm infant ingesting maternal milk is approximately 78 mg/kg/day. The suggested intravenous dosage level for Cysteine Hydrochloride Injection, USP is 500 mg (10 mL) for every 12.5 g (125 mL) of Aminosyn-PF 10% administered (see package insert for Cysteine Hydrochloride Injection, USP). In order to avoid potential insolubility of cysteine hydrochloride in admixtures, the foregoing concentration should not be exceeded.

In many patients, provision of adequate calories in the form of hypertonic dextrose may require the administration of exogenous insulin to prevent hyperglycemia and glycosuria. To prevent rebound hypoglycemia, a solution containing 5% dextrose should be administered when hypertonic dextrose solutions are abruptly discontinued.

SERUM ELECTROLYTES SHOULD BE MONITORED FREQUENTLY. Electrolytes may be added to the nutrient solution as indicated by the patient’s clinical condition and laboratory determinations of plasma values. Major electrolytes are sodium, chloride, potassium, phosphate, magnesium and calcium. Daily administration of intravenous vitamin supplements including a complete complement of fat and water-soluble vitamins is required. Trace metal additives including zinc, copper, manganese, and chromium should also be provided, especially when long-term parenteral therapy is anticipated.

Calcium and phosphorus are added to the solution as indicated.

Potentially incompatible ions such as calcium and phosphate may be added to alternate infusate bottles to avoid precipitation. In patients with hyperchloremic or other metabolic acidosis, sodium and potassium may be added as the acetate or lactate salts to provide bicarbonate alternates. Bicarbonate should not be administered during infusion of the nutritional solution unless deemed absolutely necessary.

Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic technique, mix thoroughly and do not store.

To ensure the precise delivery of the small volumes of fluid necessary for total parenteral nutrition in infants, accurately calibrated and reliable infusion systems should be used.

Central Venous Nutrition

Hypertonic mixtures of amino acids and dextrose may be safely administered by continuous infusion through a central venous catheter with the tip located in the superior vena cava. Initial infusion rates should be slow, and gradually increased to the recommended 60-125 mL per kilogram body weight per day. If administration rate should fall behind schedule, no attempt to “catch up” to planned intake should be made. In addition to meeting protein needs, the rate of administration, particularly during the first few days of therapy, is governed by the patient’s glucose tolerance. Daily intake of amino acids and dextrose should be increased gradually to the maximum required dose as indicated by frequent determinations of glucose levels in blood and urine.

Peripheral Parenteral Nutrition

For patients in whom the central venous route is not indicated and who can consume adequate calories enterally, Aminosyn-PF 10% may be administered by peripheral vein with parenteral nonprotein calories. The concentration of dextrose in the final admixture is 5 to 10%, and simultaneous administration of lipid emulsion is recommended both as a calorie source and to attenuate the potentially irritating effects of the hypertonic nutritional admixture. Fat emulsion may comprise up to 60% of the daily caloric intake at a dosage level not to exceed 4 g fat/kg/day. It is essential that peripheral infusion be accompanied by adequate caloric intake.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. COLOR VARIATION FROM PALE YELLOW TO YELLOW IS NORMAL AND DOES NOT ALTER EFFICACY.

Recommended Directions for Use of the Pharmacy Bulk Package

Use Aseptic Technique

1. 
   

   During use, container must be stored, and all manipulations performed, in an appropriate laminar flow hood.

   
   


2. 
   

   Remove cover from outlet port at bottom of container.

   
   


3. 
   

   Insert piercing pin of sterile transfer set and suspend unit in a laminar flow hood. Insertion of a piercing pin into the outlet port should be performed only once in a Pharmacy Bulk Package solution. Once the outlet site has been entered, the withdrawal of container contents should be completed promptly in one continuous operation. Should this not be possible, a maximum time of 4 hours from transfer set pin or implement insertion is permitted to complete fluid transfer operations; i.e., discard container no later than 4 hours after initial closure puncture.

   
   


4. 
   

   Sequentially dispense aliquots of Aminosyn-PF 10% into I.V. containers using appropriate transfer set. During fluid transfer operations, the Pharmacy Bulk Package should be maintained under the storage conditions recommended in the labeling.

   
   
   

   Additives may be incompatible with fluid withdrawn from this container. Consult with pharmacist, if available. When compounding admixtures, use aseptic technique. Mix thoroughly. Do not store solutions containing additives. Because of the potential for life-threatening events, caution should be taken to ensure that precipitates have not formed in any parenteral nutrient mixture.

   
   

WARNING: Do not use flexible container in series connections.

How is Aminosyn-PF Injection Supplied

Aminosyn -PF 10%, Sulfite-Free, (an amino acid injection — pediatric formula) is supplied as a Pharmacy Bulk Package in 1000 mL flexible plastic containers NDC 0409-4179-05.

Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Protect from freezing. It is recommended that the product be stored at room temperature (25°C). Avoid exposure to light.

Revised: June, 2008

Printed in USA	EN-1817
Hospira, Inc., Lake Forest, IL 60045 USA

IM-1003

WR-0310

AMINOSYN-PF  isoleucine,leucine,lysine acetate,methionine,phenylalanine,threonine,tryptophan,valine,alanine,arginine,aspartic acid,glutamic acid,glycine,histidine,proline,serine,taurine,tyrosine  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0409-4179 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Isoleucine (Isoleucine) Isoleucine 760 mg  in 100 mL Leucine (Leucine) Leucine 1200 mg  in 100 mL Lysine acetate (Lysine) Lysine acetate 677 mg  in 100 mL Methionine (Methionine) Methionine 180 mg  in 100 mL Phenylalanine (Phenylalanine) Phenylalanine 427 mg  in 100 mL Threonine (Threonine) Threonine 512 mg  in 100 mL Tryptophan (Tryptophan) Tryptophan 180 mg  in 100 mL Valine (Valine) Valine 673 mg  in 100 mL Alanine (Alanine) Alanine 698 mg  in 100 mL Arginine (Arginine) Arginine 1227 mg  in 100 mL Aspartic Acid (Aspartic Acid) Aspartic Acid 527 mg  in 100 mL Glutamic Acid (Glutamic Acid) Glutamic Acid 820 mg  in 100 mL Glycine (Glycine) Glycine 385 mg  in 100 mL Histidine (Histidine) Histidine 312 mg  in 100 mL Proline (Proline) Proline 812 mg  in 100 mL Serine (Serine) Serine 495 mg  in 100 mL Taurine (Taurine) Taurine 70 mg  in 100 mL Tyrosine (Tyrosine) Tyrosine 44 mg  in 100 mL

Inactive Ingredients Ingredient Name Strength Water

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0409-4179-05 6 BAG In 1 CASE contains a BAG 1 1000 mL In 1 BAG This package is contained within the CASE (0409-4179-05)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA019492	12/24/2009

Labeler - Hospira, Inc. (141588017)

Revised: 12/2009Hospira, Inc.

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