Clobetasol Lotion

Dosage Form: lotion
Clobetasol Propionate Lotion, 0.05%

Rx Only

For dermatologic use only

Not for ophthalmic, oral or intravaginal use

DESCRIPTION

Clobetasol Propionate Lotion, 0.05% contains clobetasol propionate, a synthetic fluorinated corticosteroid, for topical dermatologic use. The corticosteroids constitute a class of primarily synthetic steroids used topically as anti-inflammatory and antipruritic agents. Clobetasol propionate is 21-chloro-9-fluoro-11β,17-dihydroxy-16β-methylpregna-1,4-diene-3, 20-dione 17-propionate, with the molecular formula C25H32ClFO5, a molecular weight of 466.97 (CAS Registry Number 25122-46-7).

The following is the chemical structure:

Clobetasol propionate

Clobetasol propionate is a white to practically-white crystalline powder insoluble in water.

Each gram of Clobetasol Propionate Lotion, 0.05% contains 0.5 mg of clobetasol propionate, in a vehicle base composed of carbomer 940, hypromellose, mineral oil, polyoxyethylene glycol 300 isostearate, polysorbate 80, propylene glycol, purified water, and sodium hydroxide.

CLINICAL PHARMACOLOGY

Like other topical corticosteroids, clobetasol propionate lotion, 0.05% has anti-inflammatory, antipruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids in general is unclear. However, corticosteroids are thought to act by induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2.

Pharmacokinetics

The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle, the integrity of the epidermal barrier and occlusion. For example, occlusive dressing with hydrocortisone for up to 24 hours has not been demonstrated to increase penetration; however, occlusion of hydrocortisone for 96 hours markedly enhances penetration. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and other disease processes in the skin may increase percutaneous absorption.

There are no human data regarding the distribution of corticosteroids to body organs following topical application. Nevertheless, once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Due to the fact that circulating levels are usually below the level of detection, the use of pharmacodynamic endpoints for assessing the systemic exposure of topical corticosteroids is necessary. They are metabolized, primarily in the liver, and are then excreted by the kidneys. In addition, some corticosteroids and their metabolites are also excreted in the bile.

Clobetasol propionate lotion, 0.05% is in the super-high range of potency as compared with other topical corticosteroids in vasoconstrictor studies.

In studies evaluating the potential for hypothalamic-pituitary-adrenal (HPA) axis suppression, clobetasol propionate lotion, 0.05% demonstrated rates of suppression that were numerically higher than those of a clobetasol propionate 0.05% cream, (See PRECAUTIONS).

CLINICAL STUDIES

The efficacy of clobetasol propionate lotion, 0.05% in psoriasis and atopic dermatitis has been demonstrated in two adequate and well-controlled clinical trials. The first study was conducted in patients with moderate to severe plaque psoriasis. Patients were treated twice daily for 4 weeks with either clobetasol propionate lotion, 0.05% or vehicle lotion. Study results demonstrated that the efficacy of clobetasol propionate lotion, 0.05% in treating moderate to severe plaque psoriasis was superior to that of vehicle.

At the end of treatment (4 weeks), 30 of 82 patients (36.6%) treated with clobetasol propionate lotion, 0.05% compared with 0 of 29 (0%) treated with vehicle achieved success. Success was defined as a score of none or very mild (no or very slight clinical signs or symptoms of erythema, plaque elevation, or scaling) on the Global Severity scale of psoriasis.

The second study was conducted in patients with moderate to severe atopic dermatitis. Patients were treated twice daily for 2 weeks with either clobetasol propionate lotion, 0.05% or vehicle lotion. Study results demonstrated that the efficacy of clobetasol propionate lotion, 0.05% in treating moderate to severe atopic dermatitis was superior to that of vehicle.

At the end of treatment (2 weeks), 41 of 96 of patients (42.7%) treated with clobetasol propionate lotion, 0.05% compared with 4 of 33 (12.1%) treated with vehicle achieved success. Success was defined as a score of none or very mild (no or very slight clinical signs or symptoms of erythema, induration/papulation, oozing/crusting, or pruritus) on the Global Severity scale of atopic dermatitis.

INDICATIONS AND USAGE

Clobetasol Propionate Lotion, 0.05% is a super-high potent corticosteroid formulation indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses only in patients 18 years of age or older (see PRECAUTIONS). Treatment should be limited to 2 consecutive weeks. The total dosage should not exceed 50 g (50 mL or 1.75 fl. oz.) per week.

For the treatment of moderate to severe plaque psoriasis, localized lesions (less than 10% body surface area) that have not sufficiently improved after the initial 2-week treatment with clobetasol propionate lotion, 0.05% may be treated for up to 2 additional weeks. Any additional benefits of extending treatment should be weighed against the risk of HPA axis suppression before prescribing for more than 2 weeks.

Patients should be instructed to use clobetasol propionate lotion, 0.05% for the minimum amount of time necessary to achieve the desired results (see PRECAUTIONS).

Use in patients younger than 18 years of age is not recommended due to numerically high rates of HPA axis suppression (see PRECAUTIONS: Pediatric Use).

CONTRAINDICATIONS

Clobetasol Propionate Lotion, 0.05% is contraindicated in patients who are hypersensitive to clobetasol propionate, to other corticosteroids, or to any ingredient in this preparation.

PRECAUTIONS

General

Clobetasol propionate is a highly potent topical corticosteroid that has been shown to suppress the HPA axis at the lowest doses tested.

Systemic absorption of topical corticosteroids has caused reversible adrenal suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment.

Conditions which increase systemic absorption include the application of the more potent steroids, use over large surface areas, prolonged use, and the addition of occlusive dressings. Therefore, patients applying a topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of adrenal suppression (see laboratory tests below). If adrenal suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur requiring supplemental systemic corticosteroids. For information on systemic supplementation, see prescribing information for those products.

The effect of clobetasol propionate lotion, 0.05% on HPA axis function was compared to clobetasol propionate cream 0.05% in adults in two studies, one for psoriasis and one for atopic dermatitis. In total, 8 of 10 evaluable patients with moderate to severe plaque psoriasis experienced adrenal suppression following 4 weeks of clobetasol propionate lotion, 0.05% therapy (treatment beyond 4 consecutive weeks is not recommended in moderate to severe plaque psoriasis). In follow-up testing, 1 of 2 patients remained suppressed after 8 days. In this comparative study, for clobetasol propionate cream, 0.05% there were 3 of 10 evaluable patients with HPA axis suppression. Furthermore, 5 of 9 evaluable patients with moderate to severe atopic dermatitis experienced adrenal suppression following 2 weeks of clobetasol propionate lotion, 0.05% therapy (treatment beyond 2 consecutive weeks is not recommended in moderate to severe atopic dermatitis). Of the 3 patients that had follow-up testing, one patient failed to recover adrenal function 7 days post-treatment. For patients treated with clobetasol propionate cream, 0.05%, 4 of 9 evaluable patients experienced adrenal suppression following 2 weeks of treatment. Of the 2 patients that had follow-up testing, both recovered adrenal function 7 days post-treatment. The proportion of subjects suppressed may be underestimated because the adrenal glands were stimulated weekly with cosyntropin in these studies.

The potential increase in systemic exposure does not correlate with any proven benefit, but may lead to an increased potential for hypothalamic-pituitary-adrenal (HPA) axis suppression.  Patients with acute illness or injury may have increased morbidity and mortality with intermittent HPA axis suppression. Patients should be instructed to use clobetasol propionate lotion, 0.05% for the minimum amount of time necessary to achieve the desired results (See INDICATIONS AND USAGE).

If irritation develops, clobetasol propionate lotion, 0.05% should be discontinued and appropriate alternative therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing a failure to heal rather than noting a clinical exacerbation, as with most topical products not containing corticosteroids.

In the presence of dermatological infections, the use of an appropriate antifungal or antibacterial agent should be instituted. If a favorable response does not occur promptly, use of clobetasol propionate lotion, 0.05% should be discontinued until the infection has been adequately controlled.

Clobetasol propionate lotion, 0.05% should not be used in the treatment of rosacea or perioral dermatitis, and should not be used on the face, groin, or axillae.

Information for Patients

Patients using topical corticosteroids should receive the following information and instructions:

• This medication is to be used as directed by the physician and should not be used longer than the prescribed time period.


• This medication should not be used for any disorder other than that for which it was prescribed.


• The treated skin area should not be bandaged, otherwise covered, or wrapped so as to be occlusive unless directed by the physician.


• Patients should wash their hands after applying the medication.


• Patients should report any signs of local or systemic adverse reactions to the physician.


• Patients should inform their physicians that they are using clobetasol propionate lotion, 0.05% if surgery is contemplated.


• This medication is for external use only. It should not be used on the face, underarms or groin area, and avoid contact with the eyes and lips.


• As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, contact the physician.


• Patients should be informed to not use more than 50 g (50 mL or 1.75 fl. oz.) per week of clobetasol propionate lotion, 0.05%.

Laboratory Tests

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

―    Cosyntropin stimulation test

―    AM plasma cortisol test

―    Urinary free cortisol test

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of clobetasol propionate.

Clobetasol propionate was non-mutagenic in three different test systems: the Ames test, the Saccharomyces cerevisiae gene conversion assay, and the E. coli B WP2 fluctuation test.

Studies in the rat following subcutaneous administration at dosage levels up to 50 μg/kg per day revealed that the females exhibited an increase in the number of resorbed embryos and a decrease in the number of living fetuses at the highest dose.

Pregnancy

Teratogenic Effects

Pregnancy category C.

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 to laboratory animals.

Clobetasol propionate is absorbed percutaneously, and when administered subcutaneously it was a significant teratogen in both the rabbit and mouse. Clobetasol propionate has greater teratogenic potential than steroids that are less potent.

Teratogenicity studies in mice using the subcutaneous route resulted in fetotoxicity at the highest dose tested (1 mg/kg) and teratogenicity at all dose levels tested down to 0.03 mg/kg. These doses are approximately 1.4 and 0.04 times, respectively, the human topical dose of clobetasol propionate lotion, 0.05%. Abnormalities seen included cleft palate and skeletal abnormalities.

In rabbits, clobetasol propionate was teratogenic at doses of 3 and 10 μg/kg. These doses are approximately 0.02 and 0.05 times, respectively, the human topical dose of clobetasol propionate lotion, 0.05%. Abnormalities seen included cleft palate, cranioschisis, and other skeletal abnormalities.

A teratogenicity study in rats using the dermal route resulted in dose related maternal toxicity and fetal effects from 0.05 to 0.5 mg/kg/day of clobetasol propionate. These doses are approximately 0.14 to 1.4 times, respectively, the human topical dose of clobetasol propionate lotion, 0.05%. Abnormalities seen included low fetal weights, umbilical herniation, cleft palate, reduced skeletal ossification, and other skeletal abnormalities.

There are no adequate and well-controlled studies of the teratogenic potential of clobetasol propionate in pregnant women. Clobetasol propionate lotion, 0.05% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Because many drugs are excreted in human milk, caution should be exercised when clobetasol propionate lotion, 0.05% is administered to a nursing woman.

Pediatric Use

Use of Clobetasol Propionate Lotion, 0.05% in pediatric patients is not recommended due to the potential for HPA axis suppression (see PRECAUTIONS: General).

The HPA axis suppression potential of clobetasol propionate lotion, 0.05% has been studied in adolescents (12 to 17 years of age) with moderate to severe atopic dermatitis covering a minimum of 20% of the total body surface area. In total 14 patients were evaluated for HPA axis function. Patients were treated twice daily for 2 weeks with clobetasol propionate lotion, 0.05%. After 2 weeks of treatment, 9 out of 14 of the patients experienced adrenal suppression. One out of 4 patients treated with clobetasol propionate lotion, 0.05% who were retested remained suppressed two weeks post-treatment. In comparison, 2 of 10 of the patients treated with clobetasol propionate cream, 0.05% demonstrated HPA axis suppression. One patient who was retested recovered.

None of the patients who developed HPA axis suppression had concomitant clinical signs of adrenal suppression and none of them was discontinued from the study for reasons related to the safety or tolerability of clobetasol propionate lotion, 0.05%. However, patients with acute illness or injury may have increased morbidity and mortality with intermittent HPA axis suppression.

Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA axis suppression and Cushing’s syndrome when they are treated with topical corticosteroids. They are therefore also at greater risk of glucocorticosteroid insufficiency during and/or after withdrawal of treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in infants and children.

HPA axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include low plasma cortisol levels and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.

Geriatric Use

Clinical studies of clobetasol propionate lotion, 0.05% did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be made with caution, 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 controlled clinical trials with clobetasol propionate lotion, 0.05%, the following adverse reactions have been reported: burning/stinging, skin dryness, irritation, erythema, folliculitis, pruritus, skin atrophy, and telangiectasia.

The pooled incidence of local adverse reactions in trials for psoriasis and atopic dermatitis with clobetasol propionate lotion, 0.05% at 1.0% or greater was:

Adverse Reaction	Incidence
Skin Atrophy	4.2%
Telangiectasia	3.2%
Discomfort Skin	1.3%
Skin Dry	1.0%

Other local adverse events occurred at rates less than 1.0%. Similar rates of local adverse reactions were reported in the comparator (clobetasol propionate cream, 0.05%). Most local adverse events were rated as mild to moderate and they are not affected by age, race or gender.

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

OVERDOSAGE

Topically applied clobetasol propionate lotion, 0.05% can be absorbed in sufficient amount to produce systemic effects (See PRECAUTIONS).

DOSAGE AND ADMINISTRATION

Clobetasol Propionate Lotion, 0.05% should be applied to the affected skin areas twice daily and rubbed in gently and completely. (See INDICATIONS AND USAGE).

Clobetasol Propionate Lotion, 0.05% contains a super-high potent topical corticosteroid; therefore treatment should be limited to:

―   2 consecutive weeks for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses,

―   and up to 2 additional weeks in very localized lesions of moderate to severe plaque psoriasis (no more than 10 % body surface area) that have not sufficiently improved after the initial 2 weeks of treatment with clobetasol

    propionate lotion, 0.05%.

The total dosage should not exceed 50 g (50 mL or 1.75 fl. oz.) per week because of the potential for the drug to suppress the hypothalamic-pituitary-adrenal (HPA) axis.

Therapy should be discontinued when control has been achieved. If no improvement is seen within 2 weeks, reassessment of diagnosis may be necessary.

Use in patients younger than 18 years is not recommended because of numerically high rates of HPA axis suppression (See PRECAUTIONS: Pediatric Use).

Unless directed by physician, Clobetasol Propionate Lotion, 0.05% should not be used with occlusive dressings.

HOW SUPPLIED

Clobetasol Propionate Lotion, 0.05% is supplied in the following sizes:

1 fl. oz. (30 mL) high density polyethylene bottles.

2 fl. oz. (59 mL) high density polyethylene bottles.

4 fl. oz. (118 mL) high density polyethylene bottles.

Store at 20-25°C (68-77°F) [see USP Controlled Room Temperature]

Manufactured by:

Actavis Mid Atlantic LLC

1877 Kawai Road

Lincolnton, NC 28092 USA

FORM NO. 0404

Rev. 09/08

VC3210

Patient Information

Clobetasol Propionate Lotion, 0.05%

For External Use Only

Not for Ophthalmic (Eye) Use

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

What is Clobetasol Propionate Lotion?

Clobetasol Propionate Lotion is a medicine called a topical (skin use only) corticosteroid. It is used for a short time to reduce the inflammation and itching of:

• Moderate to severe skin conditions (atopic dermatitis and other skin problems)


• Moderate to severe plaque psoriasis.

Clobetasol Propionate Lotion is a super-high potent (very strong) topical corticosteroid. It is very important that you use Clobetasol Propionate Lotion only as directed, in order to avoid serious side effects.

Who should not use Clobetasol Propionate Lotion?

Do not use Clobetasol Propionate Lotion if you are allergic to any of its ingredients, or to any other corticosteroid. The active ingredient is clobetasol propionate. See the end of this leaflet for the complete list of other ingredients in Clobetasol Propionate Lotion. Ask your doctor or pharmacist if you need a list of other corticosteroids.

Clobetasol Propionate Lotion is not recommended for use on anyone younger than 18 years of age. Clobetasol Propionate Lotion has not been studied in children under 12 years old. Children have smaller body sizes and have a higher chance of side effects.

What should I tell my doctor before using Clobetasol Propionate Lotion?

Tell your doctor:

• if you are pregnant, think you are pregnant, or plan to be pregnant. Talk with your doctor before using Clobetasol Propionate Lotion or if you are already using Clobetasol Propionate Lotion, as it is not known if Clobetasol Propionate Lotion can harm your unborn child.


• if you are breastfeeding. It is not known if Clobetasol Propionate Lotion passes into your milk.


• if you think you have a skin infection. You may need another medicine to treat the skin infection before you use Clobetasol Propionate Lotion.

Tell your doctor about all the other medicines and skin products you use, including prescription and non-prescription medicines, cosmetics, vitamins, and herbal supplements. Some medicines can cause serious side effects if used while you are using Clobetasol Propionate Lotion.

How should I use Clobetasol Propionate Lotion?

• Use Clobetasol Propionate Lotion exactly as directed by your doctor. Clobetasol Propionate Lotion is for skin use only.


• Apply Clobetasol Propionate Lotion twice a day, once in the morning and once at night, or as directed by your doctor. Use only enough to cover the affected areas. Do not apply Clobetasol Propionate Lotion to your face, neck, groin or armpits. Do not get Clobetasol Propionate Lotion on your lips or in or near your eyes.


• Make sure your skin is clean and dry before applying Clobetasol Propionate Lotion.


• Turn the bottle of Clobetasol Propionate Lotion upside down. Pour a small amount, less than 1 teaspoonful of Clobetasol Propionate Lotion onto your fingertips, or directly on your affected skin area. Gently, rub the Clobetasol Propionate Lotion into your affected skin area, until the lotion disappears.


• Wash your hands after using Clobetasol Propionate Lotion.


• If you forget to apply Clobetasol Propionate Lotion at the scheduled time, use it as soon as you remember. Then go back to your regular schedule. If it is about time for your next dose, apply just that 1 dose, and continue with your normal application schedule. Do not try to make up for the missed dose. If you miss several doses, tell your doctor.


• Throw away unused Clobetasol Propionate Lotion.

What should I avoid while using Clobetasol Propionate Lotion?

Do not do the following while using Clobetasol Propionate Lotion:

• Do not get Clobetasol Propionate Lotion on your face, lips, or in or near your eyes because this might cause irritation. If you do, use a lot of water to rinse the Clobetasol Propionate Lotion off your face, lips, or out of your eyes. If your eyes keep stinging after rinsing them well with water, call your doctor right away.

• Do not apply Clobetasol Propionate Lotion to your groin or armpits.


• Do not bandage or cover your treated areas unless your doctor tells you to do so.


• Do not wear tight fitting clothes over your treated skin areas.


• Do not use Clobetasol Propionate Lotion any longer than 2 weeks (14 days) for moderate to severe conditions (atopic dermatitis and other skin problems).


• Do not use Clobetasol Propionate Lotion any longer than an extra 2 weeks (4 weeks total) for psoriasis on a small area of your body (less than 10 percent of your body surface area) that is not much better after the first 2 weeks of treatment.


• Do not use more than 50 grams (50 mL or 1.75 fluid ounces) of Clobetasol Propionate  Lotion a week. Clobetasol Propionate Lotion comes in 3 different size bottles, a 1-ounce, a 2-ounce, and a 4-ounce bottle.

What are the possible side effects of Clobetasol Propionate Lotion?

Clobetasol Propionate Lotion can pass through your skin. Too much Clobetasol Propionate Lotion passing through your skin can shut down your adrenal glands. This usually happens if you use too much Clobetasol Propionate Lotion, or you use it for too long. If this happens, your adrenal glands may not start working immediately once you stop using Clobetasol Propionate Lotion. Shutting down of the adrenal glands can cause nausea, vomiting, fever, low blood pressure, heart attack, and even death because your body cannot respond to any stress or illness.

Your doctor may do special blood and urine tests to check your adrenal gland function while you are using Clobetasol Propionate Lotion.

Other possible side effects with Clobetasol Propionate Lotion include mild burning, stinging, itching, redness, irritation, and dry skin. Also, thinning of the skin, widening of small blood vessels in the skin, and skin discomfort at the site of application may happen. Sometimes your condition will get worse with use of Clobetasol Propionate Lotion.

If you are ill or injured, or going to have surgery, tell your doctor that you are using Clobetasol Propionate Lotion.

Tell your doctor if you:

• are going to have surgery.


• get sick or don’t feel right. Call your doctor right away.

• have irritation of the treated skin area that does not go away.


• have any unusual effects that you do not understand.


• have affected areas that do not seem to be getting better after 2 weeks of using Clobetasol Propionate Lotion.

These are not all the possible side effects of Clobetasol Propionate Lotion. For more information, ask your doctor or pharmacist.

General information about the safe and effective use of Clobetasol Propionate Lotion.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Clobetasol Propionate Lotion for a condition for which it was not prescribed. Do not give Clobetasol Propionate Lotion to other people, even if they have the same symptoms you have. It may harm them. Keep Clobetasol Propionate Lotion and all medicines out of reach of children.

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

What are the ingredients of Clobetasol Propionate Lotion?

Active Ingredient: clobetasol propionate

Inactive Ingredients: carbomer 940, hypromellose, mineral oil, polyoxyethylene glycol 300 isostearate, polysorbate 80, propylene glycol, purified water, and sodium hydroxide.

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

Manufactured by:

Actavis Mid Atlantic LLC

1877 Kawai Road

Lincolnton, NC 28092 USA

FORM NO. 0404

Rev. 09/08

VC3210

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

CLOBETASOL PROPIONATE  clobetasol propionate  lotion

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0472-0404 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLOBETASOL PROPIONATE (CLOBETASOL) CLOBETASOL PROPIONATE 0.05 mL  in 100 mL

Inactive Ingredients Ingredient Name Strength CARBOMER HOMOPOLYMER TYPE C   HYPROMELLOSES   MINERAL OIL   POLYSORBATE 80   PROPYLENE GLYCOL   WATER   SODIUM HYDROXIDE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0472-0404-91 1 BOTTLE In 1 CARTON contains a BOTTLE 1 30 mL In 1 BOTTLE This package is contained within the CARTON (0472-0404-91) 2 0472-0404-92 1 BOTTLE In 1 CARTON contains a BOTTLE 2 59 mL In 1 BOTTLE This package is contained within the CARTON (0472-0404-92) 3 0472-0404-94 1 BOTTLE In 1 CARTON contains a BOTTLE 3 118 mL In 1 BOTTLE This package is contained within the CARTON (0472-0404-94)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA078223	01/03/2012

Labeler - Actavis Mid Atlantic LLC (809515898)

Registrant - Actavis Mid Atlantic LLC (809515898)

Establishment
Name	Address	ID/FEI	Operations
Actavis Mid Atlantic LLC		809515898	MANUFACTURE

Revised: 09/2008Actavis Mid Atlantic LLC

Hemorrhoidal HC cream, ointment, suppository

Generic Name: hydrocortisone rectal (cream, ointment, suppository) (hye dro KORT i zone REK tal)

Brand Names: Anucort-HC, Anumed-HC, Anusol-HC, Cortizone-10 Anal Itch Cream, Hemorrhoidal HC, Hemril-30, Hemril-HC Uniserts, Preparation H Hydrocortisone, Procto-Kit 1%, Procto-Kit 2.5%, Procto-Pak 1%, Proctocort, Proctocream-HC, Proctosert HC, Proctosol-HC, Proctozone HC, Proctozone-H, Recort Plus, Rectasol-HC, Tucks HC

What is hydrocortisone rectal?

Hydrocortisone is a steroid medicine that reduces inflammation in the body.

The information in this medication guide is specific to hydrocortisone rectal cream, ointment, or suppository.

Hydrocortisone rectal is used to treat itching or swelling caused by hemorrhoids or other inflammatory conditions of the rectum or anus.

Hydrocortisone rectal is also used together with other medications to treat ulcerative colitis, proctitis, and other inflammatory conditions of the lower intestines and rectal area.

Hydrocortisone rectal may also be used for purposes not listed in this medication guide.

What is the most important information I should know about hydrocortisone rectal?

The information in this medication guide is specific to hydrocortisone rectal cream, ointment, or suppository.

Do not take hydrocortisone rectal by mouth. It is for use only in your rectum.

This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions. You may need to use this medication for up to 8 weeks.

Call your doctor at once if you have any bleeding from your rectum, feeling short of breath (even with mild exertion), swelling of your ankles or feet, or rapid weight gain.

There may be other drugs that can interact with hydrocortisone rectal. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Call your doctor if your symptoms do not improve or if they get worse after using this medicine for a few days.

What should I discuss with my health care provider before using hydrocortisone rectal?

Ask a doctor or pharmacist if it is safe for you to use this medicine if you have:

• 
  

  congestive heart failure;

  
  


• 
  

  a history of tuberculosis;

  
  


• 
  

  stomach ulcer or diverticulitis;

  
  


• 
  

  a colostomy or ileostomy;

  
  


• 
  

  fever or any type of infection;

  
  


• 
  

  kidney disease;

  
  


• 
  

  high blood pressure; or

  
  


• 
  

  myasthenia gravis.

  
  

Also tell your doctor if you have diabetes. Steroid medicines may increase the glucose (sugar) levels in your blood or urine. You may also need to adjust the dose of your diabetes medications.

FDA pregnancy category C. It is not known whether hydrocortisone rectal will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether hydrocortisone passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I use hydrocortisone rectal?

Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Do not take hydrocortisone rectal by mouth. It is for use only in your rectum.

This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions. You may need to use this medication for up to 8 weeks.

Wash your hands before and after using this medicine.

Try to empty your bowel and bladder just before using hydrocortisone rectal.

Remove the outer wrapper from the suppository before inserting it. Avoid handling the suppository too long or it will melt in your hands. The rectal suppository can stain clothing or other fabrics it comes into contact with.

For best results from the suppository, lie down after inserting it and hold in the suppository. The suppository will melt quickly once inserted and you should feel little or no discomfort while holding it in.

For best results from the cream, use only the applicator provided with the medication. Otherwise, follow the directions provided with your rectal cream.

Avoid using the bathroom for one to three hours after inserting the cream or suppository.

Apply the ointment to the rectum and surrounding skin of the rectal area as directed on the package label.

Call your doctor if your symptoms do not improve or if they get worse after using this medicine for a few days.

Store the rectal cream at room temperature away from moisture and heat. Store the rectal suppositories at cool room temperature away from moisture and heat. Do not refrigerate or freeze them.

What happens if I miss a dose?

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

An overdose of hydrocortisone rectal is not expected to produce life-threatening symptoms. However, long-term use of high steroid doses can lead to symptoms such as thinning skin, easy bruising, changes in the shape or location of body fat (especially in your face, neck, back, and waist), increased acne or facial hair, menstrual problems, impotence, or loss of interest in sex.

What should I avoid while using hydrocortisone rectal ?

Avoid getting a vaccine during your treatment with hydrocortisone rectal. Vaccines may not work as well while you are using a steroid medicine.

Hydrocortisone rectal side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

• 
  

  feeling short of breath, even with mild exertion;

  
  


• 
  

  swelling of your ankles or feet;

  
  


• 
  

  muscle weakness;

  
  


• 
  

  rapid weight gain, especially in your face and midsection;

  
  


• 
  

  severe rectal pain or burning;

  
  


• 
  

  bleeding from your rectum;

  
  


• 
  

  severe stomach pain;

  
  


• 
  

  sudden and severe headache or pain behind your eyes; or

  
  


• 
  

  seizure (convulsions).

  
  

Less serious side effects may include:

• 
  

  mild rectal pain or burning;

  
  


• 
  

  acne;

  
  


• 
  

  changes in your menstrual periods;

  
  


• 
  

  increased sweating; or

  
  


• 
  

  increased facial or body hair growth.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect hydrocortisone rectal ?

Before using hydrocortisone rectal, tell your doctor if you also use insulin or take oral diabetes medication.

There may be other drugs that can interact with hydrocortisone rectal. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Hemorrhoidal HC resources

• Hemorrhoidal HC Side Effects (in more detail)
• Hemorrhoidal HC Use in Pregnancy & Breastfeeding
• Hemorrhoidal HC Drug Interactions
• Hemorrhoidal HC Support Group
• 0 Reviews for Hemorrhoidal HC - Add your own review/rating

Compare Hemorrhoidal HC with other medications

• Anal Itching
• Aphthous Stomatitis, Recurrent
• Atopic Dermatitis
• Dermatitis
• Eczema
• Gingivitis
• Proctitis
• Pruritus
• Psoriasis
• Seborrheic Dermatitis
• Skin Rash
• Ulcerative Colitis, Active

Where can I get more information?

• Your pharmacist can provide more information about hydrocortisone rectal cream, ointment, or suppository.

See also: Hemorrhoidal HC side effects (in more detail)

Clotrimazole Lozenge

Dosage Form: troche, lozenge
Clotrimazole Lozenge

(Clotrimazole Troche)

FOR TOPICAL ORAL ADMINISTRATION

Clotrimazole Lozenge Description

Each Clotrimazole Lozenge contains 10 mg clotrimazole [1-(o-chloro-α, α-diphenylbenzyl) imidazole], a synthetic antifungal agent, for topical use in the mouth.

Structural Formula:

Chemical Formula:

C22H17ClN2

The lozenge dosage form is a large, slowly dissolving tablet (troche) containing 10 mg of clotrimazole dispersed in dextrose, microcrystalline cellulose, povidone, and magnesium stearate.

Clotrimazole Lozenge - Clinical Pharmacology

Clotrimazole is a broad-spectrum antifungal agent that inhibits the growth of pathogenic yeasts by altering the permeability of cell membranes. The action of clotrimazole is fungistatic at concentrations of drug up to 20 mcg/mL and may be fungicidal in vitro against Candida albicans and other species of the genus Candida at higher concentrations. No single-step or multiple-step resistance to clotrimazole has developed during successive passages of Candida albicans in the laboratory; however, individual organism tolerance has been observed during successive passages in the laboratory. Such in vitro tolerance has resolved once the organism has been removed from the antifungal environment.

After oral administration of a 10 mg Clotrimazole Lozenge to healthy volunteers, concentrations sufficient to inhibit most species of Candida persist in saliva for up to three hours following the approximately 30 minutes needed for a lozenge to dissolve. The long term persistence of drug in saliva appears to be related to the slow release of clotrimazole from the oral mucosa to which the drug is apparently bound. Repetitive dosing at three hour intervals maintains salivary levels above the minimum inhibitory concentrations of most strains of Candida; however, the relationship between in vitro susceptibility of pathogenic fungi to clotrimazole and prophylaxis or cure of infections in humans has not been established.

In another study, the mean serum concentrations were 4.98 ± 3.7 and 3.23 ± 1.4 nanograms/mL of clotrimazole at 30 and 60 minutes, respectively, after administration as a lozenge.

Indications and Usage for Clotrimazole Lozenge

Clotrimazole Lozenges are indicated for the local treatment of oropharyngeal candidiasis. The diagnoses should be confirmed by a KOH smear and/or culture prior to treatment.

Clotrimazole Lozenges are also indicated prophylactically to reduce the incidence of oropharyngeal candidiasis in patients immunocompromised by conditions that include chemotherapy, radiotherapy, or steroid therapy utilized in the treatment of leukemia, solid tumors, or renal transplantation. There are no data from adequate and well-controlled trials to establish the safety and efficacy of this product for prophylactic use in patients immunocompromised by etiologies other than those listed in the previous sentence. (See DOSAGE AND ADMINISTRATION.)

Contraindications

Clotrimazole Lozenges are contraindicated in patients who are hypersensitive to any of its components.

Warning

Clotrimazole Lozenges are not indicated for the treatment of systemic mycoses including systemic candidiasis.

Precautions

Abnormal liver function tests have been reported in patients treated with Clotrimazole Lozenges; elevated SGOT levels were reported in about 15% of patients in the clinical trials. In most cases the elevations were minimal and it was often impossible to distinguish effects of clotrimazole from those of other therapy and the underlying disease (malignancy in most cases). Periodic assessment of hepatic function is advisable particularly in patients with pre-existing hepatic impairment.

Since patients must be instructed to allow each lozenge to dissolve slowly in the mouth in order to achieve maximum effect of the medication, they must be of such an age and physical and/or mental condition to comprehend such instructions.

Carcinogenesis:

An 18 month dosing study with clotrimazole in rats has not revealed any carcinogenic effect.

Usage in Pregnancy:

Pregnancy Category C:

Clotrimazole has been shown to be embryotoxic in rats and mice when given in doses 100 times the adult human dose (in mg/kg), possibly secondary to maternal toxicity. The drug was not teratogenic in mice, rabbits, and rats when given in doses up to 200, 180, and 100 times the human dose.

Clotrimazole given orally to mice from nine weeks before mating through weaning at a dose 120 times the human dose was associated with impairment of mating, decreased number of viable young, and decreased survival to weaning. No effects were observed at 60 times the human dose. When the drug was given to rats during a similar time period at 50 times the human dose, there was a slight decrease in the number of pups per litter and decreased pup viability.

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

PEDIATRIC USE

Safety and effectiveness of clotrimazole in children below the age of 3 years have not been established; therefore, its use in such patients is not recommended.

The safety and efficacy of the prophylactic use of Clotrimazole Lozenges in children have not been established.

GERIATRIC USE

Clinical studies of clotrimazole did not include sufficient numbers 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.

Adverse Reactions

Abnormal liver function tests have been reported in patients treated with Clotrimazole Lozenges; elevated SGOT levels were reported in about 15% of patients in the clinical trials (See Precautions section).

Nausea, vomiting, unpleasant mouth sensations and pruritus have also been reported with the use of the lozenge.

Overdosage

No data available.

Drug Abuse and Dependence

No data available.

Clotrimazole Lozenge Dosage and Administration

Clotrimazole Lozenges must be slowly dissolved in the mouth. The recommended dose is one lozenge five times a day for fourteen consecutive days. Only limited data are available on the safety and effectiveness of the Clotrimazole Lozenge after prolonged administration; therefore, therapy should be limited to short term use, if possible.

For prophylaxis to reduce the incidence of oropharyngeal candidiasis in patients immunocompromised by conditions that include chemotherapy, radiotherapy, or steroid therapy utilized in the treatment of leukemia, solid tumors, or renal transplantation, the recommended dose is one lozenge three times daily for the duration of chemotherapy or until steroids are reduced to maintenance levels.

How is Clotrimazole Lozenge Supplied

Clotrimazole Lozenges, 10 mg, white discoid, uncoated tablets, debossed with "PAD" over "0107" on one side and plain on the other, are supplied as follows:

	Strength	NDC Code	Lozenge Identification
Bottles of 70:	10 mg	0574-0107-70	PAD 0107
Bottles of 140:	10 mg	0574-0107-14	PAD 0107
Boxes of 70 foil packs:	10 mg	0574-0107-77	PAD 0107

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]

Avoid freezing.

Paddock Laboratories, Inc.

Minneapolis, MN 55427

(02-08)

PRINCIPAL DISPLAY PANEL - 70 Lozenge Box

NDC 0574-0107-70

CLOTRIMAZOLE

LOZENGE

(Clotrimazole Troche)

10 mg

Rx ONLY

DOSAGE: Each lozenge

must be dissolved

slowly in the mouth.

NET CONTENTS

70 LOZENGES

Paddock

Laboratories, Inc.

CLOTRIMAZOLE  clotrimazole  lozenge

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0574-0107 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength clotrimazole (clotrimazole) clotrimazole 10 mg

Inactive Ingredients Ingredient Name Strength dextrose   cellulose, microcrystalline   povidone   magnesium stearate

Product Characteristics Color WHITE Score no score Shape ROUND Size 16mm Flavor Imprint Code PAD;0107 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0574-0107-70 70 LOZENGE In 1 BOTTLE, PLASTIC None 2 0574-0107-14 140 LOZENGE In 1 BOTTLE, PLASTIC None 3 0574-0107-77 70 PACKET In 1 BOX contains a PACKET 3 1 LOZENGE In 1 PACKET This package is contained within the BOX (0574-0107-77)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA076763	12/01/2005

Labeler - Paddock Laboratories, Inc. (086116803)

Establishment
Name	Address	ID/FEI	Operations
Paddock Laboratories, Inc.		086116803	MANUFACTURE

Revised: 11/2010Paddock Laboratories, Inc.

More Clotrimazole Lozenge resources

• Clotrimazole Lozenge Use in Pregnancy & Breastfeeding
• Drug Images
• Clotrimazole Lozenge Drug Interactions
• Clotrimazole Lozenge Support Group
• 5 Reviews for Clotrimazole - Add your own review/rating

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• Oral Thrush

Ibumol

Ibumol may be available in the countries listed below.

Ingredient matches for Ibumol

Ibuprofen

Ibuprofen is reported as an ingredient of Ibumol in the following countries:

• South Africa

Paracetamol

Paracetamol is reported as an ingredient of Ibumol in the following countries:

• South Africa

International Drug Name Search

Xigris 20mg powder for solution for infusion, 5mg powder for solution for infusion

1. Name Of The Medicinal Product

Xigris* 5mg powder for solution for infusion.

Xigris 20mg powder for solution for infusion.

2. Qualitative And Quantitative Composition

Xigris 5mg: Each vial contains 5mg of Drotrecogin alfa (activated).

After reconstitution with 2.5ml of Water for Injection each ml contains 2mg of Drotrecogin alfa (activated).

Excipient: Each vial contains approximately 17mg sodium.

Xigris 20mg: Each vial contains 20mg of drotrecogin alfa (activated).

After reconstitution with 10ml of Water for Injection, each ml contains 2mg of Drotrecogin alfa (activated).

Excipient: Each vial contains approximately 68mg sodium.

Drotrecogin alfa (activated) is a recombinant version of the endogenous activated Protein C and is produced by genetic engineering from an established human cell line.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder for solution for infusion. Xigris is supplied as a lyophilised, white to off-white powder.

4. Clinical Particulars

4.1 Therapeutic Indications

Xigris is indicated for the treatment of adult patients with severe sepsis with multiple organ failure when added to best standard care. The use of Xigris should be considered mainly in situations when therapy can be started within 24 hours after the onset of organ failure (for further information see section 5.1).

4.2 Posology And Method Of Administration

Xigris should be used by experienced doctors in institutions skilled in the care of patients with severe sepsis.

Treatment should be started within 48 hours, and preferably within 24 hours, of onset of the first documented sepsis-induced organ dysfunction (see section 5.1).

The recommended dose of Xigris is 24μg/kg/hr (based on actual body weight) given as a continuous intravenous infusion for a total duration of 96 hours. It is recommended that Xigris be infused with an infusion pump to accurately control the infusion rate. If the infusion is interrupted for any reason, Xigris should be restarted at the 24μg/kg/hr infusion rate and continued to complete the full recommended 96 hours of dosing administration. Dose escalation or bolus doses of Xigris are not necessary to account for the interruption in the infusion.

No dose adjustments are required in adult patients with severe sepsis with regard to age, gender, hepatic function (as measured by transaminase levels), renal function, obesity or co-administration of prophylactic heparin. The pharmacokinetics of drotrecogin alfa (activated) have not been studied in patients with severe sepsis and pre-existing end-stage renal disease and chronic hepatic disease.

Paediatrics: Data from a placebo-controlled clinical trial, which was stopped for futility after 477 patients 0 to 17 years old had received the study treatment, did not establish efficacy of Xigris in paediatric patients and showed a higher rate of central nervous system bleeding in the Xigris versus placebo group. Xigris is contraindicated in children below the age of 18 (see sections 4.3 and 5.1).

4.3 Contraindications

Hypersensitivity to the active substance, to any of the excipients, or to bovine thrombin (a trace residue from the manufacturing process).

Drotrecogin alfa (activated) is contraindicated in children below the age of 18 years (see section 5.1).

Because drotrecogin alfa (activated) may increase the risk of bleeding, Xigris is contraindicated in the following situations:

• Active internal bleeding. • Patients with intracranial pathology; neoplasm or evidence of cerebral herniation. • Concurrent heparin therapy • Known bleeding diathesis except for acute coagulopathy related to sepsis. • Chronic severe hepatic disease. • Platelet count <30,000 x 106 /l, even if the platelet count is increased after transfusions. • Patients at increased risk for bleeding (for example):

a) Any major surgery, defined as surgery that requires general or spinal anaesthesia, performed within the 12-hour period immediately preceding drug infusion, or any postoperative patient who demonstrates evidence of active bleeding, or any patient with planned or anticipated surgery during the drug infusion period. b) History of severe head trauma that required hospitalisation, intracranial or intraspinal surgery, or haemorrhagic stroke within the previous 3 months, or any history of intracerebral arteriovenous malformation, cerebral aneurysm, or central nervous system mass lesion; patients with an epidural catheter or who are anticipated to receive an epidural catheter during drug infusion. c) History of congenital bleeding diatheses. d) Gastro-intestinal bleeding within the last 6 weeks that has required medical intervention unless definitive surgery has been performed. e) Trauma patients at increased risk of bleeding.

4.4 Special Warnings And Precautions For Use

No further study has confirmed the efficacy results of the single pivotal trial.

Patients With Single Organ Dysfunction and Recent Surgery

Xigris is not approved for the treatment of patients with single organ dysfunction and should not be used in this particular subgroup of patients, especially if they had recent surgery (within 30 days). In each of two randomised, placebo-controlled trials, PROWESS and ADDRESS (see section 5.1), 28-day and in-hospital mortality were higher in patients treated with drotrecogin alfa (activated) compared to placebo for the sub-population of patients with single organ dysfunction and recent surgery (n = 98 in PROWESS and n = 636 in ADDRESS).

Bleeding

Drotrecogin alfa (activated) increases the risk of bleeding. In the following conditions, the risks of the administration of Xigris should be weighed against the anticipated benefits:

• Recent administration (within 3 days) of thrombolytic therapy.

• Recent administration (within 7 days) of oral anticoagulants.

• Recent administration (within 7 days) of aspirin or other platelet inhibitors.

• Recent (within 3 months) ischaemic stroke.

• Any other condition in which the physician considers significant bleeding is likely.

For procedures with an inherent bleeding risk, discontinue Xigris for 2 hours prior to the start of the procedure. Xigris may be restarted 12 hours after major invasive procedures or surgery if adequate haemostasis has been achieved. The incidence of serious bleeding events with Xigris was higher in patients with recent (within 30 days) surgery than in “medical” patients without surgery (see section 4.8). Bleeding risk should be taken into account when considering the risk benefit for individual patients. Xigris may be restarted immediately after uncomplicated less invasive procedures if adequate haemostasis has been achieved.

As a component of routine care, measures of haemostasis (e.g., activated partial thromboplastin time [APTT], prothrombin time [PT], and platelet count) should be obtained during the infusion of Xigris. If sequential tests of haemostasis indicate an uncontrolled or worsening coagulopathy that significantly increases the risk of bleeding, the benefits of continuing the infusion must be weighed against the potential increased risk of bleeding for that patient.

Laboratory Tests

Drotrecogin alfa (activated) has minimal effect on the PT. Prolongation of the APTT in patients with severe sepsis receiving Xigris may be due to the underlying coagulopathy, the pharmacodynamic effect of drotrecogin alfa (activated), and/or the effect of other concurrent medicinal products. The pharmacodynamic effect of drotrecogin alfa (activated) on the APTT assay is dependent on the reagent and instrument used to perform the assay and the time that elapses between sample acquisition and assay performance. Drotrecogin alfa (activated) that is present in a blood or plasma sample drawn from a patient who is being infused with the drug will be gradually neutralised by endogenous plasma protease inhibitors present in the sample. Virtually no measurable activity of drotrecogin alfa (activated) is present 2 hours after obtaining the blood sample. Due to these biological and analytical variables, the APTT should not be used to assess the pharmacodynamic effect of drotrecogin alfa (activated). In addition, approximately 2 hours after terminating the infusion of the drug, there is virtually no measurable activity of drotrecogin alfa (activated) remaining in the circulation of the patient; blood samples drawn for APTT determination after this point are no longer affected by the drug. The interpretation of sequential determinations of the PT and/or APTT should take these variables into consideration.

Because drotrecogin alfa (activated) may affect the APTT assays, drotrecogin alfa (activated) present in plasma samples may interfere with one-stage coagulation assays based on the APTT (such as Factor VIII, IX, and XI assays). Drotrecogin alfa (activated) present in plasma samples does not interfere with one-stage factor assays based on the PT (such as Factor II, V, VII and X assays).

If sequential measures of coagulopathy (including platelet count) indicate severe or worsening coagulopathy, the risk of continuing the infusion should be weighed against the expected benefit.

Immunogenicity

In adult patients in severe sepsis clinical studies, the frequency of anti-human Activated Protein C IgA/IgG/IgM antibodies or neutralising antibodies is low and is similar between drotrecogin alfa (activated) and placebo-treated patients tested. In patients developing antibodies, adverse events were not more frequent in drotrecogin alfa (activated) than in placebo patients. There was no evidence that the antibodies detected represented a specific immune response to drotrecogin alfa (activated) therapy.

There have been no clinical trials in severe sepsis specifically studying drotrecogin alfa (activated) re-administration. However, a small number of patients in severe sepsis controlled clinical trials received a prior course of drotrecogin alfa (activated). No hypersensitivity reactions were reported in these patients. Samples available were subsequently tested and all were negative for anti-human Activated Protein C antibody.

No anti-activated Protein C antibody formation was detected in healthy subjects, even after repeat administration.

However, the possibility of allergic reactions to constituents of the preparation cannot be completely excluded in certain predisposed patients. If allergic or anaphylactic reactions occur, treatment should be discontinued immediately and appropriate therapy initiated. If Xigris is readministered to patients, caution should be employed.

Xigris 5mg: This medicinal product contains approximately 17mg sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

Xigris 20mg: This medicinal product contains approximately 68mg sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Caution should be employed when Xigris is used with other drugs that affect haemostasis (see sections 4.3 and 4.4), including Protein C, thrombolytics (e.g., streptokinase, tPA, rPA and urokinase), oral anticoagulants (e.g., warfarin), hirudins, antithrombin, aspirin and other anti-platelets agents, e.g., non-steroidal anti-inflammatory drugs, ticlopidine and clopidogrel, glycoprotein IIb/IIIa antagonists (such as abciximab, eptifibatide, tirofiban) and prostacyclins, such as iloprost.

Co-administration of Low-dose Heparin for Prophylaxis of Venous Thrombotic Events (VTE)

Low-dose heparin for VTE prophylaxis may be co-administered with drotrecogin alfa (activated). In a randomised study of heparin versus placebo (XPRESS) in 1,935 adult severe sepsis patients, all treated with drotrecogin alfa (activated), prophylactic heparin did not adversely affect mortality (heparin 28.3% versus placebo 31.9% in the overall ITT population, and heparin 30.3% versus placebo 26.9% in patients with multiple organ dysfunction treated within 24 hours of their first sepsis-induced organ dysfunction (n=890)). In the subgroup of 885 patients who were already receiving prophylactic heparin at study entry, mortality was 26.9% in the group randomised to continue heparin versus 35.6% in the group whose randomisation (to placebo) led to the discontinuation of heparin. However, the reasons for this difference are unknown and could be related to other factors. Additionally, there was no increased risk of serious bleeding, including central nervous system (CNS) bleeding. Prophylactic heparin increased the risk of non-serious bleeding (see section 4.8). There was no statistical difference in the rates of VTE between study arms.

4.6 Pregnancy And Lactation

Animal studies with respect to effects on pregnancy, embryonal/foetal development, parturition, and post-natal development have not been conducted with Xigris. Therefore, the potential risk for humans is unknown. Xigris should not be used during pregnancy unless clearly necessary.

It is not known whether Xigris is excreted in human milk or if there is a potential effect on the breast-fed infant. Therefore, the patient should not breast-feed whilst treated with Xigris.

4.7 Effects On Ability To Drive And Use Machines

Not relevant.

4.8 Undesirable Effects

Xigris increases the risk of bleeding.

The Phase 3 international, multi-centre, randomised, double-blind, placebo-controlled clinical trial (PROWESS) involved 850 drotrecogin alfa (activated)-treated and 840 placebo-treated patients. The percentage of patients experiencing at least one bleeding event in the two treatment groups was 24.9% and 17.7%, respectively. In both treatment groups, the majority of bleeding events were ecchymosis or gastro-intestinal tract bleeding. The difference in the incidence of serious bleeding events between the two treatment groups occurred primarily during study drug administration.

A total of 2,378 adult patients with severe sepsis received drotrecogin alfa (activated) in a Phase 3b, international, single-arm, open-label clinical trial (ENHANCE).

The incidence of serious bleeding events in the PROWESS and ENHANCE studies is provided below. In these studies, serious bleeding events included any intracranial haemorrhage, any life-threatening or fatal bleed, any bleeding event requiring the administration of

A Phase 3b, international, multi-centre, randomised, double-blind, placebo-controlled clinical trial (ADDRESS) of adult severe sepsis patients at low risk of death involved 1,317 drotrecogin alfa (activated)-treated and 1,293 placebo-treated patients. The percentage of patients experiencing at least one bleeding event in the two treatment groups was 10.9% and 6.4%, respectively (P <0.001). Bleeding events included serious bleeding events, bleeding events assessed as possibly study drug related by the investigator, bleeding events associated with the need for a red blood cell transfusion, and bleeding events that led to permanent discontinuation of the study drug. In the ADDRESS trial, serious bleeding events included any fatal bleed, any life-threatening bleed, any CNS bleed, or any bleeding event assessed as serious by the investigator.

Serious Bleeding Events During the Infusion Period

The following table lists the percentage of patients in PROWESS and ENHANCE experiencing serious bleeding events by site of haemorrhage during the study drug infusion period (defined as the duration of infusion plus the next full calendar day following the end of the infusion).

Site of Haemorrhage	Drotrecogin Alfa (Activated) [PROWESS] n = 850	Placebo [PROWESS] n = 840	Drotrecogin Alfa (Activated) [ENHANCE] n = 2,378
Gastro-intestinal	5 (0.6%)	4 (0.5%)	19 (0.8%)
Intra-abdominal	2 (0.2%)	3 (0.4%)	18 (0.8%)
Intra-thoracic	4 (0.5%)	0	11 (0.5%)
Retroperitoneal	3 (0.4%)	0	4 (0.2%)
Central nervous system (CNS)1	2 (0.2%)	0	15 (0.6%)
Genito-urinary	2 (0.2%)	0	0
Skin/soft tissue	1 (0.1%)	0	16 (0.7%)
Nasopharyngeal	0	0	4 (0.2%)
Joint/bone	0	0	1 (0.04%)
Site unknown2	1 (0.1%)	1 (0.1%)	6 (0.3%)
Total	20 (2.4%)	8 (1.0%)	853 (3.6%)
1 CNS bleeding is defined as any bleed in the central nervous system, including the following types of haemorrhage: petechial, parenchymal, subarachnoid, subdural, and stroke with haemorrhagic transformation. 2 Patients requiring the administration of 3 In ENHANCE, six patients experienced multiple serious bleeding events during the study drug infusion period (94 events observed in 85 patients).

During the infusion period in PROWESS and ENHANCE, the incidence of serious bleeding events with Xigris was numerically higher in patients with recent (within 30 days) surgery than in patients without surgery (PROWESS: 3.3% versus 2.0%; ENHANCE: 5.0% versus 3.1% respectively. Placebo rates in PROWESS 0.4% versus 1.2% respectively).

In ADDRESS, the percentage of treated patients experiencing a serious bleeding event by site of haemorrhage was similar to that observed in PROWESS. The incidence of serious bleeding events during infusion (defined as study day 0 through study day 6) was 31 (2.4%) and 15 (1.2%) in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively (P = 0.02). The incidence of CNS bleeds during infusion was 4 (0.3%) and 3 (0.2%) for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. Recent surgery (within 30 days prior to study entry) was associated with a numerically higher risk of serious bleeding during infusion in both the Xigris-treated and the placebo-treated patients (Xigris: 3.6% in patients with recent surgery versus 1.6% in patients without recent surgery; placebo: 1.6% versus 0.9%, respectively).

In XPRESS, a randomised study of prophylactic heparin versus placebo in adult severe sepsis patients, all treated with drotrecogin alfa (activated), serious bleeding rates were consistent with those observed in previous studies over the treatment period of 0-6 days, and prophylactic heparin did not increase the risk of serious bleeding compared to placebo (2.3% versus 2.5%, respectively), including CNS bleeding (0.3% on both arms). However, prophylactic heparin increased the risk of non-serious bleeding compared with placebo (8.7% versus 5.7%, respectively; P = 0.0116).

Serious Bleeding Events During the 28-Day Study Period

In PROWESS, the incidence of serious bleeding events during the 28-day study period was 3.5% and 2.0% in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. The incidence of CNS bleeds during the 28-day study period was 0.2% and 0.1% for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. The risk of CNS bleeding may increase with severe coagulopathy and severe thrombocytopenia (see sections 4.3 and 4.4).

In the open-label ENHANCE study, the incidence of serious bleeding events during the 28-day study period was 6.5%, and the incidence of CNS bleeds during the 28-day study period was 1.5%.

In the placebo-controlled ADDRESS study, the incidence of serious bleeding events during the 28-day study period was 51 (3.9%) and 28 (2.2%) in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively (P = 0.01). The incidence of CNS bleeds during the 28-day study period was 6 (0.5%) and 5 (0.4%) for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively.

In XPRESS, serious bleeding rates were consistent with those observed in previous studies during the 28-day study period (days 0-28). Prophylactic heparin did not increase the risk of serious bleeding compared to placebo (3.9% versus 5.2%, respectively), including CNS bleeding (1.0% versus 0.7%, respectively).

In the Phase 1 studies, adverse events with a frequency of

4.9 Overdose

In clinical trials and in post-marketing experience there have been reports of accidental overdosing. In the majority of cases, no reactions have been observed. For the other reports, the observed events were consistent with known undesirable effects of the drug (see section 4.8), effects of the drug on laboratory tests (see section 4.4), or consequences of the underlying condition of sepsis.

There is no known antidote for drotrecogin alfa (activated). In case of overdose, immediately stop the infusion (see section 5.2).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antithrombotic agents, enzymes. ATC code: B01AD10.

This medicinal product has been authorised under “Exceptional Circumstances”. This means that for scientific reasons it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency (EMEA) will review any new information which may become available every year, and this SPC will be updated as necessary.

Mechanism of Action

Xigris is a recombinant version of the natural plasma-derived Activated Protein C, from which it differs only by unique oligosaccharides in the carbohydrate portion of the molecule. Activated Protein C is a crucial coagulation regulator. It limits thrombin formation by inactivating Factors Va and VIIIa, thereby providing negative feedback regulation of coagulation. Excessive coagulation activation in the microcirculatory bed plays a significant part in the pathophysiology of severe sepsis. Furthermore, Activated Protein C is an important modulator of the systemic response to infection and has antithrombotic and profibrinolytic properties. Xigris has similar properties to those of endogenous human Activated Protein C.

Pharmacodynamic Effects

In placebo-controlled clinical trials in patients with severe sepsis, Xigris exerted an antithrombotic effect by limiting thrombin generation and improved sepsis-associated coagulopathy, as shown by a more rapid improvement in markers of coagulation and fibrinolysis. Xigris caused a more rapid decline in thrombotic markers, such as D-dimer, prothrombin F1.2, and thrombin-antithrombin levels, and a more rapid increase in Protein C and antithrombin levels. Xigris also restored endogenous fibrinolytic potential, as evidenced by a more rapid trend toward normalisation in plasminogen levels and a more rapid decline in plasminogen activator inhibitor-1 levels. Additionally, patients with severe sepsis treated with Xigris had a more rapid decline in interleukin-6 levels, a global marker of inflammation, consistent with a reduction in the inflammatory response.

Clinical Efficacy

Xigris was studied in one Phase 3, international, multi-centre, randomised, double-blind, placebo-controlled trial (PROWESS) in 1,690 patients with severe sepsis. Severe sepsis is defined as sepsis associated with acute organ dysfunction. Patients meeting the clinical diagnosis of severe sepsis had: a) known or suspected infection; b) clinical evidence of systemic response to infection, including fever or hypothermia, leucopenia or leucocytosis, tachycardia and tachypnoea; and c) acute organ dysfunction. Organ dysfunction was defined as shock, hypotension or the need for vasopressor support despite adequate fluid resuscitation, relative hypoxemia (ratio of partial pressure of oxygen in arterial blood in mmHg to the percentage of oxygen in the inspired air expressed as a decimal [PaO₂/FiO₂ ratio] <250), oliguria despite adequate fluid resuscitation, marked reduction in blood platelet counts, and/or elevated lactic acid concentrations.

Exclusion criteria encompassed patients at high risk of bleeding (see sections 4.3 and 4.4), patients who were not expected to survive for 28 days due to a pre-existing, non-sepsis related medical condition, HIV positive patients whose most recent CD₄ count was ³, patients on chronic dialysis, and patients who had undergone bone marrow, lung, liver, pancreas, or small bowel transplantation, and patients with acute clinical pancreatitis without a proven source of infection.

In the PROWESS trial, treatment was initiated within 48 hours of onset of the first sepsis-induced organ dysfunction. The median duration of organ dysfunction prior to treatment was 18 hours. Patients were given a 96-hour constant rate infusion of Xigris at 24μg/kg/hr (n = 850) or placebo (n = 840). Xigris was added to best standard care. Best standard care includes adequate antibiotics, source control and supportive treatment (fluids, inotropes, vasopressors and support of failing organs, as required).

Patients treated with Xigris experienced improved 28-day survival compared to those treated with placebo. At 28 days, the overall mortality rates were 24.7% for the Xigris-treated group and 30.8% for the placebo-treated group (P = 0.005).

Significant absolute death reduction was limited to the subgroup of patients with greater disease severity, i.e., baseline APACHE II score

A consistent treatment effect on mortality with Xigris administration was observed across patient subgroups defined by age, gender, and infection type.

PROWESS Follow-Up Study

Survival status was assessed in a follow-up study of PROWESS survivors. In-hospital and 3-month survival status was reported for 98% and 94% of the 1,690 PROWESS subjects, respectively. In the overall population, the in-hospital mortality was significantly lower in patients on Xigris than in patients on placebo (29.4% versus 34.6%; P = 0.023). Survival through 3 months was also better in the Xigris group compared to placebo (log rank P = 0.048). These data confirmed that the benefit of Xigris is limited to the more severely affected sepsis patients, such as patients with multiple organ failure and shock.

Further Clinical Experience

In a Phase 3b, international, single-arm, open-label clinical trial (ENHANCE), 2,378 adult patients with severe sepsis received drotrecogin alfa (activated). The entry criteria were similar to those employed in PROWESS. Patients received drotrecogin alfa (activated) within 48 hours of onset of the first sepsis-induced organ dysfunction. The median duration of organ dysfunction prior to treatment was 25 hours. At 28 days, the mortality rate in the Phase 3b study was 25.3%. The mortality rate was lower for patients treated within 24 hours of organ dysfunction compared to those treated after 24 hours, even after adjustment for differences in disease severity.

A total of 2,640 adult patients with severe sepsis who were at low risk of death (e.g., patients with APACHE II <25 or with only one sepsis-induced organ failure) were enrolled in a randomised, double-blind, placebo-controlled trial (ADDRESS). The trial was stopped for futility after an interim analysis.

No benefit of drotrecogin alfa (activated) was observed in the subgroup of 872 patients at low risk of death with multiple organ dysfunction, so ADDRESS did not confirm the efficacy results of the PROWESS study.

In the multiple organ dysfunction subgroup of ADDRESS the 28-day placebo mortality was 21.9%, similar to the single organ dysfunction subgroup of PROWESS (21.2%), confirming the lack of efficacy in patients with severe sepsis who are at low risk of death.

Paediatric Patients

Xigris is contraindicated in children below the age of 18 years (see also sections 4.2 and 4.3).

Data from a placebo-controlled clinical trial (RESOLVE) did not establish efficacy of Xigris in paediatric patients suffering from severe sepsis, acute infection, systemic inflammation and respiratory and cardiovascular organ dysfunction. This trial was stopped for futility after 477 patients had received the study drug (out of 600 patients intended). A planned interim analysis (with 400 patients enrolled) showed a low likelihood of demonstrating a significant difference in the primary endpoint of “Composite Time to Complete Organ Failure Resolution” (CTCOFR score of 9.8 versus 9.7 mean days over 14 days). There was also no difference in 28-day mortality (17.1% versus 17.3% in the Xigris and placebo groups, respectively).

Investigators attributed 2 deaths in the Xigris group and 5 deaths in the placebo group to bleeding events. There was a higher rate of central nervous system (CNS) bleeding in the drotrecogin alfa (activated) versus the placebo group. Over the infusion period (study days 0-6) the number of patients experiencing CNS bleeding was 5 versus 1 (2.1% versus 0.4%) for the overall population (drotrecogin alfa (activated) versus placebo), with 4 of the 5 events in the drotrecogin alfa (activated) group occurring in patients

In placebo controlled clinical trials, the treatment effect was most evident at sites enrolling larger numbers of patients.

5.2 Pharmacokinetic Properties

Drotrecogin alfa (activated) and endogenous human Activated Protein C are inactivated in plasma by endogenous protease inhibitors, but the mechanism by which they are cleared from plasma is unknown. Plasma concentrations of endogenous Activated Protein C in healthy subjects and patients with severe sepsis are usually below detection limits (<5ng/ml) and do not significantly influence the pharmacokinetic properties of drotrecogin alfa (activated).

In healthy subjects, greater than 90% of the steady-state condition is attained within 2 hours following the start of a constant-rate intravenous infusion of Xigris. Following the completion of an infusion, the decline in plasma drotrecogin alfa (activated) concentrations is biphasic and is comprised of a rapid initial phase (t_½α = 13 minutes) and a slower second phase (t_½β = 1.6 hours). The short half-life of 13 minutes accounts for approximately 80% of the area under the plasma concentration curve and governs the initial rapid accrual of plasma drotrecogin alfa (activated) concentrations towards the steady-state. Plasma drotrecogin alfa (activated) steady-state concentrations are proportional to the infusion rate over a range of infusion rates from 12μg/kg/hr to 48μg/kg/hr. The mean steady-state plasma concentration of drotrecogin alfa (activated) in healthy subjects receiving 24μg/kg/hr is 72ng/ml.

In patients with severe sepsis, infusion of drotrecogin alfa (activated) from 12μg/kg/hr to 30μg/kg/hr rapidly produced steady-state plasma concentrations that were proportional to infusion rates. In the Phase 3 trial, the pharmacokinetics of drotrecogin alfa (activated) were evaluated in 342 patients with severe sepsis administered a 96-hour continuous infusion at 24µg/kg/hr. The pharmacokinetics of drotrecogin alfa (activated) were characterised by attainment of steady-state plasma concentration within 2 hours following the start of the infusion. In the majority of patients, measurements of Activated Protein C beyond 2 hours after termination of the infusion were below the quantifiable limit, suggesting rapid elimination of drotrecogin alfa (activated) from the systemic circulation. The plasma clearance of drotrecogin alfa (activated) is approximately 41.8 l/hr in sepsis patients as compared with 28.1 l/hr in healthy subjects.

In patients with severe sepsis, the plasma clearance of drotrecogin alfa (activated) was significantly decreased by renal impairment and hepatic dysfunction, but the magnitude of the differences in clearance (<30%) does not warrant any dosage adjustment.

5.3 Preclinical Safety Data

Changes observed in monkeys at, or in small excess of, the maximum human exposure during repeated dose studies were all related to the pharmacological effect of Xigris and include, beside the expected prolongation of APTT, decreases in haemoglobin, erythrocytes and haematocrit and increases in reticulocyte count and PT.

Drotrecogin alfa (activated) was not mutagenic in an in vivo micronucleus study in mice or in an in vitro chromosomal aberration study in human peripheral blood lymphocytes with or without rat liver metabolic activation.

Carcinogenicity studies and animal reproduction studies have not been conducted with Xigris. However, with respect to the latter, the potential risk for humans being unknown, Xigris should not be used during pregnancy unless clearly necessary (see section 4.6).

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sucrose

Sodium chloride

Sodium citrate

Citric acid

Hydrochloric acid

Sodium hydroxide

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf Life

3 years.

After reconstitution, immediate use is recommended. However, the reconstituted solution in the vial may be held for up to 3 hours at room temperature (15ºC- 30ºC). After preparation, the intravenous infusion solution can be used at room temperature (15ºC- 30ºC) for a period up to 14 hours.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C-8°C). Keep the vial in the outer carton in order to protect it from light.

6.5 Nature And Contents Of Container

Powder in Type I glass vial. Pack of 1 vial.

6.6 Special Precautions For Disposal And Other Handling

1.	Use appropriate aseptic technique during the preparation of Xigris for intravenous administration.
2.	Calculate the dose and the number of Xigris vials needed.
	Xigris 5mg: Each Xigris vial contains 5mg of drotrecogin alfa (activated).
	Xigris 20mg: Each Xigris vial contains 20mg of drotrecogin alfa (activated).
	The vial contains an excess of drotrecogin alfa (activated) to facilitate delivery of the label amount.
3.	Xigris 5mg: Prior to administration, 5mg vials of Xigris must be reconstituted with 2.5ml of sterile water for injection, resulting in a solution with a concentration of approximately 2mg/ml drotrecogin alfa (activated).
	Xigris 20mg: Prior to administration, 20mg vials of Xigris must be reconstituted with 10ml of sterile water for injection, resulting in a solution with a concentration of approximately 2mg/ml drotrecogin alfa (activated).
	Slowly add the sterile water for injection to the vial and avoid inverting or shaking the vial. Gently swirl each vial until the powder is completely dissolved.
4.	The solution of reconstituted Xigris must be further diluted with sterile 0.9% sodium chloride injection to a final concentration of between 100μg/ml and 200μg/ml. Slowly withdraw the appropriate amount of reconstituted drotrecogin alfa (activated) solution from the vial. Add the reconstituted drotrecogin alfa (activated) into a prepared infusion bag of sterile 0.9% sodium chloride injection. When adding the reconstituted drotrecogin alfa (activated) into the infusion bag, direct the stream to the side of the bag to minimise the agitation of the solution. Gently invert the infusion bag to obtain a homogeneous solution. Do not transport the infusion bag between locations using mechanical delivery systems.
5.	After reconstitution, immediate use is recommended. However, the reconstituted solution in the vial may be held for up to 3 hours at room temperature (15 to 30ºC).
	After preparation, the intravenous infusion solution can be used at room temperature (15 to 30ºC) for a period up to 14 hours.
6.	Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration.
7.	It is recommended that Xigris be infused with an infusion pump to accurately control the infusion rate. The solution of reconstituted Xigris should be diluted into an infusion bag containing sterile 0.9% sodium chloride injection to a final concentration of between 100µg/ml and 200µg/ml.
8.	When administering drotrecogin alfa (activated) at low flow rates (less than approximately 5ml/hr), the infusion set must be primed for approximately 15 minutes at a flow rate of approximately 5ml/hr.
9.	Xigris should be administered via a dedicated intravenous line or a dedicated lumen of a multi-lumen central venous catheter. The ONLY other solutions that can be administered through the same line are 0.9% sodium chloride injection, lactated Ringer's injection, dextrose, or dextrose and saline mixtures.
10.	Avoid exposing drotrecogin alfa (activated) solutions to heat and/or direct sunlight. No incompatibilities have been observed between drotrecogin alfa (activated) and glass infusion bottles or infusion bags made of polyvinylchloride, polyethylene, polypropylene, or polyolefin. The use of other types of infusion sets could have a negative impact on the amount and potency of drotrecogin alfa (activated) administered.
11.	Care should be taken to administer Xigris at the appropriate rate, calculated based on kg of bodyweight and infused for the correct duration. It is recommended that the bag be labelled accordingly.

7. Marketing Authorisation Holder

Eli Lilly Nederland BV, Grootslag 1-5, 3991 RA Houten, The Netherlands.

8. Marketing Authorisation Number(S)

5mg vial:	EU/1/02/225/001
20mg vial:	EU/1/02/225/002

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation:	22 August 2002
Date of latest renewal: