MetroGel

Dosage Form: gel
FULL PRESCRIBING INFORMATION

Indications and Usage for MetroGel

MetroGel® is indicated for the topical treatment of inflammatory lesions of rosacea.

MetroGel Dosage and Administration

Apply and rub in a thin film of MetroGel once daily to affected area(s).

A gentle cleanser should be used before the application of MetroGel.

Cosmetics may be applied after the application of MetroGel.

Not for oral, ophthalmic or intravaginal use.

Dosage Forms and Strengths

Gel, 1%.  MetroGel is a clear, colorless to pale yellow gel.  Each gram of MetroGel contains 10mg (1%) of metronidazole.

Contraindications

MetroGel is contraindicated in patients with a history of hypersensitivity to metronidazole or to any other ingredient in the formulation.

Warnings and Precautions

Neurologic Disease

Peripheral neuropathy, characterized by numbness or paresthesia of an extremity has been reported in patients treated with systemic metronidazole. Although not evident in clinical trials for topical metronidazole, peripheral neuropathy has been reported with the post approval use. The appearance of abnormal neurologic signs should prompt immediate reevaluation of MetroGel therapy. Metronidazole should be administered with caution to patients with central nervous system diseases.

Blood Dyscrasias

Metronidazole is a nitroimidazole; use with care in patients with evidence of, or history of, blood dyscrasia.

Contact Dermatitis

Irritant and allergic contact dermatitis have been reported.  If dermatitis occurs, patients may need to discontinue use.

Eye Irritation

Topical metronidazole has been reported to cause tearing of the eyes.  Avoid contact with the eyes.

Adverse Reactions

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 practice.

In a controlled clinical trial, 557 patients used metronidazole gel, 1% and 189 patients used the gel vehicle once daily for up to 10 weeks. The following table summarizes selected adverse reactions that occurred at a rate of ≥1%:

Table 1: Adverse Reactions That Occurred at a Rate of ≥1%

System Organ Class/Preferred Term	Metronidazole Gel, 1%	Gel Vehicle
	N= 557	N= 189
Patients with at least one AE        Number (%) of Patients	186 (33.4)	51 (27.0)
Infections and infestations	76 (13.6)	28 (14.8)
Bronchitis	6 (1.1)	3 (1.6)
Influenza	8 (1.4)	1 (0.5)
Nasopharyngitis	17 (3.1)	8 (4.2)
Sinusitis	8 (1.4)	3 (1.6)
Upper respiratory tract infection	14 (2.5)	4 (2.1)
Urinary tract infection	6 (1.1)	1 (0.5)
Vaginal mycosis	1 (0.2)	2 (1.1)
Musculoskeletal and connective tissue disorders	19 (3.4)	5 (2.6)
Back pain	3 (0.5)	2 (1.1)
Neoplasms	4 (0.7)	2 (1.1)
Basal cell carcinoma	1 (0.2)	2 (1.1)
Nervous system disorders	18 (3.2)	3 (1.6)
Headache	12 (2.2)	1 (0.5)
Respiratory, thoracic and mediastinal disorders	22 (3.9)	5 (2.6)
Nasal congestion	6 (1.1)	3 (1.6)
Skin and subcutaneous tissue disorders	36 (6.5)	12 (6.3)
Contact dermatitis	7 (1.3)	1 (0.5)
Dry skin	6 (1.1)	3 (1.6)
Vascular disorders	8 (1.4)	1 (0.5)
Hypertension	6 (1.1)	1 (0.5)

Table 2: Local Cutaneous Signs and Symptoms of Irritation That Were Worse Than Baseline

	Metronidazole Gel, 1%	Gel Vehicle
Sign/Symptom	N= 544	N= 184
Dryness	138 (25.4)	63 (34.2)
Mild	93 (17.1)	41 (22.3)
Moderate	42 (7.7)	20 (10.9)
Severe	3 (0.6)	2 (1.1)
Scaling	134 (24.6)	60 (32.6)
Mild	88 (16.2)	32 (17.4)
Moderate	43 (7.9)	27 (14.7)
Severe	3 (0.6)	1 (0.5)
Pruritus	86 (15.8)	35 (19.0)
Mild	53 (9.7)	21 (11.4)
Moderate	27 (5.0)	13 (7.1)
Severe	6 (1.1)	1 (0.5)
Stinging/burning	56 (10.3)	28 (15.2)
Mild	39 (7.2)	18 (9.8)
Moderate	7 (1.3)	9 (4.9)
Severe	10 (1.8)	1 (0.5)

The following additional adverse experiences have been reported with the topical use of metronidazole: skin irritation, transient redness, metallic taste, tingling or numbness of extremities, and nausea.

Post Marketing Experience

The following adverse reaction has been identified during post approval use of topical metronidazole: peripheral neuropathy.  Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Drug Interactions

Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and warfarin, resulting in a prolongation of prothrombin time. Drug interactions should be kept in mind when MetroGel is prescribed for patients who are receiving anticoagulant treatment, although they are less likely to occur with topical metronidazole administration because of low absorption.

USE IN SPECIFIC POPULATIONS

Pregnancy

Teratogenic Effects: Pregnancy Category B.


There are no adequate and well-controlled studies with the use of MetroGel in pregnant women.


Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. No fetotoxicity was observed after oral administration of metronidazole in rats or mice at 200 and 20 times, respectively, the expected clinical dose. However, oral metronidazole has shown carcinogenic activity in rodents. Because animal reproduction studies are not always predictive of human response, MetroGel should be used during pregnancy only if clearly needed.

Nursing Mothers

After oral administration, metronidazole is secreted in breast milk in concentrations similar to those found in the plasma. Even though blood levels taken after topical metronidazole application are significantly lower than those achieved after oral metronidazole a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother and the risk to the infant.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Sixty-six subjects aged 65 years and older were treated with metronidazole gel, 1% in the clinical study.  No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Overdosage

There are no reported human experiences with overdosage of MetroGel. Topically applied metronidazole can be absorbed in sufficient amount to produce systemic effects.

MetroGel Description

MetroGel (metronidazole) Gel, 1% contains metronidazole, USP. Chemically, metronidazole is 2-methyl-5-nitro-1 H-imidazole-1-ethanol. The molecular formula for metronidazole is C6H9N3O3. It has the following structural formula:

Metronidazole has a molecular weight of 171.16. It is a white to pale yellow crystalline powder. It is slightly soluble in alcohol and has solubility in water of 10 mg/mL at 20˚C. Metronidazole belongs to the nitroimidazole class of compounds.


MetroGel is a clear, colorless to pale yellow, aqueous gel; each gram contains 10 mg of metronidazole in a base of betadex, edetate disodium, hydroxyethyl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparaben and purified water.

MetroGel - Clinical Pharmacology

Mechanism of Action

The mechanism of action of metronidazole in the treatment of rosacea is unknown.

Pharmacodynamics

The pharmacodynamics of metronidazole in association with the treatment of rosacea are unknown.

Pharmacokinetics

Topical administration of a one gram dose of MetroGel to the face of 13 patients with moderate to severe rosacea once daily for 7 days resulted in a mean ± SD Cmax of metronidazole of 32 ± 9 ng/mL.  The mean ± SD AUC(0-24) was 595 ± 154 ng*hr/mL. The mean Cmax and AUC(0-24) are less than 1% of the value reported for a single 250 mg oral dose of metronidazole. The time to maximum plasma concentration (Tmax) was 6-10 hours after topical application.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic, oral administration in mice and rats, but not in studies involving hamsters.


In several long-term studies in mice, oral doses of approximately 225 mg/m2/day or greater (approximately 37 times the human topical dose on a mg/m2 basis) were associated with an increase in pulmonary tumors and lymphomas. Several long-term oral studies in the rat have shown statistically significant increases in mammary and hepatic tumors at doses >885 mg/m2/day (144 times the human dose).


Metronidazole has shown evidence of mutagenic activity in several in vitro bacterial assay systems. In addition, a dose-related increase in the frequency of micronuclei was observed in mice after intraperitoneal injections. An increase in chromosomal aberrations in peripheral blood lymphocytes was reported in patients with Crohn's disease who were treated with 200 to 1200 mg/day of metronidazole for 1 to 24 months. However, in another study, no increase in chromosomal aberrations in circulating lymphocytes was observed in patients with Crohn's disease treated with the drug for 8 months.


In one published study, using albino hairless mice, intraperitoneal administration of metronidazole at a dose of 45 mg/m2/day (approximately 7 times the human topical dose on a mg/m2/day basis) was associated with an increase in ultraviolet radiation-induced skin carcinogenesis. Neither dermal carcinogenicity nor photocarcinogenicity studies have been performed with MetroGel or any marketed metronidazole formulations.

Clinical Studies

In a randomized, vehicle-controlled trial, 746 subjects with rosacea were treated with metronidazole gel, 1% or gel vehicle once daily for 10 weeks.  Most subjects had “moderate” rosacea at baseline. Efficacy was determined by recording reduction in inflammatory lesion counts and success rate in the Investigator Global Assessment (percentage of subjects “clear” and “almost clear” of rosacea at the end of the study). The scale is based on the following definitions:

Table 3: Investigator Global Assessment Scale

Score	Grade	Definition
0	Clear	No signs or symptoms present; at most, mild erythema
1	Almost Clear	Very mild erythema present. Very few small papules/pustules
2	Mild	Mild erythema.  Several small papules/pustules
3	Moderate	Moderate erythema.  Several small or large papules/pustules, and up to 2 nodules
4	Severe	Severe erythema.  Numerous small and/or large papules/pustules, up to several nodules

The results are shown in the following table:

Table 4: Inflammatory Lesion Counts and Global Scores in a Clinical Trial of Rosacea

	Metronidazole Gel, 1%		Vehicle
	N	Results N (%)	N	Results N (%)
Inflammatory lesions	557		189
Baseline, mean count		18.3		18.4
Week-10, mean count		8.9		12.8
Reduction		9.4 (50.7)		5.6 (32.6)
Investigator Global Assessment	557		189
Subject clear or almost clear		214 (38.42)		52 (27.51)
Subject with no change		159 (28.5)		77 (40.7)

Subjects treated with metronidazole gel, 1% experienced a mean reduction of 9.4 inflammatory lesions in the Week-10 LOCF group, compared to a reduction of 5.6 for those treated with vehicle, or a difference in means of 3.8 lesions.


The contribution to efficacy of individual components of the vehicle has not been established.

How Supplied/Storage and Handling

MetroGel® a clear, colorless to pale yellow in color, and is supplied as follows:


60 gram tube - NDC 0299-3820-60

55 gram pump - NDC 0299-3820-01

Storage Conditions: Store at controlled room temperature: 20˚ to 25˚C (68˚ to 77˚F), excursions permitted between 15˚ and 30˚C (59˚ and 86˚F).

Patient Counseling Information

Patients using MetroGel should receive the following information and instructions:

1. This medication is to be used as directed.


2. It is for external use only.


3. Avoid contact with the eyes.


4. Cleanse affected area(s) before applying MetroGel.


5. This medication should not be used for any other condition than that for which it is prescribed.


6. Keep out of reach of children.


7. Patients should report any adverse reaction to their physicians.

RX Only

US Patent No. 6,881,726 and 7,348,317

Manufactured by:

G Production Inc.

Baie d'Urfé, Quebec, H9X 3S4 Canada

Made in Canada


Marketed by:

GALDERMA LABORATORIES, L.P.

Fort Worth, Texas 76177 USA

Part Number

MetroGel 1%


(metronidazole gel), 1%


NDC 0299-3820-60


Rx Only


NET WT. 60 g


GALDERMA


For topical use only. Not for oral, ophthalmic or intravaginal use.


Store at controlled room temperature, 20° - 25°C (68° to 77°F), excursions permitted between 15° - 30°C (59° and 86°F). Keep out of reach of children.


Ususal dosage: Apply a thin film to the entire affected areas after washing once daily in the evening or as directed by the physician. Avoid applicaton close to the eyes.


Each gram contains: 10 mg (1%) metronidazole as active ingredient in a gel base consisting of betadex, edetate disodium, hydroxeyethyl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparaben, and purified water.


US Patent No. 6,881,726 and 7,348,317


Marketed by:

GALDERMA LABORATORIES, L.P.

Fort Worth, Texas 76177 USA


Manufactured by:

G Production Inc.

Baie d'Urfé Quebec H9X 3S4 Canada

Made in Canada.

www.MetroGel.com

P50741-3

LOT:


EXP.:

Rx Only     NDC 0299-3820-01

MetroGel 1%


(metronidazole gel), 1%

PUMP

For topical use only       NET WT. 55 g


GALDERMA


For topical use only. Not for oral, ophthalmic or intravaginal use.


Store at controlled room temperature, 20° - 25°C (68° to 77°F), excursions permitted between 15° - 30°C (59° and 86°F). Keep out of reach of children.


Ususal dosage: Apply a thin film to the entire affected areas after washing once daily in the evening or as directed by the physician. Avoid applicaton close to the eyes.


Each gram contains: 10 mg (1%) metronidazole as active ingredient in a gel base consisting of betadex, edetate disodium, hydroxeyethyl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparaben, and purified water.


US Patent No. 6,881,726 and 7,348,317


Marketed by:

GALDERMA LABORATORIES, L.P.

Fort Worth, Texas 76177 USA


Manufactured by:

G Production Inc.

Baie d'Urfé Quebec H9X 3S4 Canada

Made in Canada.

GALDERMA is a registered trademark.

P51727-1

LOT:


EXP.:

MetroGel  metronidazole  gel

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0299-3820 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength METRONIDAZOLE (Metronidazole) Metronidazole 10 mg  in 1 g

Inactive Ingredients Ingredient Name Strength betadex   edetate disodium   methylparaben   niacinamide   phenoxyethanol   propylene glycol   propylparaben   water

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0299-3820-60 60 g In 1 TUBE None 2 0299-3820-01 55 g In 1 BOTTLE, PUMP None 3 0299-3820-03 3 g In 1 TUBE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA021789	06/30/2005

Labeler - Galderma Laboratories, L.P. (047350186)

Establishment
Name	Address	ID/FEI	Operations
G Production Inc.		251676961	manufacture

Revised: 10/2011Galderma Laboratories, L.P.

Enbrel 50 mg solution for injection in pre-filled syringe

Enbrel 50 mg solution for injection in pre-filled syringe

Etanercept

Read all (both sides) of this leaflet carefully before you start using this medicine.

• Keep this leaflet. You may need to read it again.


• Your doctor will also give you a Patient Alert Card, which contains important safety information that you need to be aware of before and during treatment with Enbrel.


• If you any have further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If you are concerned about any side effect, or if you notice any side effects that are not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

Information in this leaflet is organised under the following 7 sections:

1. What Enbrel is and what it is used for

2. Before you use Enbrel

3. How to use Enbrel

4. Possible side effects

5. How to store Enbrel

6. Further information

7. Instructions for preparing and giving an injection of Enbrel (See overleaf)

What Enbrel Is And What It Is Used For

Enbrel is a medicine that is made from two human proteins. It blocks the activity of another protein in the body that causes inflammation. Enbrel works by reducing the inflammation associated with certain diseases.

In adults (aged 18 and over), Enbrel can be used for moderate or severe rheumatoid arthritis, psoriatic arthritis, severe ankylosing spondylitis and moderate or severe psoriasis – in each case usually when other widely used treatments have not worked well enough or are not suitable for you.

For rheumatoid arthritis, Enbrel is usually used in combination with methotrexate, although it may also be used alone if treatment with methotrexate is unsuitable for you. Whether used alone or in combination with methotrexate, Enbrel can slow down the damage to your joints caused by the rheumatoid arthritis and improve your ability to do normal daily activities.

For psoriatic arthritis patients with multiple joint involvement, Enbrel can improve your ability to do normal daily activities. For patients with multiple symmetrical painful or swollen joints (e.g., hands, wrists and feet), Enbrel can slow down the structural damage to those joints caused by the disease.

Enbrel is also prescribed for the treatment of severe psoriasis in patients from the age of 8 years who have had an inadequate response to (or are unable to take) phototherapies or other systemic therapies.

Before You Use Enbrel

Do not use Enbrel

• Allergy: Do not use Enbrel if you, or the child you are caring for, are allergic to etanercept or any of the other ingredients of Enbrel. If you or the child experience allergic reactions such as chest tightness, wheezing, dizziness or rash, do not inject more Enbrel, and contact your doctor immediately.



• Serious blood infection: Do not use Enbrel if you or the child have, or are at risk of developing a serious blood infection called sepsis. If you are not sure, please contact your doctor.



• Infections: Do not use Enbrel if you or the child have an infection of any kind. If you are not sure, please talk to your doctor.

Take special care with Enbrel

• Allergic reactions: If you or the child experience allergic reactions such as chest tightness, wheezing, dizziness or rash, do not inject more Enbrel, and contact your doctor immediately.



• Infections/surgery: If you or the child develop a new infection, or are about to have
  any major surgery, your doctor may wish to monitor the treatment with Enbrel.



• Infections/diabetes: Tell your doctor if you or the child have a history of recurrent infections or suffer from diabetes
  or other conditions that increase the risk of infection.



• Infections/monitoring: Tell your doctor of any recent travel outside the European region. If you or the child develop symptoms of an infection such as fever, chills or cough, notify your doctor immediately. Your doctor may decide to continue to monitor
  you or the child for the presence of infections after you or the child stop using Enbrel.



• Tuberculosis: As cases of tuberculosis have been reported in patients treated with Enbrel, your doctor will check for signs and symptoms of tuberculosis before starting Enbrel. This may include a thorough medical history, a chest X-ray and a tuberculin test. The conduct of these tests should be recorded on the Patient Alert Card. It is very important that you tell your doctor if you or the child have ever had tuberculosis, or have been in close contact with someone who has had tuberculosis. If symptoms of tuberculosis (such as persistent cough, weight loss, listlessness, mild fever), or any other infection appear during or after therapy, tell your doctor immediately.



• Hepatitis B: Your doctor may decide to test for the presence of hepatitis B infection before you or the child begin treatment with Enbrel.



• Hepatitis C: Tell your doctor if you or the child have hepatitis C. Your doctor may wish to monitor the treatment with Enbrel in case the infection worsens.



• Blood disorders: Seek medical advice immediately if you or the child have any signs or symptoms such as persistent fever, sore throat, bruising, bleeding or paleness. Such symptoms may point to the existence of potentially life-threatening blood disorders, which may require discontinuation of Enbrel.



• Nervous system and eye disorders: Tell your doctor if you or the child have multiple sclerosis, optic neuritis (inflammation of the nerves of the eyes) or transverse myelitis (inflammation of the spinal cord). Your doctor will determine if Enbrel is an appropriate treatment.



• Congestive heart failure: Tell your doctor if you or the child have a history of congestive heart failure, because Enbrel needs to be used with caution under these circumstances.



• Cancer: Tell your doctor if you have ever had lymphoma (a type of blood cancer) or any other cancer before you are given Enbrel.
  
  Patients with severe rheumatoid arthritis, who have had the disease for a long time, may be at higher than average risk of developing lymphoma.
  
  Children and adults taking Enbrel may have an increased risk of developing lymphoma or another cancer.
  
  Some children and teenage patients who have received Enbrel or other medicines that work the same way as Enbrel have developed cancers, including unusual types, which sometimes resulted in death.
  
  Some patients receiving Enbrel have developed skin cancers called non-melanoma skin cancer. Tell your doctor if you or the child develop any change in the appearance of the skin or growths on the skin.



• Vaccinations: If possible, children should be up to date with all vaccinations before using Enbrel. Some vaccines, such as oral polio vaccine, should not be given while using Enbrel. Please consult your doctor before you or the child receive any vaccines.



• Chickenpox: Tell your doctor if you or the child are exposed to chickenpox when using Enbrel. Your doctor will determine if preventive treatment for chickenpox is appropriate.



• Latex: The needle cover is made from latex (dry natural rubber). Contact your doctor before using Enbrel if the needle cover will be handled by, or Enbrel will be given to, someone with a known or possible hypersensitivity (allergy) to latex.



• Alcohol abuse: Enbrel should not be used for the treatment of hepatitis related to alcohol abuse. Please tell your doctor if you or the child in your care have a history of alcohol abuse.



• Wegener’s granulomatosis: Enbrel is not recommended for the treatment of Wegener’s granulomatosis, a rare inflammatory disease. If you or the child in your care have Wegener’s granulomatosis, talk to your doctor.



• Anti-diabetic medicines: Tell your doctor if you or the child have diabetes or are taking medicines to treat diabetes. Your doctor may decide if you or the child need less anti-diabetic medicine while taking Enbrel.

Using other medicines

Tell the doctor or pharmacist if you or the child are taking or have recently taken any other medicines (including anakinra, abatacept or sulfasalazine), even those not prescribed by the doctor. You or the child should not use Enbrel with medicines that contain the active substance anakinra or abatacept.

Taking Enbrel with food and drink

Enbrel can be taken with or without food or drink.

Pregnancy and breast-feeding

The effects of Enbrel in pregnant women are not known, and so the use of Enbrel during pregnancy is not recommended. Women using Enbrel should not become pregnant. If the patient becomes pregnant, you should consult the patient's doctor.

Women using Enbrel should not breast-feed, since it is not known if Enbrel passes into human breast milk.

Driving and using machines

The use of Enbrel is not expected to affect the ability to drive or use machines.

How To Use Enbrel

Always use Enbrel exactly as the doctor has told you. You should check with the doctor or pharmacist if you are not sure.

If you feel that the effect of Enbrel is too strong or too weak, talk to your doctor or pharmacist.

You have been prescribed a 50 mg strength of Enbrel. A 25 mg strength of Enbrel is available for doses of 25 mg (or less).

Dosing for adult patients (aged 18 years or over)

Rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis

The usual dose is 25 mg given twice a week or 50 mg once a week as an injection under the skin. However, your doctor may determine an alternative frequency at which to inject Enbrel.

Plaque psoriasis

The usual dose is 25 mg twice a week or 50 mg once a week.

Alternatively, 50 mg may be given twice a week for up to 12 weeks, followed by 25 mg twice a week or 50 mg once a week.

Your doctor will decide how long you should take Enbrel and whether retreatment is needed based on your response. If Enbrel has no effect on your condition after 12 weeks, your doctor may tell you to stop taking this medicine.

Dosing for children and adolescents

The appropriate dose and frequency of dosing for the child or adolescent will depend on body weight and disease. This is a single-use syringe for patients weighing 62.5 kg or more. 25 mg vials are available for paediatric use from which doses less than 25 mg can be administered. The doctor will provide you with detailed directions for preparing and measuring the appropriate dose.

For psoriasis in patients from the age of 8 years, the usual dose is 0.8 mg of Enbrel per kg bodyweight (up to a maximum of 50 mg), and should be given once weekly. If Enbrel has no effect on the child’s condition after 12 weeks, your doctor may tell you to stop using this medicine.

Method and route of administration

Enbrel is administered by an injection under the skin (by subcutaneous injection).

Enbrel can be taken with or without food or drink.

Detailed instructions on how inject Enbrel are provided in section 7, “INSTRUCTIONS FOR PREPARING AND GIVING AN INJECTION OF ENBREL”. Do not mix the Enbrel solution with any other medicine.

To help you remember, it may be helpful to write in a diary which day(s) of the week Enbrel should be used.

If you use more Enbrel than you should

If you have used more Enbrel than you should (either by injecting too much on a single occasion or by using it too frequently), talk to a doctor or pharmacist immediately. Always have the outer carton of the medicine with you, even if it is empty.

If you forget to inject Enbrel

If you forget a dose, you should inject it as soon as you remember, unless the next scheduled dose is the next day; in which case you should skip the missed dose. Then continue to inject the medicine on the usual day(s). If you do not remember until the day that the next injection is due, do not take a double dose (two doses on the same day) to make up for a forgotten dose.

If you stop using Enbrel

Your symptoms may return upon discontinuation.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Possible Side Effects

Like all medicines, Enbrel can cause side effects, although not everybody gets them.

Other side effects that are not listed in this leaflet may occur. If you are concerned about any side effect, or if you notice any side effects that are not listed in this leaflet, please tell your doctor or pharmacist.

Allergic reactions

If any of the following happen, do not inject more Enbrel. Tell your doctor immediately, or go to the casualty department at your nearest hospital.

• Trouble swallowing or breathing


• Swelling of the face, throat, hands, or feet


• Feeling nervous or anxious, throbbing sensations, sudden reddening of the skin and/or a warm feeling


• Severe rash, itching, or hives (elevated patches of red or pale skin that often itch)

Serious allergic reactions are rare. However, any of the above symptoms may indicate an allergic reaction to Enbrel, so you should seek immediate medical attention.

Serious side effects

If you notice any of the following, you or the child may need urgent medical attention.

• Signs of serious infections, such as high fever that may be accompanied by cough, shortness of breath, chills, weakness, or a hot, red, tender, sore area on the skin or joints



• Signs of blood disorders, such as bleeding, bruising, or paleness



• Signs of nerve disorders, such as numbness or tingling, changes in vision, eye pain, or onset of weakness in an arm or leg



• Signs of worsening heart failure, such as fatigue or shortness of breath with activity, swelling in the ankles, a feeling of fullness in the neck or abdomen, night-time shortness of breath or coughing, bluish colour of the nails or the lips

These are rare or uncommon side effects, but are serious conditions (some of which may rarely be fatal). If these signs occur, tell your doctor immediately, or visit the casualty department at your nearest hospital.

The frequency of possible side effects listed below is defined using the following convention:

• Very common (affects more than 1 user in 10)


• Common (affects 1 to 10 users in 100)


• Uncommon (affects 1 to 10 users in 1,000)


• Rare (affects 1 to 10 users in 10,000)


• Very rare (affects less than 1 user in 10,000)


• Not known (frequency cannot be estimated from the available data)

The side effects listed below are those that have been seen in adult patients. The side effects seen in children and adolescents are similar to those seen in adults.

• Very common: Infections (including colds, sinusitis, bronchitis, urinary tract infections and skin infections); injection site reactions (including bleeding, bruising, redness, itching, pain, and swelling). Reactions at the injection site are very common, but do not occur as often after the first month of treatment. Some patients have developed a reaction at an injection site that was used before.



• Common: allergic reactions; fever; itching; antibodies directed against normal tissue (autoantibody formation).



• Uncommon: serious infections (including pneumonia, deep skin infections, joint infections, blood infection, and infections at various sites); low blood platelet count; skin cancer (excluding melanoma); localised swelling of the skin (angioedema); hives (elevated patches of red or pale skin that often itch); eye inflammation; psoriasis (new or worsening); rash; inflammation or scarring of the lungs.



• Rare: serious allergic reactions (including severe localised swelling of the skin and wheezing); lymphoma (a type of blood cancer); combined low platelet, red, and white blood cell count; nervous system disorders (with signs and symptoms similar to those of multiple sclerosis or inflammation of the nerves of the eyes or spinal cord); tuberculosis; worsening congestive heart failure; seizures; lupus or lupus-like syndrome (symptoms may include persistent rash, fever, joint pain, and tiredness); inflammation of the blood vessels; low red blood cell count, low white blood cell count, low neutrophil (a type of white blood cell) count; elevated liver blood tests; skin rash, which may lead to severe blistering and peeling of the skin.



• Very rare: failure of the bone marrow to produce crucial blood cells.



• Not known: leukaemia (cancer affecting the blood and bone marrow); excessive activation of white blood cells associated with inflammation (macrophage activation syndrome).

How To Store Enbrel

Keep out of the reach and sight of children.

Do not use Enbrel after the expiry date which is stated on the carton and pre-filled syringe after EXP. The expiry date refers to the last day of that month.

Store in a refrigerator (2° – 8°C). Do not freeze.

Keep the pre-filled syringes in the outer carton in order to protect from light.

After taking a syringe from the refrigerator, wait approximately 15-30 minutes to allow the Enbrel solution in the syringe to reach room temperature. Do not warm in any other way. Immediate use is then recommended.

Inspect the solution in the syringe. Only inject the solution in the syringe if it is clear, colourless or pale yellow, and free from easily visible particles. If it is not, use a different syringe, then contact your pharmacist for assistance.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further Information

What Enbrel contains

The active substance in Enbrel is etanercept. Each pre-filled syringe contains 1.0 ml of solution, providing 50 mg of etanercept.

The other ingredients are sucrose, sodium chloride, L-arginine hydrochloride, sodium phosphate monobasic dihydrate and sodium phosphate dibasic dihydrate, and water for injections.

What Enbrel looks like and contents of the pack

Enbrel is supplied as a pre-filled syringe containing a clear, colourless or pale yellow solution for injection (solution for injection). Each pack contains 2, 4 or 12 pre-filled syringes and 4, 8 or 24 alcohol swabs. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Wyeth Europa Ltd.

Huntercombe Lane South

Taplow

Maidenhead

Berkshire

SL6 0PH

United Kingdom

Manufacturer:

Wyeth Pharmaceuticals

New Lane

Havant

Hampshire

PO9 2NG

United Kingdom

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder.

United Kingdom

Wyeth Pharmaceuticals

Tel:+ 44 845 367 0098

This leaflet was last approved in 07/2010

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu

Instructions For Preparing And Giving An Injection Of Enbrel

This section is divided into the following subsections:

Introduction

Step 1: Setting up for an injection

Step 2: Choosing an injection site

Step 3: Injecting the Enbrel solution

Step 4: Disposing of supplies

Introduction

The following instructions explain how to prepare and inject Enbrel. Please read the instructions carefully and follow them step by step. You will be instructed by your doctor or his/her assistant on the techniques of self-injection. Do not attempt to administer an injection until you are sure that you understand how to prepare and give the injection.

The Enbrel solution should not be mixed with any other medicine before use.

Step 1: Setting up for an injection

1. Select a clean, well-lit, flat working surface.

2. Take the Enbrel carton containing the pre-filled syringes out of the refrigerator and place it on a flat work surface. Remove one pre-filled syringe and one alcohol swab and place them on your work surface. Do not shake the pre-filled syringe of Enbrel. Place the carton containing any remaining pre-filled syringes back into the refrigerator. Please see section 5 for instructions on how to store Enbrel. If you have any questions about storage, contact your doctor, nurse, or pharmacist for further instructions.

3. You should allow 15 to 30 minutes for the Enbrel solution in the syringe to reach room temperature. DO NOT remove the needle cover while allowing it to reach room temperature. Waiting until the solution reaches room temperature may make the injection more comfortable for you. Do not warm Enbrel in any other way (for example, do not warm it in a microwave or in hot water).

4. Assemble the additional supplies you will need for your injection. These include an alcohol swab and a cotton ball or gauze.

5. Wash your hands with soap and warm water.

6. Inspect the solution in the syringe. Only inject the solution in the syringe if it is clear, colourless or pale yellow, and free from easily visible particles. If it is not, use a different syringe, then contact your pharmacist for assistance.

Step 2: Choosing an injection site

1. Three recommended injection sites for Enbrel using a pre-filled syringe include: (1) the front of the middle thighs; (2) the abdomen, except for the 5 cm area right around the navel; and (3) the outer area of the upper arms (see Diagram 1). If you are self injecting, you should not use the outer area of the upper arms.

2. A different site should be used for each new injection. Each new injection should be given at least 3 cm from an old site. Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid areas with scars or stretch marks. (It may be helpful to keep notes on the location of the previous injections.)

3. If you have psoriasis, you should try not to inject directly into any raised, thick, red, or scaly skin patches (“psoriasis skin lesions”).

Step 3: Injecting the Enbrel solution

1. Wipe the site where Enbrel is to be injected with an alcohol swab, using a circular motion. Do NOT touch this area again before giving the injection.

2. Pick up the pre-filled syringe from the flat work surface. Remove the needle cover by firmly pulling it straight off the syringe (see Diagram 2). Be careful not to bend or twist the cover during removal to avoid damage to the needle.

When you remove the needle cover, there may be a drop of liquid at the end of the needle; this is normal. Do not touch the needle or allow it to touch any surface. Do not touch or bump the plunger. Doing so could cause the liquid to leak out.

3. When the cleaned area of skin has dried, pinch and hold it firmly with one hand. With the other hand, hold the syringe like a pencil.

4. With a quick, short motion, push the needle all the way into the skin at an angle between 45° and 90° (see Diagram 3). With experience, you will find the angle that is most comfortable for you. Be careful not to push the needle into the skin too slowly, or with great force.

5. When the needle is completely inserted into the skin, release the skin that you are holding. With your free hand, hold the syringe near its base to stabilise it. Then push the plunger to inject all of the solution at a slow, steady rate (see Diagram 4).

6. When the syringe is empty, pull the needle out of the skin, being careful to keep it at the same angle as inserted. There may be a little bleeding at the injection site. You can press a cotton ball or gauze over the injection site for 10 seconds. Do not rub the injection site. If needed, you may cover the injection site with a bandage.

Step 4: Disposing of supplies

• The pre-filled syringe is for single-use administration only. The syringe and needle should NEVER be reused. NEVER recap a needle. Dispose of the needle and syringe as instructed by your doctor, nurse or pharmacist.

If you have any questions, please talk to a doctor, nurse or pharmacist who is familiar with Enbrel.

Doc ID: 61178 (Taken from Doc ID: 61177 and annex)

Quinzyme

Pronunciation: ue-BIK-wi-none
Generic Name: Ubiquinone
Brand Name: Quinzyme

Quinzyme is used for:

Dietary management of low levels of ubiquinone (coenzyme Q-10) in certain patients with high cholesterol.

Quinzyme is a medical food. It works by providing ubiquinone (coenzyme Q-10) to the body to meet nutritional requirements.

Do NOT use Quinzyme if:

• you are allergic to any ingredient in Quinzyme

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

Before using Quinzyme:

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

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


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


• if you have allergies to medicines, foods, or other substances


• if you have heart problems (eg, congestive heart failure) or diabetes

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

• Anticoagulants (eg, warfarin) because their effectiveness may be decreased by Quinzyme

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

How to use Quinzyme:

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

• Do not swallow this tablet whole. Place the tablet in your mouth and allow it to completely dissolve. The tablet dissolves quickly and can be swallowed with saliva. Quinzyme may be taken with or without water.


• Take Quinzyme on a regular schedule to get the most benefit from it.


• Taking Quinzyme at the same time each day will help you remember to take it.


• If you miss a dose of Quinzyme, take it as soon as you remember. Continue to take it as directed by your doctor or on the package label.

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

Important safety information:

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


• Quinzyme should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Quinzyme while you are pregnant. It is not know if Quinzyme is found in breast milk. If you are or will be breast-feeding while you use Quinzyme, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Quinzyme:

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

Diarrhea; loss of appetite; nausea; stomach upset.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue).

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

See also: Quinzyme side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Quinzyme:

Store Quinzyme at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Most herbal products are not in childproof containers. Keep Quinzyme out of the reach of children and away from pets.

General information:

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


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


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


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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Quinzyme resources

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

• Ubiquinone Natural MedFacts for Professionals (Wolters Kluwer)


• Ubiquinone Natural MedFacts for Consumers (Wolters Kluwer)


• QuinZyme Concise Consumer Information (Cerner Multum)

Compare Quinzyme with other medications

• Dietary Supplementation

ATNAA

atropine and pralidoxime chloride

Dosage Form: injection

FOR USE IN NERVE AGENT POISONING ONLY STERILE SOLUTIONS FOR INTRAMUSCULAR USE ONLY

ATNAA Description

The Antidote Treatment - Nerve Agent, Auto-Injector (ATNAA) provides Atropine Injection and Pralidoxime Chloride Injection in separate chambers as sterile, pyrogen-free solutions for intramuscular injection.

The ATNAA is a specially designed unit for automatic self-or buddy-administration by military personnel. When activated, the ATNAA sequentially administers atropine and pralidoxime chloride through a single needle. The recommended procedure (see DOSAGE AND ADMINISTRATION) is to inject the contents of the auto-injector into the muscles of an outer thigh or into the buttocks.

When activated, each ATNAA dispenses:

2.1 mg atropine in 0.7 mL of a sterile, pyrogen-free solution containing 12.47 mg glycerin and not more than 2.8 mg phenol, citrate buffer, and Water for Injection. The pH range is 4.0 - 5.0.

And

600 mg of pralidoxime chloride in 2 mL of a sterile, pyrogen-free solution containing 40 mg benzyl alcohol, 22.5 mg glycine, and Water for Injection. The pH is adjusted with hydrochloric acid. The pH range is 2.0-3.0.

After a ATNAA has been activated, the empty container should be disposed of properly (see DOSAGE AND ADMINISTRATION).It cannot be refilled, nor can the protruding needle be retracted.

Atropine, an anticholinergic agent (muscarinic antagonist), occurs as white crystals, usually needle-like, or as a white, crystalline powder. It is slightly soluble in water, soluble in glycerin and ether, and freely soluble in alcohol and chloroform with a molecular weight of 289.38. Atropine, a naturally occurring belladonna alkaloid, is a racemic mixture of equal parts of d- and I- hyoscyamine, whose activity is due almost entirely to the levo isomer of the drug. Chemically, atropine is designated as 1[[alpha]]H,5[[alpha]]H-Tropan-3[[alpha]]-ol ([[plusmn]])-tropate. Its empirical formula is C17H23NO3 and its structural formula is:

Pralidoxime chloride, a cholinesterase reactivator, is an odorless, white to pale-yellow crystalline powder, freely soluble in water, with a molecular weight of 172.61. Chemically, pralidoxime chloride is designated as 2-formyl-1-methylpyridinium chloride oxime. Its empirical formula is C7H9CIN2O and its structural formula is:

The specific activity of the drug resides in the 2-formyl-1-methylpyridinium ion and is independent of the particular salt employed. The chloride salt is preferred because of physiologic compatibility, excellent water solubility at all temperatures, and high potency per gram, due to its low molecular weight.

ATNAA - Clinical Pharmacology

Mechanism of Action:

Atropine

Atropine is commonly classified as an anticholinergic or antiparasympathetic (parasympatholytic) drug. More precisely, however, it is termed an antimuscarinic agent since it antagonizes the muscarine-like actions of acetylcholine and other choline esters.

Atropine inhibits the muscarinic actions of acetylcholine on structures innervated by postganglionic cholinergic nerves, and on smooth muscles which respond to endogenous acetylcholine but are not so innervated. As with other antimuscarinic agents, the major action of atropine is a competitive or surmountable antagonism which can be overcome by increasing the concentration of acetylcholine at receptor sites of the effector organ (e.g., by using anticholinesterase agents which inhibit the enzymatic destruction of acetylcholine). The receptors antagonized by atropine are the peripheral structures that are stimulated or inhibited by muscarine,(i.e., exocrine glands and smooth and cardiac muscle). Responses to postganglionic cholinergic nerve stimulation may also be inhibited by atropine but this occurs less readily than with responses to injected (exogenous) choline esters.

Pralidoxime Chloride

The principal action of pralidoxime is to reactivate cholinesterase (mainly outside the central nervous system) which has been inactivated by phosphorylation due to an organophosphorous nerve agent or related compound, although pralidoxime does not reactivate cholinesterase inactivated by all organophosphate nerve agents (e.g. soman). The destruction of accumulated acetylcholine can then proceed and neuromuscular junctions will again function normally. Pralidoxime also slows the process of "aging" of phosphorylated cholinesterase to a non-reactivatable form and detoxifies certain organophosphates by direct chemical reaction.

Pharmacodynamics:

Atropine

Atropine reduces secretions in the mouth and respiratory passages, relieves the constriction and spasm of the respiratory passages, and may reduce the paralysis of respiration which results from actions of the toxic agent on the central nervous system. Atropine-induced parasympathetic inhibition may be preceded by a transient phase of stimulation, especially on the heart where small doses first slow the rate before characteristic tachycardia develops due to paralysis of vagal control. Although mild vagal excitation occurs, the increased respiratory rate and occasionally increased depth of respiration produced by atropine are more probably the result of bronchiolar dilatation. Accordingly, atropine is an unreliable respiratory stimulant and large or repeated doses may depress respiration.

Adequate doses of atropine abolish various types of reflex vagal cardiac slowing or asystole. The drug also prevents or abolishes bradycardia or asystole produced by injection of choline esters, anticholinesterase agents or other parasympathomimetic drugs, and cardiac arrest produced by stimulation of the vagus. Atropine may also lessen the degree of partial heart block when vagal activity is an etiologic factor. In some patients with complete heart block, the idioventricular rate may be accelerated by atropine; in others, the rate is stabilized. Occasionally, a large dose may cause atrioventricular (A-V) block and nodal rhythm.

Atropine in clinical doses counteracts the peripheral dilatation and abrupt decrease in blood pressure produced by choline esters. However, when given by itself, atropine does not exert a striking or uniform effect on blood vessels or blood pressure. Systemic doses slightly raise systolic and lower diastolic pressures and can produce significant postural hypotension. Such doses also slightly increase cardiac output and decrease central venous pressure. Occasionally, therapeutic doses dilate cutaneous blood vessels, particularly in the "blush" area (atropine flush), and may cause atropine "fever" due to suppression of sweat gland activity in infants and small children.

Pralidoxime Chloride

Pralidoxime chloride has its most critical effect in relieving paralysis of the muscles of respiration. Because pralidoxime is less effective in relieving depression of the respiratory center, atropine is always required concomitantly to block the effect of accumulated acetylcholine at this site. Pralidoxime relieves muscarinic signs and symptoms, salivation, bronchospasm, etc., but this action is relatively unimportant since atropine is adequate for this purpose.

Published reports have established the safety and efficacy of atropine and pralidoxime chloride used separately, as well as the safety and increased efficacy of atropine and pralidoxime chloride when administered concomitantly in the treatment of nerve agent poisoning in humans3.

Pharmacokinetics:

Atropine

Atropine is rapidly and well absorbed after intramuscular administration. Atropine disappears rapidly from the blood and is distributed throughout the various body tissues and fluids. Much of the drug is destroyed by enzymatic hydrolysis, particularly in the liver; from 13 to 50% is excreted unchanged in the urine. Traces are found in various secretions, including milk. Atropine readily crosses the placental barrier and enters the fetal circulation.

The Cmax , Tmax , and T1/2 of atropine following 2.09 mg atropine given intramuscularly by multichambered delivery system was 13 [[plusmn]] 3 ng/mL, 31 [[plusmn]] 30 minutes, and 2.4 [[plusmn]] 0.3 hours, respectively. The protein binding of atropine is 14 to 22% in plasma. There are gender differences in the pharmacokinetics of atropine. The AUC(0-inf) and Cmax were 15% higher in females than males. The half-life of atropine is slightly shorter (approximately 20 minutes) in females than males.

Pralidoxime Chloride

Pralidoxime is distributed throughout the extracellular water; it is not bound to plasma protein. The drug is rapidly excreted in the urine partly unchanged, and partly as a metabolite produced by the liver. Consequently, pralidoxime is relatively short acting and repeated doses may be needed, especially where there is any evidence of continuing absorption of the poison.

The Cmax , Tmax , and T1/2 of pralidoxime following 600 mg pralidoxime given intramuscularly by multi-chambered delivery system was 7 [[plusmn]] 3 ng/mL, 28 [[plusmn]] 15 minutes, and 2 [[plusmn]] 1 hour, respectively. The Cmax of pralidoxime was about 36% higher in females than males but the AUC was comparable between the two genders.

Indications and Usage for ATNAA

The ATNAA is indicated for the treatment of poisoning by susceptible organophosphorous nerve agents having anticholinesterase activity.

Contraindications

In the face of life-threatening poisoning by organophosphorous nerve agents, there are no absolute contraindications for the use of the ATNAA (see WARNINGS).

Warnings

While ATNAA can be administered to all individuals with a life-threatening exposure to organophosphorous nerve agents, it should be administered with extreme caution to individuals with the following disorders when the symptoms of nerve agent poisoning are less severe: individuals who are hypersensitive to any component of the product, disorders of heart rhythm such as atrial flutter, severe narrow angle glaucoma, pyloric stenosis, or prostatic hypertrophy.

More than one dose of ATNAA, to a maximum of three doses, may be necessary, especially when exposure is massive or symptoms are severe (see DOSAGE AND ADMINISTRATION). Children are more susceptible than adults to the toxic effects of anticholinergic agents.

Severe difficulty in breathing requires artificial respiration in addition to the use of the ATNAA.

Pralidoxime is not effective in the treatment of poisoning due to phosphorus, inorganic phosphates, or organophosphates not having anticholinesterase activity.

Precautions

General: The desperate condition of the organophosphorous-poisoned patient will generally mask such minor signs and symptoms of atropine and pralidoxime treatment as have been noted in normal subjects.

Because pralidoxime is excreted in the urine, a decrease in renal function will result in increased blood levels of the drug.

The ATNAA should be used with caution in all individuals over 40 years of age. Conventional systemic doses may precipitate acute glaucoma in susceptible patients, convert partial organic pyloric stenosis into complete pyloric obstruction, precipitate urinary retention in patients with prostatic hypertrophy, or cause inspiration of bronchial secretions and formation of dangerous viscid plugs in patients with chronic lung disease.

Information for Patients: Appropriate steps must be taken to insure that personnel understand the indications for, and use of, the ATNAA, including review of symptoms of poisoning and operation of the ATNAA (see DOSAGE AND ADMINISTRATION and Patient Instruction Sheet).

Drug Interactions: When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone because pralidoxime may potentiate the effect of atropine.2,3,4

The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of atropine and pralidoxime. Since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions. Morphine, theophylline, aminophylline, succinylcholine, reserpine, and phenothiazine-type tranquilizers should be avoided in treating personnel with organophosphorous poisoning.

Carcinogenesis, Mutagenesis, Impairment of Fertility: No reports regarding the potential of atropine or pralidoxime chloride for carcinogenesis, mutagenesis, or impairment of fertility have been published in the literature. Since the ATNAA is indicated for short-term emergency use only, no investigations of these aspects have been conducted.

Pregnancy: Teratogenic Effects - Pregnancy Category C: Adequate animal reproduction studies have not been conducted with atropine, pralidoxime,or the combination. It is not known whether pralidoxime or atropine can cause fetal harm when administered to a pregnant woman or if these agents can affect reproductive capacity. The ATNAA should be administered to a pregnant woman only if clearly needed.

Nursing Mothers: It is not known whether these drugs are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when the ATNAA is administered to a nursing woman.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Adverse Reactions

Mild to moderate pain may be experienced at the site of injection.

Atropine

The major side effects of atropine can be attributed to antimuscarinic action. These include dryness of the mouth, blurred vision, photophobia, confusion, headache, dizziness, tachycardia, palpitations, flushing, urinary hesitance or retention, constipation, abdominal distention, nausea, vomiting, loss of libido, and impotency. Anhidrosis may produce heat intolerance and impairment of temperature regulation in a hot environment. Larger or toxic doses may produce such central effects as restlessness, tremor, fatigue, locomotor difficulties, delirium, followed by hallucinations, depression, and, ultimately, medullary paralysis and death. Large doses can also lead to circulatory collapse. In such cases, blood pressure declines and death due to respiratory failure may ensue following paralysis and coma. Hypersensitivity reactions will occasionally occur with atropine; these are usually seen as skin rashes, on occasion progressing to exfoliation.

Pralidoxime Chloride

Pralidoxime may cause blurred vision, diplopia and impaired accommodation, dizziness, headache, drowsiness, nausea, tachycardia, increased systolic and diastolic blood pressure, hyperventilation, decreased renal function, and muscular weakness when given parenterally to normal volunteers who have not been exposed to anticholinesterase poisons. In actual cases of poisoning, it is very difficult to differentiate some of the toxic effects produced by atropine or the organophosphate compound from those of pralidoxime chloride.

Excitement and manic behavior immediately following recovery of consciousness after organophosphorous poisoning treated with pralidoxime chloride have been reported in several cases. However, similar behavior has occurred in cases that were not treated with pralidoxime.3,5,6

Elevations in SGOT and/or SGPT enzyme levels were observed in one of six normal volunteers given 1200 mg of pralidoxime chloride intramuscularly, and in 4 of 6 volunteers given 1800 mg intramuscularly. Levels returned to normal in about two weeks.

Transient elevations in creatine phosphokinase were observed in all normal volunteers given the drug. A single intramuscular injection of 330 mg in 1 mL in rabbits caused myonecrosis, inflammation, and hemorrhage.

Atropine and Pralidoxime Chloride

When atropine and pralidoxime are used together, the signs of atropinization may occur earlier than might be expected when atropine is used alone.

Drug Abuse and Dependence

Atropine and pralidoxime chloride are not subject to abuse and possess no known potential for dependence.

Overdosage

Symptoms:

Atropine

Serious overdosage with atropine is characterized by widespread paralysis of parasympathetically innervated organs. Dry mucous membranes, widely dilated and nonresponsive pupils, tachycardia, fever, and cutaneous flush are especially prominent, as are mental and neurological symptoms. Disorientation, mania, hallucinations, gait disturbances, and symptoms may last 48 hours or longer. In instances of severe intoxication, respiratory depression, coma, circulatory collapse, and death may occur.

The fatal dose of atropine is not known. In the treatment of organophosphorous poisoning, 200 mg doses have been used and doses as high as 1000 mg have been given.

In children, 10 mg or less may be fatal. With a dose as low as 0.5 mg, undesirable minimal symptoms or responses of overdosage may occur. These increase in severity and extent with larger doses of the drug (excitement, hallucinations, delerium, and coma with a dose of 10 mg or more). However, in the presence of organophosphate poisoning, higher doses of atropine may be tolerated.

Pralidoxime Chloride

Symptoms of pralidoxime chloride overdose have been observed in normal subjects only: dizziness, blurred vision, diplopia, headache, impaired accommodation, nausea, slight tachycardia. In therapy it has been difficult to differentiate side effects due to the drug from those due to effects of the poison.

Treatment:

Supportive treatment should be administered as indicated. If respiration is depressed, artificial respiration with oxygen is necessary. Ice bags, alcohol sponges or a hypothermia blanket may be required to reduce fever, especially in children. Catheterization may be necessary if urinary retention occurs. Since atropine elimination takes place through the kidney, urinary output must be maintained and increased if possible; intravenous fluids may be indicated. Because of the affected person's photophobia, the room should be darkened.

In the event of toxic overdosage, a short acting barbiturate or diazepam may be given as needed to control marked excitement and convulsions. Large doses for sedation should be avoided because central depressant action may coincide with the depression occurring late in atropine poisoning. Central stimulants are not recommended. Physostigmine, given as an atropine antidote by slow intravenous injection of 1 to 4 mg (0.5 to 1.0 mg in children), rapidly abolishes delirium and coma caused by large doses of atropine. Since physostigmine has a short duration of action, the patient may again lapse into coma after one or two hours and repeated doses are likely to be required. Neostigmine, pilocarpine, and methacholine are of little real benefit, since they do not penetrate the blood-brain barrier.

ATNAA Dosage and Administration

For optimal reactivation of organophosphorous-inhibited cholinesterase, the ATNAA should be administered as soon as possible after appearance of symptoms of nerve agent poisoning (see below).

The ATNAA should be self- or buddy-administered by military personnel after donning protective mask and hood at the first sign of a chemical attack, and only if some or all of the following mild symptoms of nerve agent exposure are present:

-

Unexplained runny nose

-

Unexplained sudden headache

-

Sudden drooling

-

Difficulty in seeing (dimness of vision and miosis)

-

Tightness of chest or difficulty in breathing

-

Wheezing and coughing

-

Localized sweating and muscular twitching in the area of contaminated skin

-

Stomach cramps

-

Nausea, with or without vomiting

-

Tachycardia followed by bradycardia

The following are the instructions that should be given to military personnel.

Self-Aid

1. Administer one (1) ATNAA into your lateral thigh muscle or buttocks as follows:
   
   1. Remove gray safety cap from back end.
   
   
   2. Place front end on outer thigh and push hard until injector functions.
      
      Hold firmly in place for ten seconds.
   
   
   3. Using a hard surface, bend needle into hook. Push ejected needle through a pocket flap (or other thick and conspicuous part of outer clothing).
   
   


2. Wait 10 to 15 minutes for the antidote to take effect. If you are able to ambulate, know who you are, and where you are, you will NOT need a second injection. Warning: Giving yourself a second set of injections may cause an overdose of the ATNAA which could result in incapacitation.


3. If symptoms of nerve agent poisoning are not relieved after administering one injection, seek someone else to check your symptoms. A buddy must administer the second and third injections, if needed.

Buddy-Aid

1. Casualties with severe symptoms may experience most or all of the mild symptoms described above, plus most or all of the following:
   

   -

   
   

   Strange or confused behavior

   
   

   -

   
   

   Increased wheezing and increased difficulty in breathing

   
   

   -

   
   

   Severely pinpointed pupils

   
   

   -

   
   

   Red eyes with tearing

   
   

   -

   
   

   Vomiting

   
   

   -

   
   

   Severe muscular twitching and general weakness

   
   

   -

   
   

   Involuntary urination and defecation

   
   

   -

   
   

   Convulsions

   
   

   -

   
   

   Unconsciousness

   
   

   -

   
   

   Respiratory failure

   
   

   -

   
   

   Bradycardia

   
   



2. If you encounter a service member suffering from severe signs of nerve agent poisoning, render the following aid:
   
   1. Mask the casualty, if necessary. Do not fasten the hood.
   
   
   2. If self-aid (one ATNAA) has been administered, administer, in rapid succession, two (2) additional ATNAAs into the casualty's lateral thigh muscle or buttocks.
      

      Note: Use the casualty's own ATNAAs when providing aid. Do not use your own injectors on a casualty. If you do, you may not have any antidote available when needed for self-aid.

      
      
   
   
   3. If self-aid (one ATNAA) has not been administered, administer, in rapid succession, three (3) ATNAAs into the casualty's lateral thigh muscle or buttocks.
   
   

IMPORTANT: PHYSICIANS AND/OR MEDICAL PERSONNEL ASSISTING EVACUATED VICTIMS OF NERVE AGENTS, SHOULD AVOID EXPOSING THEMSELVES TO CONTAMINATION BY THE VICTIM'S CLOTHING.

How is ATNAA Supplied

The Antidote Treatment - Nerve Agent, Auto-Injector (ATNAA) provides Atropine Injection (atropine, 2.1 mg/0.7 mL) and Pralidoxime Chloride Injection (pralidoxime chloride, 600 mg/2 mL) in sterile solutions for intramuscular injection. The ATNAA is a self-contained unit designed for automatic self- or buddy-administration by military personnel. ATNAAs are supplied through the Directorate of Medical Materiel, Defense Supply Center, Philadelphia.

Store at 25°C (77°F); excursions permitted to 15 - 30°C (59 - 86°F)

[see USP Controlled Room Temperature]

Keep from Freezing. Protect from Light.

Manufactured by:

MERIDIAN MEDICAL TECHNOLOGIES, INC. GOVERNMENT SYSTEMS

COLUMBIA, MD 21046

Rx only.

0000979

3/02

REFERENCES

1. Landauer, W: Cholinomimetic teratogens. V. The effect of oximes and related cholinesterase reactivators. Teratology 15: 33 (Feb) 1977.


2. Moller, K.O., Jensen-Holm, J. and Lausen, H.H.: Ugeskr Laeg. 123: 501,1961.


3. Namba, T, Nolte, C.T., Jackrel, J. and Grob, D: Poisoning due to organophosphate insecticides. Acute and chronic manifestations. Amer. J. Med. 50: 475 (Apr), 1971.


4. Arena, J.M.: Poisoning, Toxicology Symptoms, Treatments, ed. 4, Springfield, IL, Charles C.Thomas, 1979, p. 133.


5. Brachfeld, J., and Zavon, M.R.: Organic phosphate (Phosdrin®) intoxication. Report of a case and the results of treatment with 2-PAM, Arch. Environ. Health 11: 859, 1965.


6. Hayes, W.J., Jr.: Toxicology of Pesticides. Baltimore, The Williams &Wilkins Company, 1975, p. 416.

– Patient Information

BUDDY-AID LIST	SELF-AID LIST
Use your buddy's own ATNAAs to give your buddy injections. If self-aid (one ATNAA) has been administered, give your buddy a second or third injection in rapid succession OR if self-aid has not been administered, give three (3) ATNAAs in rapid succession, if most or all of the following symptoms occur: - severe symptoms from the Self-Aid List - strange or confused behavior - pinpoint pupils - red, watery eyes - very weak feeling - loss of bladder or bowel control - seizures (fits) - unconsciousness - not breathing - slow heart rate Hook the used ATNAAs to your buddy's pocket flap	Put on protective mask and hood. If you have any of the following symptoms, Inject yourself with one (1) ATNAA right away: - runny nose - headache - drooling - vision problems - tight feeling in chest - breathing problems - wheezing or coughing - sweating - muscle twitching - stomach cramps - nausea or vomiting - heart rate changes from fast to slow Do not give yourself more than one (1) ATNAA. If you are able to move around and know who and where you are, you will NOT need a second ATNAA. If you still have symptoms, have a buddy check your symptoms to decide if you need another injection.
How to Use the Antidote Treatment Nerve Agent Auto-Injector (Delivers 2.1mg atropine and 600mg pralidoxime chloride)

ATNAA  atropine and pralidoxime chloride  kit

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 11704-777

Packaging # NDC Package Description Multilevel Packaging 1 11704-777-01 1 KIT In 1 SYRINGE, GLASS None

QUANTITY OF PARTS Part # Package Quantity Total Product Quantity Part 1   0.7 MILLILITER  in 1  Part 2   2 MILLILITER  in 1

Part 1 of 2 ATROPINE  atropine  injection

Product Information       Route of Administration INTRAMUSCULAR DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength Atropine (Atropine) Active 2.1 MILLIGRAM  In 0.7 MILLILITER Glycerin Inactive   phenol Inactive   citrate buffer Inactive   water Inactive

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging Package Information Not Applicable

Part 2 of 2 PRALIDOXIME CHLORIDE  pralidoxime chloride  injection

Product Information       Route of Administration INTRAMUSCULAR DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength Pralidoxime Chloride (Pralidoxime cation) Active 600 MILLIGRAM  In 2 MILLILITER benzyl alcohol Inactive   glycine Inactive   hydrochloric acid Inactive   water Inactive

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging Package Information Not Applicable

Revised: 05/2007MERIDIAN MEDICAL TECHNOLOGIES INC

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