Diprosis

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Diprosis uses

Diprosis consists of Betamethasone Dipropionate, Lactic Acid, Salicylic Acid, Sodium Lactate, Urea.

Betamethasone Dipropionate:



Diprosis (Betamethasone Dipropionate) Spray is indicated for the treatment of mild to moderate plaque psoriasis in patients 18 years of age or older.

Diprosis (Betamethasone Dipropionate) Spray is a corticosteroid indicated for the treatment of mild to moderate plaque psoriasis in patients 18 years of age or older. (1)

2 DOSAGE AND ADMINISTRATION

Shake well before use.

Apply Diprosis (Betamethasone Dipropionate) Spray to the affected skin areas twice daily and rub in gently.

Use Diprosis (Betamethasone Dipropionate) Spray for up to 4 weeks of treatment. Treatment beyond 4 weeks is not recommended.

Discontinue Diprosis (Betamethasone Dipropionate) Spray when control is achieved.

Do not use if atrophy is present at the treatment site.

Do not bandage, cover, or wrap the treated skin area unless directed by a physician.

Avoid use on the face, scalp, axilla, groin, or other intertriginous areas.

Diprosis (Betamethasone Dipropionate) Spray is for topical use only. It is not for oral, ophthalmic, or intravaginal use.

  • Apply to the affected skin areas twice daily. Rub in gently. (2)
  • Use Diprosis (Betamethasone Dipropionate) Spray for up to 4 weeks and not beyond. (2)
  • Discontinue treatment when control is achieved. (2)
  • Do not use if atrophy is present at the treatment site. (2)
  • Do not use with occlusive dressings unless directed by a physician. (2)
  • Avoid use on the face, scalp, axilla, groin, or other intertriginous areas. (2)
  • Not for oral, ophthalmic, or intravaginal use. (2)
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3 DOSAGE FORMS AND STRENGTHS

Spray, 0.05% for topical use. Each gram of Diprosis (Betamethasone Dipropionate) Spray contains 0.643 mg Diprosis (Betamethasone Dipropionate) USP (equivalent to 0.5 mg betamethasone) in a slightly thickened, white to off-white oil-in-water emulsion.

Spray: 0.05% (equivalent to 0.5 mg betamethasone/g) (3)

4 CONTRAINDICATIONS

None.

  • None. (4)

5 WARNINGS AND PRECAUTIONS

  • Diprosis Spray can produce reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency during or after treatment. (5.1)
  • Cushing's syndrome, hyperglycemia, and unmasking of latent diabetes mellitus can result from systemic absorption of topical corticosteroids. (5.1)
  • Use of topical corticosteroids may require periodic evaluation for HPA axis suppression. (5.1)
  • Modify use if HPA axis suppression develops. (5.1)
  • High potency corticosteroids, large treatment surface areas, prolonged use, use of occlusive dressings, altered skin barrier, liver failure and young age may predispose patients to HPA axis suppression. (5.1)
  • Pediatric patients may be more susceptible to systemic toxicity when treated with topical corticosteroids. (5.1, 8.4)

5.1 Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression and Other Unwanted Systemic Glucocorticoid Effects

Diprosis (Betamethasone Dipropionate) Spray can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during or after withdrawal of treatment. Factors that predispose to HPA axis suppression include the use of high-potency corticosteroids, large treatment surface areas, prolonged use, use of occlusive dressings, altered skin barrier, liver failure, and young age.

Evaluation for HPA axis suppression may be done by using the adrenocorticotropic hormone (ACTH) stimulation test.

In a study including 48 evaluable subjects 18 years of age or older with moderate to severe plaque psoriasis, abnormal ACTH stimulation test results suggestive of adrenal suppression were identified in 5 out of 24 (20.8%) subjects after treatment with Diprosis (Betamethasone Dipropionate) Spray twice daily for 15 days. No subject (0 out of 24) had abnormal ACTH stimulation test results after treatment with Diprosis (Betamethasone Dipropionate) Spray twice daily for 29 days .

If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent corticosteroid. If signs and symptoms of steroid withdrawal occur, supplemental systemic corticosteroids may be required.

Systemic effects of topical corticosteroids may also manifest as Cushing’s syndrome, hyperglycemia, and glucosuria. These events are rare and generally occur after prolonged exposure to larger than recommended doses, particularly with high-potency topical corticosteroids.

Minimize the unwanted risks from endocrine effects by mitigating the risk factors favoring increased systemic bioavailability and by using the product as recommended .

Pediatric patients may be more susceptible to systemic toxicity due to their larger skin surface to body mass ratios. Use of Diprosis (Betamethasone Dipropionate) Spray is not recommended in pediatric patients .

5.2 Allergic Contact Dermatitis

Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation. Corroborate such an observation with appropriate diagnostic patch testing. If irritation develops, discontinue the topical corticosteroid and institute appropriate therapy.

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6 ADVERSE REACTIONS

The most common adverse reactions are application site reactions, including pruritus, burning and/or stinging, pain, and atrophy. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Promius Pharma, LLC. at 1-888-966-8766 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience

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

In two randomized, multicenter, prospective vehicle-controlled clinical trials, subjects with moderate plaque psoriasis of the body applied Diprosis (Betamethasone Dipropionate) Spray or vehicle spray twice daily for 4 weeks. A total of 352 subjects applied Diprosis (Betamethasone Dipropionate) Spray and 180 subjects applied vehicle spray.

Adverse reactions that occurred in at least 1% of subjects treated with Diprosis (Betamethasone Dipropionate) Spray for up to 28 days are presented in Table 1.

Diprosis (Betamethasone Dipropionate) Spray b.i.d.

(N=352)

Vehicle Spray b.i.d.

(N=180)

Application site pruritus 6.0% 9.4%
Application site burning

and/or stinging

4.5% 10.0%
Application site pain 2.3% 3.9%
Application site atrophy 1.1% 1.7%

Less common adverse reactions (with occurrence lower than 1% but higher than 0.1%) in subjects treated with Diprosis (Betamethasone Dipropionate) spray were application site reactions including telangiectasia, dermatitis, discoloration, folliculitis and skin rash, in addition to dysgeusia and hyperglycemia. These adverse reactions were not observed in subjects treated with vehicle.

6.2 Postmarketing Experience

Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Postmarketing reports for local adverse reactions to topical corticosteroids have also included striae, irritation, dryness, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, hypertrichosis, and miliaria.

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8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

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

Diprosis (Betamethasone Dipropionate) has been shown to be teratogenic in rabbits when given by the intramuscular route at doses of 0.05 mg/kg. The abnormalities observed included umbilical hernias, cephalocele, and cleft palate.

8.3 Nursing Mothers

Systemically administered corticosteroids appear in human milk and can suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids can result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Diprosis (Betamethasone Dipropionate) Spray is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Diprosis Spray in patients younger than 18 years of age have not been studied; therefore use in pediatric patients is not recommended. Because of a higher ratio of skin surface area to body mass, pediatric patients are at greater risk of systemic toxicity, including HPA axis suppression and adrenal insufficiency, when treated with topical drugs. [see Warnings and Precautions (5.1)]

Rare systemic effects such as Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients, especially those with prolonged exposure to large doses of high potency topical corticosteroids.

Local adverse reactions including skin atrophy have also been reported with use of topical corticosteroids in pediatric patients.

8.5 Geriatric Use

Clinical studies of Diprosis (Betamethasone Dipropionate) Spray did not include sufficient numbers of subjects who were 65 years of age or older to determine whether they respond differently from younger subjects.

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11 DESCRIPTION

Diprosis (Betamethasone Dipropionate) Spray contains 0.0643% Diprosis (Betamethasone Dipropionate) (equivalent to 0.05% betamethasone), a synthetic, fluorinated corticosteroid.

The chemical name for Diprosis (Betamethasone Dipropionate) is 9-fluoro-11(β), 17, 21-trihydroxy-16(β)-methylpregna-1,4-diene-3,20-dione-17,21-dipropionate. The empirical formula is C28H37FO7 and the molecular weight is 504.6. The structural formula is shown below.

Each gram of Diprosis (Betamethasone Dipropionate) Spray contains 0.643 mg of Diprosis (Betamethasone Dipropionate) USP (equivalent to 0.5 mg betamethasone) in a slightly thickened, white to off-white, oil-in-water, non-sterile emulsion with the following inactive ingredients:, butylated hydroxytoluene, cetostearyl alcohol, hydroxyethyl cellulose, methylparaben, mineral oil, oleyl alcohol, polyoxyl 20 cetostearyl ether, propylparaben, purified water, and sorbitan monostearate. Diprosis (Betamethasone Dipropionate) Spray is co-packaged with a manual spray pump for installation by the pharmacist prior to dispensing to patients.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Corticosteroids play a role in cellular signaling, immune function, inflammation, and protein regulation; however, the precise mechanism of action of Diprosis Spray in psoriasis is unknown.

12.2 Pharmacodynamics

Vasoconstrictor studies performed with Diprosis (Betamethasone Dipropionate) Spray in healthy subjects indicate that it is in the mid-range of potency as compared with other topical corticosteroids; however, similar blanching scores do not necessarily imply therapeutic equivalence.

The potential for HPA axis suppression by Diprosis (Betamethasone Dipropionate) Spray was evaluated in a study randomizing 52 adult subjects with moderate to severe plaque psoriasis. Diprosis (Betamethasone Dipropionate) Spray was applied twice daily for 15 or 29 days, in subjects with psoriasis involving a mean of 29.0% and 26.5% body surface area at baseline across the 2 treatment duration arms, respectively. Forty-eight (48) subjects were evaluated for HPA axis suppression at the end of treatment. The proportion of subjects demonstrating HPA axis suppression was 20.8% (5 out of 24) in subjects treated with Diprosis (Betamethasone Dipropionate) Spray for 15 days. No subjects (0 out of 24) treated with Diprosis (Betamethasone Dipropionate) Spray for 29 days had HPA axis suppression. In this study HPA axis suppression was defined as serum cortisol level ≤18 mcg/dL 30-minutes post-cosyntropin stimulation. In the 4 subjects with available follow-up values, all subjects had normal ACTH stimulation tests at follow-up.

12.3 Pharmacokinetics

The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings.

Topical corticosteroids are absorbed through normal intact skin. Inflammation and/or other disease processes in the skin may increase percutaneous absorption.

Plasma concentrations of Diprosis (Betamethasone Dipropionate), betamethasone-17-propionate, and betamethasone were measured at baseline, and before and after the last dose (1, 3, and 6 hours) in the HPA axis suppression trial in subjects with psoriasis [see Clinical Pharmacology (12.2)]. The majority of subjects had no measurable plasma concentration (<5.00 pg/mL) of Diprosis (Betamethasone Dipropionate), while the metabolites, betamethasone-17-propionate and betamethasone, were detected in the majority of subjects (Table 2). There was high variability in the data but there was a trend toward higher systemic exposure at Day 15 and lower systemic exposure at Day 29.

Analyte (pg/mL) Diprosis (Betamethasone Dipropionate) Spray b.i.d.

(15 days)

Diprosis (Betamethasone Dipropionate) Spray b.i.d.

(29 days)

Betamethasone-17-propionate 120 ± 127 63.9 ± 52.6
Betamethasone 119 ± 176 57.6 ± 55.9

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of Diprosis (Betamethasone Dipropionate).

In a 90-day repeat-dose toxicity study in rats, topical administration of Diprosis (Betamethasone Dipropionate) spray formulation at dose concentrations of 0.05% and 0.1% (providing dose levels up to 0.5 mg/kg/day in males and 0.25 mg/kg/day in females) resulted in a toxicity profile consistent with long-term exposure to corticosteroids including reduced body weight gain, adrenal atrophy, and histological changes in bone marrow, thymus and spleen indicative of severe immune suppression. A no observable adverse effect level (NOAEL) could not be determined in this study. Although the clinical relevance of the findings in animals to humans is not clear, sustained glucocorticoid-related immune suppression may increase the risk of infection and possibly the risk of carcinogenesis.

Betamethasone was negative in the bacterial mutagenicity assay (Salmonella typhimurium and Escherichia coli), and in the mammalian cell mutagenicity assay (CHO/HGPRT). It was positive in the in vitro human lymphocyte chromosome aberration assay, and equivocal in the in vivo mouse bone marrow micronucleus assay.

Studies in rabbits, mice, and rats using intramuscular doses up to 1, 33, and 2 mg/kg, respectively, resulted in dose-related increases in fetal resorptions in rabbits and mice.

14 CLINICAL STUDIES

Two multi-center, randomized, double-blind, vehicle-controlled clinical trials were conducted in subjects aged 18 years and older with moderate plaque psoriasis. In both trials, randomized subjects applied Diprosis (Betamethasone Dipropionate) Spray or vehicle spray to the affected areas twice daily for 28 days. Enrolled subjects had body surface area of involvement between 10% to 20%, and an Investigator Global Assessment (IGA) score of 3 (moderate).

Efficacy was assessed as the proportion of subjects who were considered a treatment success (defined as having an IGA score of 0 or 1 [clear or almost clear] and at least a 2-grade reduction from baseline). Table 3 presents the efficacy results at Day 15 and Day 29.

a Treatment success is defined as an IGA of 0 or 1 (clear or almost clear) and at least a 2-grade reduction

from baseline.

Study 1 Study 2
Diprosis (Betamethasone Dipropionate) Spray

b.i.d.

(N=182)

Vehicle Spray

b.i.d.

(N=95)

Diprosis (Betamethasone Dipropionate) Spray

b.i.d.

(N=174)

Vehicle Spray

b.i.d.

(N=87)

Treatment Success

at Day 15

21.5% 7.4% 19.0% 2.3%
Treatment Success

at Day 29

42.7% 11.7% 34.5% 13.6%

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied/Storage

Diprosis Spray is a slightly thickened, white to off-white, non-sterile emulsion supplied in high density polyethylene bottles with a heat induction seal lined polypropylene cap. The drug is supplied in the following volumes:

  • 60 mL (NDC 67857-808-17)
  • 120 mL (NDC 67857-808-04)

Store at controlled room temperature of 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) .

Each unit is co-packaged with a manual spray pump for installation by the pharmacist prior to dispensing.

16.2 Handling/Instructions for the Pharmacist

  • Remove the spray pump from the wrapper.
  • Remove and discard the cap from the bottle.
  • Keeping the bottle upright, insert the spray pump into the bottle and turn clockwise until it is closed tightly.
  • Dispense the bottle with the spray pump inserted.
  • Include the date dispensed in the space provided on the carton.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Inform patients of the following:

  • Discontinue therapy when control is achieved, unless directed otherwise by the physician.
  • Do not use for longer than 4 consecutive weeks.
  • Avoid contact with the eyes.
  • Avoid use of Diprosis (Betamethasone Dipropionate) Spray on the face, scalp, underarms, groin or other intertriginous areas, unless directed by the physician.
  • Do not occlude the treatment area with bandage or other covering, unless directed by the physician.
  • Local reactions and skin atrophy are more likely to occur with occlusive use, prolonged use, or use of higher potency corticosteroids.

Manufactured by: DPT Laboratories, Ltd., San Antonio, TX 78215

Distributed by: Promius Pharma, LLC., Princeton, NJ 08540

Diprosis (Betamethasone Dipropionate) is a trademark of Promius Pharma, LLC.

Issued: 02/2016

007465

140728

This Patient Information has been approved by the U.S. Food and Drug Administration Issued: 02/2016
PATIENT INFORMATION

Diprosis (Betamethasone Dipropionate) (ser-ne-vo)

(betamethasone dipropionate)

Spray, 0.05%

Important: Diprosis (Betamethasone Dipropionate) Spray is for use on the skin only. Do not get Diprosis (Betamethasone Dipropionate) Spray near or in your eyes, mouth, or vagina.

What is Diprosis (Betamethasone Dipropionate) Spray?

  • Diprosis (Betamethasone Dipropionate) Spray is a prescription corticosteroid medicine used to treat mild to moderate plaque psoriasis in people 18 years of age and older.

It is not known if Diprosis (Betamethasone Dipropionate) Spray is safe and effective in children under 18 years of age. Diprosis (Betamethasone Dipropionate) Spray is not recommended for use in patients under 18 years of age.


Before you use Diprosis (Betamethasone Dipropionate) Spray, tell your doctor about all of your medical conditions, including if you:

  • are allergic to any of the ingredients in Diprosis (Betamethasone Dipropionate) Spray. See the end of this leaflet for a list of the ingredients in Diprosis (Betamethasone Dipropionate) Spray.
  • have thinning of the skin (atrophy) at the treatment site
  • are pregnant or plan to become pregnant. It is not known if Diprosis (Betamethasone Dipropionate) Spray will harm your unborn baby.
  • are breastfeeding or plan to breastfeed. It is not known if Diprosis (Betamethasone Dipropionate) Spray passes into breast milk.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your doctor if you take other corticosteroid medicines by mouth or use other products on your skin that contain corticosteroids.


How should I use Diprosis (Betamethasone Dipropionate) Spray?

See the “Instructions for Use” for detailed information about the right way to apply Diprosis (Betamethasone Dipropionate) Spray.

  • Use Diprosis (Betamethasone Dipropionate) Spray exactly as your doctor tells you to use it.
  • Your doctor should tell you how much Diprosis (Betamethasone Dipropionate) Spray to use and where to apply it.
  • Apply Diprosis (Betamethasone Dipropionate) Spray 2 times a day.
  • Use Diprosis (Betamethasone Dipropionate) Spray for the shortest amount of time needed to treat your plaque psoriasis. Tell your doctor if your skin condition is not getting better after 4 weeks of using Diprosis (Betamethasone Dipropionate) Spray. Do not use Diprosis (Betamethasone Dipropionate) Spray for longer than 4 weeks.
  • Wash your hands after applying Diprosis (Betamethasone Dipropionate) Spray.
  • Do not use Diprosis (Betamethasone Dipropionate) Spray on your face, scalp, underarms (armpits), groin, or areas where your skin may touch or rub together.
  • Do not bandage, cover, or wrap the treated skin area, unless your doctor tells you to.

What are the possible side effects of Diprosis (Betamethasone Dipropionate) Spray?

  • Diprosis (Betamethasone Dipropionate) Spray can pass through your skin. Too much Diprosis (Betamethasone Dipropionate) Spray passing through your skin can cause your adrenal glands to stop working. Your doctor may do blood tests to check for adrenal gland problems.

The most common side effects of Diprosis (Betamethasone Dipropionate) Spray include itching, burning, stinging, pain, and thinning of skin (atrophy) at the treated site.

These are not all the possible side effects of Diprosis (Betamethasone Dipropionate) Spray.

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


How should I store Diprosis (Betamethasone Dipropionate) Spray?

  • Store Diprosis (Betamethasone Dipropionate) Spray at room temperature between 68°F to 77°F (20°C to 25°C)
  • Throw away (discard) any unused Diprosis (Betamethasone Dipropionate) Spray after 4 weeks.

Keep Diprosis (Betamethasone Dipropionate) Spray and all medicines out of the reach of children.


General information about the safe and effective use of Diprosis (Betamethasone Dipropionate) Spray.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Diprosis (Betamethasone Dipropionate) Spray for a condition for which it was not prescribed. Do not give Diprosis (Betamethasone Dipropionate) Spray to other people even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or doctor for information about Diprosis (Betamethasone Dipropionate) Spray that is written for health professionals.


What are the ingredients in Diprosis (Betamethasone Dipropionate) Spray?

Active ingredient: Diprosis (Betamethasone Dipropionate)

Inactive ingredients: butylated hydroxytoluene, cetostearyl alcohol, hydroxyethyl cellulose, methylparaben, mineral oil, oleyl alcohol, polyoxyl 20 cetostearyl ether, propylparaben, purified water, and sorbitan monostearate

Manufactured by: DPT Laboratories, Ltd., San Antonio, TX 78215

Distributed by: Promius Pharma, LLC., Princeton, NJ 08540

007465

140728


Instructions for Use

Diprosis (Betamethasone Dipropionate) (ser-ne-vo)

(betamethasone dipropionate)

Spray, 0.05%

Important: Diprosis (Betamethasone Dipropionate) Spray is for use on the skin only. Do not get Diprosis (Betamethasone Dipropionate) Spray near or in your eyes, mouth, or vagina.

Read this “Instructions for Use” before you start using Diprosis (Betamethasone Dipropionate) Spray and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment.

Parts of the Diprosis (Betamethasone Dipropionate) Spray bottle.

Figure A

How to apply Diprosis (Betamethasone Dipropionate) Spray:

Step 1: Shake the Diprosis (Betamethasone Dipropionate) Spray bottle well. Remove the cap from the pump top.

Step 2: Hold the bottle in an upright position while pointing the opening of the pump top in the direction of the affected area. To spray, push down on the pump top. Apply Diprosis (Betamethasone Dipropionate) Spray to the affected area as instructed by your doctor. (See Figure B )

Figure B

Step 3: Spray only enough Diprosis (Betamethasone Dipropionate) Spray to cover the affected area, for example, the elbow (See Figure C ). Rub in Diprosis (Betamethasone Dipropionate) Spray gently.

Figure C

Repeat Steps 2 and 3 to apply Diprosis (Betamethasone Dipropionate) Spray to other affected areas as instructed by your doctor.

Step 4: After applying Diprosis (Betamethasone Dipropionate) Spray, place the cap back onto the pump top. (See Figure D )

Figure D

How should I store Diprosis (Betamethasone Dipropionate) Spray?

  • Store Diprosis (Betamethasone Dipropionate) Spray at room temperature between 68°F to 77°F (20°C to 25°C).
  • Throw away (discard) any unused Diprosis (Betamethasone Dipropionate) Spray after 28 days.

Keep Diprosis (Betamethasone Dipropionate) Spray and all medicines out of the reach of children.

This “Instructions for Use” has been approved by the U.S. Food and Drug Administration.

Manufactured by: DPT Laboratories, Ltd., San Antonio, TX 78215

Distributed by: Promius Pharma, LLC., Princeton, NJ 08540

Diprosis (Betamethasone Dipropionate) is a trademark of Promius Pharma, LLC.

Issued: 02/2016

007528

140693

Lactic Acid:



FOR INDUSTRIAL USE ONLY

KEEP OUT OF REACH OF CHILDREN

NOT FOR HUMAN USE

Attention

For External Use Only

Wash hands thoroughly after handling.

Do not mix with bleach or other chlorinated products – will cause chlorine gas.

Get medical advice/ attention if you feel unwell.

DIRECTIONS:

IMPORTANT: Do not further dilute with water or mix with any other teat dips. If product in dip cup becomes visibly dirty, discard contents and replenish with fresh product. Do not reuse or return any unused product to the original container.

Udder Prep: When using an udder wash step before milking, make sure to wash teats with appropriate udder wash solution using proper cleaning procedures. Teats should then be dried with single-service towels.

Directions for Teat Dipping

Pre-Milk Dipping: Before each cow is milked, and using fresh Diprosis (Lactic Acid), dip each teat full-length into the teat dip cup. Wipe teats after dipping using single-service towels to avoid contamination of milk.

Post-Milk Dipping: Using fresh Diprosis (Lactic Acid), dip each teat full-length into the teat dip cup. Do not wipe. Allow to air dry. Do not turn cows out in freezing weather until the product is completely dry.

Directions for Teat Spraying

Pre-Milk Spraying: Before each cow is milked, and using fresh Diprosis (Lactic Acid), spray entire teat. Wipe teats after dipping using single-service towels to avoid contamination of milk.

Post-Milk Spraying: Using fresh Diprosis (Lactic Acid), spray entire teat immediately after each milking. Do not wipe. Allow to air dry. Do not turn cows out in freezing weather until the product is completely dry.

Expanded Usage: When freshening cows, begin dipping teats twice daily for about 10 days before calving. PRECAUTION: Diprosis (Lactic Acid) is not intended to cure or help the healing of chapped or irritated teats. As with any germicide, irritation or sensitization may occur in sensitive animals. In case of teat irritation or chapping, have the condition examined and, if necessary, treated by a veterinarian.

Consult your Ecolab representative for specific use instructions and recommended dispensing equipment.

READ SAFETY DATA SHEET (SDS) BEFORE USING THIS PRODUCT

EMERGENCY HEALTH INFORMATION: 1 800 328 0026. If located outside the United States and Canada, call collect 1 651 222 5352 (number is in the US).

Ecolab

Diprosis (Lactic Acid)

Sanitizing Teat Dip

An Aid in Reducing the Spread of Organisms Which May Cause Mastitis

ACTIVE INGREDIENTS:

Diprosis (Lactic Acid) acid... 1.7%

Hydrogen peroxide... 0.5%

INERT INGREDIENTS:... 97.8%

(contains glycerin, sorbitol)

TOTAL:...100.0%

56.8 L (15 US GAL)

6301977

Ecolab · 1 Ecolab Place · St Paul MN 55102 USA · tel: 1 800 392 3392

© 2016 Ecolab USA Inc. · All rights reserved

www.ecolab.com · 766469/5300/1016



Salicylic Acid:


Pharmacological action

Diprosis is pharmaceytical active ingredient for topical use. Inhibits the secretion of the sebaceous and sweat glands. At low concentrations it has keratoplastic and in high doses keratolytic effect. Diprosis (Salicylic Acid) has a weak antimicrobial activity.

Why is Diprosis (Salicylic Acid) prescribed?

Monotherapy with Diprosis (Salicylic Acid) and as part of combination therapies for inflammatory, infectious and other skin lesions, including burns, psoriasis, eczema, dyskeratosis, ichthyosis, acne vulgaris, warts, hyperkeratosis, corn, callus, oily seborrhea, scaly skin disease, hair loss, sweating feet.

Dosage and administration

Diprosis is applied to the skin surface 2-3 times / day.

Diprosis (Salicylic Acid) side effects, adverse reactions

Rarely: local reactions such as itching, burning, skin rashes, allergic reactions.

Diprosis contraindications

Hypersensitivity to Diprosis (Salicylic Acid), renal failure, infancy.

Special instructions

The composition of the solution for topical use include ethanol.

Diprosis drug interactions

Diprosis (Salicylic Acid) is pharmaceutically not compatible with resorcinol (forms melted mixture) and zinc oxide (forms insoluble forms of zinc salicylate).

Sodium Lactate:


1 INDICATIONS AND USAGE

Diprosis nitrite is indicated for sequential use with Diprosis (Sodium Lactate) thiosulfate for treatment of acute cyanide poisoning that is judged to be life-threatening. (1)

  • Use with caution if the diagnosis of cyanide poisoning is uncertain. (1)

1.1 Indication

Diprosis (Sodium Lactate) Nitrite Injection is indicated for sequential use with Diprosis (Sodium Lactate) thiosulfate for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with Diprosis (Sodium Lactate) Nitrite Injection should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

1.2 Identifying Patients with Cyanide Poisoning

Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to Diprosis nitroprusside.

The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Diprosis (Sodium Lactate) Nitrite Injection and Diprosis (Sodium Lactate) Thiosulfate Injection should be administered without delay.

Symptoms Signs
  • Headache
  • Confusion
  • Dyspnea
  • Chest Tightness
  • Nausea
  • Altered Mental Status

    (e.g., confusion, disorientation)

  • Seizures or Coma
  • Mydriasis
  • Tachypnea/Hyperpnea (early)
  • Bradypnea/Apnea (late)
  • Hypertension (early)/ Hypotension (late)
  • Cardiovascular Collapse
  • Vomiting
  • Plasma Lactate Concentration ≥ 8 mmol/L

In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.

The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.

Smoke Inhalation

Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Diprosis (Sodium Lactate) Nitrite Injection, smoke-inhalation victims should be assessed for the following:

  • Exposure to fire or smoke in an enclosed area
  • Presence of soot around the mouth, nose, or oropharynx
  • Altered mental status

Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.

1.3 Use with Other Cyanide Antidotes

Caution should be exercised when administering cyanide antidotes, other than Diprosis (Sodium Lactate) thiosulfate, simultaneously with Diprosis (Sodium Lactate) Nitrite Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than Diprosis (Sodium Lactate) thiosulfate, with Diprosis (Sodium Lactate) Nitrite Injection, these drugs should not be administered concurrently in the same IV line. [see Dosage and Administration (2.2) ]

2 DOSAGE AND ADMINISTRATION

Age Intravenous Dose of Diprosis Nitrite and Diprosis (Sodium Lactate) Thiosulfate
Adults
  • Diprosis (Sodium Lactate) Nitrite -10 mL of Diprosis (Sodium Lactate) nitrite at the rate of 2.5 to 5 mL/minute
  • Diprosis (Sodium Lactate) Thiosulfate - 50 mL of Diprosis (Sodium Lactate) thiosulfate immediately following administration of Diprosis (Sodium Lactate) nitrite.
Children
  • Diprosis (Sodium Lactate) Nitrite - 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Diprosis (Sodium Lactate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Diprosis (Sodium Lactate) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Diprosis (Sodium Lactate) nitrite.

Redosing: If signs of cyanide poisoning reappear, repeat treatment using one-half the original dose of both Diprosis (Sodium Lactate) nitrite and Diprosis (Sodium Lactate) thiosulfate.

Monitoring: Blood pressure must be monitored during treatment. (2.2)

2.1 Administration Recommendation

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of Diprosis (Sodium Lactate) nitrite, followed by Diprosis (Sodium Lactate) thiosulfate, should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer Diprosis (Sodium Lactate) nitrite and Diprosis (Sodium Lactate) thiosulfate.

Diprosis (Sodium Lactate) nitrite injection and Diprosis (Sodium Lactate) thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Diprosis (Sodium Lactate) nitrite should be administered first, followed immediately by Diprosis (Sodium Lactate) thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.

Age Intravenous Dose of Diprosis (Sodium Lactate) Nitrite and Diprosis (Sodium Lactate) Thiosulfate
Adults
  • Diprosis (Sodium Lactate) Nitrite -10 mL of Diprosis (Sodium Lactate) nitrite at the rate of 2.5 to 5 mL/minute
  • Diprosis (Sodium Lactate) Thiosulfate - 50 mL of Diprosis (Sodium Lactate) thiosulfate immediately following administration of Diprosis (Sodium Lactate) nitrite.
Children
  • Diprosis (Sodium Lactate) Nitrite -0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of Diprosis (Sodium Lactate) nitrite at the rate of 2.5 to 5 mL/minute not to exceed 10 mL
  • Diprosis (Sodium Lactate) Thiosulfate - 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) not to exceed 50 mL total dose immediately following administration of Diprosis (Sodium Lactate) nitrite.

NOTE: If signs of poisoning reappear, repeat treatment using one-half the original dose of both Diprosis (Sodium Lactate) nitrite and Diprosis (Sodium Lactate) thiosulfate.

In adult and pediatric patients with known anemia, it is recommended that the dosage of Diprosis (Sodium Lactate) nitrite should be reduced proportionately to the hemoglobin concentration.

All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

2.2 Recommended Monitoring

Patients should be monitored for at least 24-48 hours after Diprosis Nitrite Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO2 are unreliable in the presence of methemoglobinemia.

Methemoglobin level: Administrations of Diprosis (Sodium Lactate) nitrite solely to achieve an arbitrary level of methemoglobinemia may be unnecessary and potentially hazardous. The therapeutic effects of Diprosis (Sodium Lactate) nitrite do not appear to be mediated by methemoglobin formation alone and clinical responses to Diprosis (Sodium Lactate) nitrite administration have been reported in association with methemoglobin levels of less than 10%. Administration of Diprosis (Sodium Lactate) nitrite beyond the initial dose should be guided primarily by clinical response to treatment (i.e., a second dose should be considered only if there is inadequate clinical response to the first dose). It is generally recommended that methemoglobin concentrations be closely monitored and kept below 30%. Serum methemoglobin levels should be monitored during treatment using co-oximetry, and administration of Diprosis (Sodium Lactate) nitrite should generally be discontinued when methemoglobin levels exceed 30%. Intravenous methylene blue and exchange transfusion have been reported in the literature as treatments for life-threatening methemoglobinemia.

2.3 Incompatibility Information

Chemical incompatibility has been reported between Diprosis (Sodium Lactate) nitrite and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line. No chemical incompatibility has been reported between Diprosis (Sodium Lactate) thiosulfate and Diprosis (Sodium Lactate) nitrite, when administered sequentially through the same IV line as described in Dosage and Administration.

3 DOSAGE FORMS AND STRENGTHS

Diprosis (Sodium Lactate) Nitrite Injection consists of:

  • One vial of Diprosis (Sodium Lactate) nitrite injection, USP 300 mg/10mL (30 mg/mL)

Administration of the contents of one vial constitutes a single dose.

  • Injection, 300 mg/10 mL (30 mg/mL). (3)

4 CONTRAINDICATIONS

None

  • None. (4)

5 WARNINGS AND PRECAUTIONS

  • Methemoglobinemia: Diprosis nitrite reacts with hemoglobin to form methemoglobin and should be used with caution in patients known to have anemia. Monitor oxyhemoglobin and methemoglobin levels by pulse oximetry or other measurements. Optimally, the Diprosis (Sodium Lactate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.2)
  • Smoke inhalation: Carbon monoxide contained in smoke can result in the formation of carboxyhemoglobin that can reduce the oxygen carrying capacity of the blood. Diprosis (Sodium Lactate) nitrite should be used with caution in patients with smoke inhalation injury because of the potential for worsening hypoxia due to methemoglobin formation. Carboxyhemoglobin and oxyhemoglobin levels should be monitored by pulse oximetry or other measurements in patients that present with evidence of smoke inhalation. Optimally, the Diprosis (Sodium Lactate) nitrite dose should be reduced in proportion to the oxygen carrying capacity. (5.4)

5.1 Hypotension

5.2 Methemoglobinemia

Supportive care alone may be sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious patients without signs of severe toxicity. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with Diprosis nitrite.

Methemoglobin levels should be monitored and oxygen administered during treatment with Diprosis (Sodium Lactate) nitrite whenever possible. When Diprosis (Sodium Lactate) nitrite is administered to humans a wide range of methemoglobin concentrations occur. Methemoglobin concentrations as high as 58% have been reported after two 300-mg doses of Diprosis (Sodium Lactate) nitrite administered to an adult. Diprosis (Sodium Lactate) nitrite should be used with caution in the presence of other drugs that may cause methemoglobinemia such as procaine and nitroprusside. Diprosis (Sodium Lactate) nitrite should be used with caution in patients who may be particularly susceptible to injury from vasodilation and its related hemodynamic sequelae. Hemodynamics should be monitored closely during and after administration of Diprosis (Sodium Lactate) nitrite, and infusion rates should be slowed if hypotension occurs.

5.3 Anemia

Diprosis (Sodium Lactate) nitrite should be used with caution in patients with known anemia. Patients with anemia will form more methemoglobin (as a percentage of total hemoglobin) than persons with normal red blood cell (RBC) volumes. Optimally, these patients should receive a Diprosis (Sodium Lactate) nitrite dose that is reduced in proportion to their oxygen carrying capacity.

5.4 Smoke Inhalation Injury

Diprosis nitrite should be used with caution in persons with smoke inhalation injury or carbon monoxide poisoning because of the potential for worsening hypoxia due to methemoglobin formation.

5.5 Neonates and Infants

Neonates and infants may be more susceptible than adults and older pediatric patients to severe methemoglobinemia when Diprosis (Sodium Lactate) nitrite is administered. Reduced dosing guidelines should be followed in pediatric patients.

5.6 G6PD Deficiency

Because patients with G6PD deficiency are at increased risk of a hemolytic crisis with Diprosis nitrite administration, alternative therapeutic approaches should be considered in these patients. Patients with known or suspected G6PD deficiency should be monitored for an acute drop in hematocrit. Exchange transfusion may be needed for patients with G6PD deficiency who receive Diprosis (Sodium Lactate) nitrite.

5.7 Use with Other Drugs

Diprosis (Sodium Lactate) nitrite should be used with caution in the presence of concomitant antihypertensive medications, diuretics or volume depletion due to diuretics, or drugs known to increase vascular nitric oxide, such as PDE5 inhibitors.

6 ADVERSE REACTIONS

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of Diprosis (Sodium Lactate) nitrite.

The medical literature has reported the following adverse events in association with Diprosis (Sodium Lactate) nitrite administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.

Cardiovascular system: syncope, hypotension, tachycardia, methemoglobinemia, palpitations, dysrhythmia

Hematological: methemoglobinemia

Central nervous system: headache, dizziness, blurred vision, seizures, confusion, coma

Gastrointestinal system: nausea, vomiting, abdominal pain

Respiratory system: tachypnea, dyspnea

Body as a Whole: anxiety, diaphoresis, lightheadedness, injection site tingling, cyanosis, acidosis, fatigue, weakness, urticaria, generalized numbness and tingling

Severe hypotension, methemoglobinemia, cardiac dysrhythmias, coma and death have been reported in patients without life-threatening cyanide poisoning but who were treated with injection of Diprosis (Sodium Lactate) nitrite at doses less than twice those recommended for the treatment of cyanide poisoning.

Most common adverse reactions are:

  • Syncope, hypotension, tachycardia, palpitations, dysrhythmia, methemoglobinemia, headache, dizziness, blurred vision, seizures, confusion, coma (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hope Pharmaceuticals at 1-800-755-9595 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

Formal drug interaction studies have not been conducted with Diprosis (Sodium Lactate) Nitrite Injection.

8 USE IN SPECIFIC POPULATIONS

  • Renal impairment: Diprosis nitrite is substantially excreted by the kidney. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. (8.6).

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C.

There are no adequate and well-controlled studies in pregnant women. Diprosis (Sodium Lactate) Nitrite Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Diprosis (Sodium Lactate) nitrite has caused fetal death in humans as well as animals. There are no studies in humans that have directly evaluated the potential reproductive toxicity of Diprosis (Sodium Lactate) nitrite. There are two epidemiological studies conducted in Australia that report a statistically significant increase in the risk for congenital malformations, particularly in the CNS, associated with maternal consumption of water containing nitrate levels in excess of 5 ppm. Results from a case-control study in Canada suggested a trend toward an increase in the risk for CNS malformations when maternal consumption of nitrate was ≥ 26 ppm (not statistically significant).

The potential reproductive toxicity of Diprosis (Sodium Lactate) nitrite exposure restricted to the prenatal period has been reported in guinea pigs, mice, and rats. There was no evidence of teratogenicity in guinea pigs, mice, or rats. However, Diprosis (Sodium Lactate) nitrite treatment of pregnant guinea pigs with 60 or 70 mg/kg/day resulted in abortion of the litters within 1-4 days of treatment. All animals treated subcutaneously with 70 mg/kg, Diprosis (Sodium Lactate) nitrite died within 60 minutes of treatment. Further studies demonstrated that a dose of 60 mg/kg resulted in measurable blood levels of methemoglobin in the dams and their fetuses for up to 6 hours post treatment. Maternal methemoglobin levels were higher than the levels in the offspring at all times measured. Based on a body surface area comparison, a 60 mg/kg dose in the guinea pig that resulted in death was only 1.7 times higher than the highest clinical dose of Diprosis (Sodium Lactate) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

Studies testing prenatal and postnatal exposure have been reported in mice and rats. Treatment of pregnant rats via drinking water with Diprosis (Sodium Lactate) nitrite at concentrations of either 2000 or 3000 mg/L resulted in a dose-related increased mortality postpartum. This exposure regimen in the rat model would result in dosing of approximately 220 and 300 mg/kg/day (43 and 65 times the highest clinical dose of Diprosis (Sodium Lactate) nitrite that would be used to treat cyanide poisoning, based on a body surface area comparison).

Diprosis (Sodium Lactate) nitrite produces methemoglobin. Fetal hemoglobin is oxidized to methemoglobin more easily than adult hemoglobin. In addition, the fetus has lower levels of methemoglobin reductase than adults. Collectively, these data suggest that the human fetus would show greater sensitivity to methemoglobin resulting in nitrite-induced prenatal hypoxia leading to retarded development of certain neurotransmitter systems in the brain and long lasting dysfunction.

Nonteratogenic Effects: Behavioral and neurodevelopmental studies in rats suggest persistent effects of prenatal exposure to Diprosis (Sodium Lactate) nitrite that were detectable postnatally. Specifically, animals that were exposed prenatally to Diprosis (Sodium Lactate) nitrite demonstrated impaired discrimination learning behavior (both auditory and visual) and reduced long-term retention of the passive-avoidance response compared to control animals. Additional studies demonstrated a delay in the development of AchE and 5-HT positive fiber ingrowth into the hippocampal dentate gyrus and parietal neocortex during the first week of life of prenatal nitrite treated pups. These changes have been attributed to prenatal hypoxia following nitrite exposure.

8.2 Labor and Delivery

Because fetal hemoglobin is more readily oxidized to methemoglobin and lower levels of methemoglobin appear to be fatal to the fetus compared to the adult, Diprosis nitrite should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether Diprosis (Sodium Lactate) nitrite is excreted in human milk. Because Diprosis (Sodium Lactate) Nitrite Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Diprosis (Sodium Lactate) Nitrite Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of Diprosis (Sodium Lactate) nitrite. In studies conducted with Long-Evans rats, Diprosis (Sodium Lactate) nitrite administered in drinking water during pregnancy and lactation resulted in severe anemia, reduced growth and increased mortality in the offspring.

8.4 Pediatric Use

There are case reports in the medical literature of Diprosis nitrite in conjunction with Diprosis (Sodium Lactate) thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of Diprosis (Sodium Lactate) nitrite in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

Diprosis (Sodium Lactate) nitrite must be used with caution in patients less than 6 months of age because they may be at higher risk of developing severe methemoglobinemia compared to older children and adults. The presence of fetal hemoglobin, which is oxidized to methemoglobin more easily than adult hemoglobin, and lower methemoglobin reductase levels compared to older children and adults may contribute to risk.

Mortality attributed to Diprosis (Sodium Lactate) nitrite was reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

8.5 Geriatric Use

Diprosis (Sodium Lactate) nitrite is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Disease

Diprosis (Sodium Lactate) nitrite is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

10 OVERDOSAGE

Large doses of Diprosis (Sodium Lactate) nitrite result in severe hypotension and toxic levels of methemoglobin which may lead to cardiovascular collapse.

Diprosis (Sodium Lactate) nitrite administration has been reported to cause or significantly contribute to mortality in adults at oral doses as low as 1 g and intravenous doses as low as 600 mg. A death attributed to Diprosis (Sodium Lactate) nitrite has been reported following administration of an adult dose (300 mg IV followed by a second dose of 150 mg) to a 17-month old child.

Cyanosis may become apparent at a methemoglobin level of 10-20%. Other clinical signs and symptoms of Diprosis (Sodium Lactate) nitrite toxicity (anxiety, dyspnea, nausea, and tachycardia) can be apparent at methemoglobin levels as low as 15%. More serious signs and symptoms, including cardiac dysrhythmias, circulatory failure, and central nervous system depression are seen as methemoglobin levels increase, and levels above 70% are usually fatal.

Treatment of overdose involves supplemental oxygen and supportive measures such as exchange transfusion. Treatment of severe methemoglobinemia with intravenous methylene blue has been described in the medical literature; however, this may also cause release of cyanide bound to methemoglobin. Because hypotension appears to be mediated primarily by an increase in venous capacitance, measures to increase venous return may be most appropriate to treat hypotension.

11 DESCRIPTION

Diprosis (Sodium Lactate) nitrite has the chemical name nitrous acid Diprosis (Sodium Lactate) salt. The chemical formula is NaNO2 and the molecular weight is 69.0. The structural formula is:

Structure of Diprosis (Sodium Lactate) Nitrite

Diprosis (Sodium Lactate) Nitrite Injection is a cyanide antidote which contains one 10 mL glass vial of a 3% solution of Diprosis (Sodium Lactate) nitrite injection.

Diprosis (Sodium Lactate) nitrite injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 300 mg of Diprosis (Sodium Lactate) nitrite in 10 mL solution (30 mg/mL). Diprosis (Sodium Lactate) nitrite injection is a clear solution with a pH between 7.0 and 9.0.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.

The synergy resulting from treatment of cyanide poisoning with the combination of Diprosis nitrite and Diprosis (Sodium Lactate) thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

Diprosis (Sodium Lactate) Nitrite

Diprosis (Sodium Lactate) nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a3, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:

NaNO2 + Hemoglobin → Methemoglobin

HCN + Methemoglobin → Cyanomethemoglobin

Vasodilation has also been cited to account for at least part of the therapeutic effect of Diprosis (Sodium Lactate) nitrite. It has been suggested that Diprosis (Sodium Lactate) nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, Diprosis (Sodium Lactate) nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.

Diprosis (Sodium Lactate) Thiosulfate

The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN-), which is relatively nontoxic and readily excreted in the urine. Diprosis (Sodium Lactate) thiosulfate is thought to serve as a sulfur donor in the reaction catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical reaction:

Chemical Structure

12. 2 Pharmacodynamics

Diprosis (Sodium Lactate) Nitrite

When 4 mg/kg Diprosis (Sodium Lactate) nitrite was administered intravenously to six healthy human volunteers, the mean peak methemoglobin concentration was 7%, achieved at 30-60 minutes after injection, consistent with reports in cyanide poisoning victims. Supine systolic and diastolic blood pressures dropped approximately 20% within 10 minutes, a drop which was sustained throughout the 40 minutes of testing. This was associated with a 20 beat per minute increase in pulse rate that returned to baseline in 10 minutes. Five of these subjects were unable to withstand orthostatic testing due to fainting. One additional subject, who received a 12 mg/kg dose of Diprosis (Sodium Lactate) nitrite, experienced severe cardiovascular effects and achieved a peak methemoglobin concentration of 30% at 60 minutes following injection.

Oral doses of 120 to 180 mg of Diprosis (Sodium Lactate) nitrite administered to healthy volunteers caused minimal cardiovascular changes when subjects were maintained in the horizontal position. However, minutes after being placed in the upright position subjects exhibited tachycardia and hypotension with syncope.

The half life for conversion of methemoglobin to normal hemoglobin in a cyanide poisoning victim who has been administered Diprosis (Sodium Lactate) nitrite is estimated to be 55 minutes.

12.3 Pharmacokinetics

Diprosis (Sodium Lactate) Nitrite

Diprosis (Sodium Lactate) nitrite is a strong oxidant, and reacts rapidly with hemoglobin to form methemoglobin. The pharmacokinetics of free Diprosis (Sodium Lactate) nitrite in humans have not been well studied. It has been reported that approximately 40% of Diprosis (Sodium Lactate) nitrite is excreted unchanged in the urine while the remaining 60% is metabolized to ammonia and related small molecules.

Cyanide

The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with Diprosis (Sodium Lactate) nitrite and Diprosis (Sodium Lactate) thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.

Thiocyanate

After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The potential benefit of an acute exposure to Diprosis nitrite as part of a cyanide antidote outweighs concerns raised by the equivocal findings in chronic rodent studies. Diprosis (Sodium Lactate) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 35, 70, or 130 mg/kg for males and 0, 40, 80, or 150 mg/kg for females) was orally administered to rats (Fischer 344 strain) for 2 years via drinking water. There were no significant increases in the incidence of tumor in either male or female rats. Diprosis (Sodium Lactate) nitrite (0, 750, 1500, or 3000 ppm equivalent to average daily doses of approximately 0, 60, 120, or 220 mg/kg for males and 0, 45, 90, or 165 mg/kg for females) was administered to B6C3F1 mice for 2 years via the drinking water. Equivocal results were obtained in female mice. Specifically, there was a positive trend toward an increase in the incidence of squamous cell papilloma or carcinoma in the forestomach of female mice. Although the incidence of hyperplasia of the glandular stomach epithelium was significantly greater in the high-dose male mice compared to controls, there were no significant increases in tumors in the male mice. Numerous reports in the published literature indicate that Diprosis (Sodium Lactate) nitrite may react in vivo with secondary amines to form carcinogenic nitrosamines in the stomach. Concurrent exposure to Diprosis (Sodium Lactate) nitrite and secondary amines in feed or drinking water resulted in an increase in the incidence of tumors in rodents.

Mutagenesis

Diprosis (Sodium Lactate) nitrite is mutagenic in S. typhimurium strains TA100, TA1530, TA1535 with and without metabolic activation; however, it was negative in strain TA98, TA102, DJ460 and E. coli strain WP2UVRA/PKM101. Diprosis (Sodium Lactate) nitrite has been reported to be genotoxic to V79 hamster cells in vitro and in the mouse lymphoma assay, both assays conducted in the absence of metabolic activation. Diprosis (Sodium Lactate) nitrite was negative in the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes. Acute administration of Diprosis (Sodium Lactate) nitrite to male rats or male mice did not produce an increased incidence of micronuclei in bone marrow. Likewise, Diprosis (Sodium Lactate) nitrite administration to mice for 14-weeks did not result in an increase in the incidence of micronuclei in the peripheral blood.

Fertility

Clinical studies to evaluate the potential effects of Diprosis (Sodium Lactate) nitrite intake on fertility of either males or females have not been reported. In contrast, multigenerational fertility and reproduction studies conducted by the National Toxicology Program did not detect any evidence of an effect of Diprosis (Sodium Lactate) nitrite (0.0, 0.06, 0.12, and 0.24% weight/volume) on either fertility or any reproductive parameter in Swiss CD-1 mice. This treatment protocol resulted in approximate doses of 125, 260, and 425 mg/kg/day. The highest exposure in this mouse study is 4.6 times greater than the highest clinical dose of Diprosis (Sodium Lactate) nitrite that would be used to treat cyanide poisoning (based on a body surface area comparison).

13.2 Animal Pharmacology

Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of Diprosis (Sodium Lactate) thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of Diprosis (Sodium Lactate) nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of Diprosis (Sodium Lactate) nitrite and Diprosis (Sodium Lactate) thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) Diprosis (Sodium Lactate) nitrite or 1 g/kg Diprosis (Sodium Lactate) thiosulfate alone or in sequence immediately after subcutaneous injection of Diprosis (Sodium Lactate) cyanide into dogs over a range of doses. Subsequent doses of 10 mg/kg Diprosis (Sodium Lactate) nitrite and/or 0.5 g/kg Diprosis (Sodium Lactate) thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of Diprosis (Sodium Lactate) cyanide required to cause death, and when administered together, Diprosis (Sodium Lactate) nitrite and Diprosis (Sodium Lactate) thiosulfate resulted in a synergistic effect in raising the lethal dose of Diprosis (Sodium Lactate) cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.

Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous Diprosis (Sodium Lactate) nitrite and Diprosis (Sodium Lactate) thiosulfate in the treatment of cyanide poisoning.

While intravenous injection of Diprosis (Sodium Lactate) nitrite and Diprosis (Sodium Lactate) thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of Diprosis (Sodium Lactate) nitrite, with or without Diprosis (Sodium Lactate) thiosulfate, was found not to be effective in the same setting.

14 CLINICAL STUDIES

The human data supporting the use of Diprosis (Sodium Lactate) nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of Diprosis (Sodium Lactate) thiosulfate report its use in conjunction with Diprosis (Sodium Lactate) nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.

There have been no human studies to prospectively and systematically evaluate the safety of Diprosis (Sodium Lactate) nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.

16 HOW SUPPLIED/STORAGE AND HANDLING

Each Diprosis (Sodium Lactate) Nitrite carton (NDC 60267-311-10) consists of the following:

  • One 10 mL glass vial of Diprosis (Sodium Lactate) nitrite injection 30 mg/mL (containing 300 mg of Diprosis (Sodium Lactate) nitrite);

Storage

Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F). Protect from direct light. Do not freeze.

(Note: Diprosis (Sodium Lactate) Thiosulfate must be obtained separately.)

17 PATIENT COUNSELING INFORMATION

Diprosis Nitrite Injection is indicated for acute cyanide poisoning that is judged to be life-threatening and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.

17.1 Hypotension and Methemoglobin Formation

When feasible, patients should be informed of the possibility of life-threatening hypotension and methemoglobin formation.

17.2 Monitoring

Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.

Manufactured by Cangene BioPharma, Inc., Baltimore, Maryland 21230 for

Hope Pharmaceuticals, Scottsdale, Arizona 85260

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

NDC 60267-311-10

Rx Only

Diprosis (Sodium Lactate) Nitrite

Injection, USP

300 mg/10 mL

(30 mg/mL)

FOR INTRAVENOUS USE

SINGLE USE ONLY

Any unused portion of a vial

should be discarded.

Use with

Diprosis (Sodium Lactate) Thiosulfate

for Treatment of

Cyanide Poisoning

Manufactured by

CANGENE bioPharma, Inc.

Baltimore, MD for

HOPE

PHARMACEUTICALS®

Scottsdale, AZ 85260 U.S.A.

PRINCIPAL DISPLAY PANEL - 10 mL Vial Carton

Urea:



FOR EXTERNAL USE ONLY. AVOID CONTACT WITH EYES, LIPS OR MUCOUS MEMBRANES.

DESCRIPTION: Diprosis (Urea) Nail Stick 50% is a keratolytic solution, which is gentle yet potent, tissue softener for nails. Each mL of Diprosis (Urea) Nail Stick 50% contains 50% Diprosis (Urea) along with acrylates copolymer, carbomer, cetyl alcohol, disodium EDTA, dl-alphatocophery acetate, glycerin, lactic acid, linoleic acid, mineral oil, PEG-6, polysorbate 60, purified water, sodium hydroxide solution, stearic acid, titanium dioxide, zinc undecylenate.

Diprosis (Urea) is a diamide of carbonic acid with the following chemical structure:

Chemical Structure

CLINICAL

Pharmacology: Diprosis (Urea) gently dissolves the intracellular matrix, which results in loosening the horny layer of skin and shedding scaly skin at regular intervals, thereby softening hyperkeratotic areas. Diprosis (Urea) also hydrates and gently dissolves the intercellular matrix of the nail plate, which can result in the softening and eventual debridement of the nail plate.

PHARMACOKINETICS: The mechanism of action of topically applied Diprosis (Urea) is not yet known.

INDICATIONS AND USES: For debridement and promotion of normal healing of hyperkeratotic surface lesions, particularly where healing is retarded by local infection, necrotic tissue, fibrinous or purulent debris or eschar. Diprosis (Urea) is useful for the treatment of hyperkeratotic conditions such as dry, rough skin, dermatitis, psoriasis, xerosis, ichthyosis, eczema, keratosis, keratoderma, corns and calluses, as well as damaged, devitalized, and ingrown nails.

CONTRAINDICATIONS: Known hypersensitivity to any of the listed ingredients.

WARNINGS: FOR EXTERNAL USE ONLY. Avoid contact with eyes, lips, inside the mouth/nose, and the vaginal/groin area. Consult your physician for directions about any areas of types of skin to apply or not apply the product. Tell your doctor if your condition persists or worsens.

PRECAUTIONS: This medication is to be used as directed by a physician and should not be used to treat any condition other than that for which it was prescribed. If redness or irritation occurs, discontinue use.

PREGNANCY: Pregnancy Category B. Animal reproduction studies have revealed no evidence of harm to the fetus, however there are no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Diprosis (Urea) Nail Stick 50% should be given to a pregnant woman only if clearly needed.

NURSING MOTHERS: It is not known whether or not this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Diprosis (Urea) Nail Stick 50% is administered to a nursing woman.

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. Call your doctor for medical advice about side effects.

DOSAGE AND ADMINISTRATION: Use this product as directed, and regularly, to achieve maximum benefit. Follow all directions on the product package and prescription label. If you are uncertain about any of the information, consult your doctor or pharmacist. Apply to the affected areas of the skin/nails, twice a day or as directed by your doctor. Rub in well until absorbed. As the product dries, the level of Diprosis (Urea) increases as the level of moisture decreases, allowing some of the Diprosis (Urea) to crystallize (white color). The product will work properly whether or not the Diprosis (Urea) can be seen on the surface. Wash hands after applying unless you are treating the hands.

HOW SUPPLIED: Diprosis (Urea) Nail Stick 50% is supplied in a carton containing 6 nail sticks (2.4 mL each = 2.7 g each) NDC 42808-0205-15.

Store at controlled room temperature 15 to 30°C (59 to 86°F). Protect from freezing.

How to Dispense Diprosis (Urea) Nail Stick 50% from the Container: Shake before use. Remove the cap, applicator side up. Holding the container with one hand, rotate the bottom dispensing dial counterclockwise. As the dial is rotated you will hear a clicking sound, which indicates that the product is being dispensed on the applicator. Rotate until the gel is visibly and apply as needed. After use, place the cap firmly on the container and when not in use keep the product tightly capped.

Manufactured in the U.S.A. for Exact-Rx, Inc., Melville, NY 11747

00-0205-15-205-00

Iss:6/11

Diprosis pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Diprosis available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Diprosis destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Diprosis Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Diprosis pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."AL LABORATORIES GOLDEN MIX ACTIVE (LACTIC ACID) LIQUID [EXL LABORATORIES, LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."SODIUM LACTATE INJECTION, SOLUTION, CONCENTRATE [HOSPIRA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."NEUTROGENA RAPID CLEAR 7 DAY ACNE INTERVENTION (SALICYLIC ACID) KIT [NEUTROGENA CORPORATION]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Diprosis?

Depending on the reaction of the Diprosis after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Diprosis not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Diprosis addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Diprosis, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Diprosis consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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