Estraderm Transdermal

Generic Name: estradiol (Transdermal route)

es-tra-DYE-ol

Transdermal route(Emulsion)

Estrogens increase the risk of endometrial cancer; monitor for abnormal vaginal bleeding. Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. Increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) have been reported. An increased risk of developing probable dementia in postmenopausal women 65 years of age or older has also been reported. Risks should be assumed to be similar for other doses, combinations, and dosage forms of estrogens and progestins. Estrogens, with or without progestins, should be prescribed at the lowest effective doses and for the shortest duration possible .

Transdermal route(Patch, Extended Release)

Estrogens increase the risk of endometrial cancer; monitor for abnormal vaginal bleeding. Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. Increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) have been reported. An increased risk of developing probable dementia in postmenopausal women 65 years of age or older has also been reported. Risks should be assumed to be similar for other doses, combinations, and dosage forms of estrogens and progestins. Estrogens, with or without progestins, should be prescribed at the lowest effective doses and for the shortest duration possible.

Transdermal route(Gel/Jelly)

Estrogens increase the risk of endometrial cancer; monitor for abnormal vaginal bleeding. Estrogens with or without progestins should not be used for the prevention of cardiovascular disease. Increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) have been reported. Risks should be assumed to be similar for other doses, combinations, and dosage forms of estrogens and progestins. Estrogens, with or without progestins, should be prescribed at the lowest effective doses and for the shortest duration possible .

Transdermal route(Spray)

Unopposed estrogens increase the risk of endometrial cancer. Adding a progestin will reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Diagnostic measures should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. Increased risks of stroke and deep vein thrombosis in postmenopausal women (50 to 79 years of age) using estrogen alone have been reported. Increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) using estrogens combined with progestins have been reported. An increased risk of developing probable dementia in postmenopausal women 65 years of age or older has also been reported in women receiving estrogen alone or estrogen combined with progestins. Risks should be assumed to be similar for other doses, combinations, and dosage forms of estrogens and progestins. Estrogens, with or without progestins, should be prescribed at the lowest effective doses and for the shortest duration possible. Breast budding and breast masses in prepubertal females and gynecomastia and breast masses in prepubertal males have been reported following unintentional secondary exposure. Patients should strictly adhere to recommended instructions for use .

Commonly used brand name(s)

In the U.S.

• Alora


• Climara


• Divigel


• Elestrin


• Esclim


• Estraderm


• Estrasorb


• EstroGel


• Evamist


• Menostar


• Vivelle


• Vivelle-Dot

In Canada

• Estradot Transdermal


• Estradot Transdermal Therapeutic System


• Estradot Transdermal Therapeutic System


• Oesclim


• Rhoxal-Estradiol Derm 50


• Rhoxal-Estradiol Derm 75


• Roxal-Estradiol Derm 100


• Vivelle 100 Mcg


• Vivelle 25 Mcg


• Vivelle 37.5 Mcg

Available Dosage Forms:

• Patch, Extended Release


• Gel/Jelly


• Spray


• Emulsion

Therapeutic Class: Endocrine-Metabolic Agent

Pharmacologic Class: Estrogen

Uses For Estraderm

Estradiol transdermal spray is used to treat moderate to severe hot flashes and other symptoms of menopause or low amounts of estrogen.

Estradiol is an estrogen hormone. The hormone from the spray is absorbed through your skin into your body. It works by preventing symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating ("hot flashes") in women during menopause.

This medicine is available only with your doctor's prescription.

Before Using Estraderm

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Use of estradiol transdermal spray is not indicated in the pediatric population. Safety and efficacy have not been established.

Geriatric

Although appropriate studies on the relationship of age to the effects of estradiol transdermal spray have not been performed in the geriatric population, no geriatric-specific problems have been documented to date. However, elderly patients are more likely to have breast cancer, stroke, or dementia, which may require caution in patients receiving estradiol transdermal spray.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	X	Studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. This drug should not be used in women who are or may become pregnant because the risk clearly outweighs any possible benefit.

Breast Feeding

Studies suggest that this medication may alter milk production or composition. If an alternative to this medication is not prescribed, you should monitor the infant for side effects and adequate milk intake.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Isotretinoin


• Theophylline


• Tizanidine


• Tranexamic Acid

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Alprazolam


• Amoxicillin


• Ampicillin


• Amprenavir


• Aprepitant


• Atazanavir


• Bacampicillin


• Betamethasone


• Bexarotene


• Bosentan


• Carbamazepine


• Clarithromycin


• Colesevelam


• Cyclosporine


• Darunavir


• Delavirdine


• Doxycycline


• Efavirenz


• Etravirine


• Fosamprenavir


• Fosaprepitant


• Fosphenytoin


• Ginseng


• Griseofulvin


• Itraconazole


• Ketoconazole


• Lamotrigine


• Levothyroxine


• Licorice


• Minocycline


• Modafinil


• Mycophenolate Mofetil


• Mycophenolic Acid


• Nelfinavir


• Nevirapine


• Oxcarbazepine


• Oxytetracycline


• Phenobarbital


• Phenytoin


• Pioglitazone


• Prednisolone


• Primidone


• Rifabutin


• Rifampin


• Rifapentine


• Ritonavir


• Rosuvastatin


• Rufinamide


• Selegiline


• St John's Wort


• Tacrine


• Telaprevir


• Tetracycline


• Tipranavir


• Topiramate


• Troglitazone


• Troleandomycin


• Voriconazole


• Warfarin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Caffeine


• Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Abnormal or unusual vaginal bleeding or


• Blood clots (e.g., deep vein thrombosis, pulmonary embolism), active or history of or


• Breast cancer, known or suspected, or a history of or


• Heart attack, active or recent (within the past 12 months) or


• Liver disease or


• Stroke, active or recent (within the past 12 months) or


• Surgery with a long period of inactivity or


• Tumors (estrogen-dependent), known or suspected—Should not be used in patients with these conditions.

• Asthma or


• Cancer, history of or


• Diabetes or


• Edema (fluid retention or body swelling) or


• Endometriosis or


• Epilepsy (seizures) or


• Gallbladder disease or


• Heart disease or


• Hypercalcemia (high calcium in the blood) or


• Hypertension (high blood pressure) or


• Hypertriglyceridemia (high triglycerides or fats in the blood) or


• Hypocalcemia (low calcium in the blood), severe or


• Hypothyroidism (an underactive thyroid) or


• Jaundice during pregnancy or from using hormonal therapy in the past or


• Liver tumors or


• Migraine headache or


• Porphyria (an enzyme problem) or


• Systemic lupus erythematosus (SLE)—Use with caution. May make these conditions worse.

Proper Use of estradiol

This section provides information on the proper use of a number of products that contain estradiol. It may not be specific to Estraderm. Please read with care.

It is very important that you use this medicine only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered. To do so may cause unwanted side effects.

This medicine is for use on the skin only. Do not get it in your eyes, nose, mouth, breast, or vagina. Do not use it on skin areas that have cuts, scrapes, or burns. If it does get on these areas, rinse it off right away with water.

This medicine comes with a patient information insert. Read and follow the instructions in the insert carefully. Ask your doctor if you have any questions.

Wash your hands with soap and water before and after using this medicine.

To use the spray:

• The spray form of this medicine comes in an applicator that delivers a measured amount of estradiol to the skin with each spray. When using a new spray applicator, prime the pump by holding the spray upright and pumping 3 times. Priming is only necessary the first time you use a new spray applicator; do not prime again.


• Apply the medicine to clean, dry, and unbroken skin on the inside of the forearm between the elbow and the wrist. Do not apply the medicine directly to your breasts or in or around the vagina.


• Allow the medicine to dry for at least 2 minutes before dressing, and at least 1 hour before washing.


• If your doctor tells you to increase your dose, move the applicator to an area of the skin next to your previous application site, before applying the second or third spray.


• Do not rub Evamist® spray into your skin.


• Do not allow your child to touch the area of the arm where the medicine was sprayed. If you cannot avoid being close with your child, wear clothes with long sleeves to cover the application site.


• If your child comes in direct contact with the arm where the medicine was sprayed, wash your child's skin right away with soap and water.


• Do not allow your pets to lick or touch the arm where the medicine was sprayed.


• Always place the protective cover back on the applicator of the spray.


• Do not use the applicator for more than 75 sprays.


• Apply sunscreen at least 1 hour before applying Evamist®.

The spray contains alcohol and is flammable. Avoid using it near an open flame or while smoking.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For transdermal dosage form (spray):
  
  • For hot flashes and other symptoms caused by menopause:
    
    • Adults—At first, one spray once a day, usually in the morning. Your doctor may adjust your dose as needed.
    
    
    • Children—Use is not recommended.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Do not use Evamist® spray if it has been more than 12 hours since you missed your last dose.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Estraderm

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and does not cause unwanted effects. Pelvic exam, breast exam, and mammogram (breast x-ray) may be needed to check for unwanted effects, unless your doctor tells you otherwise.

It is unlikely that a postmenopausal woman may become pregnant. But, you should know that using this medicine while you are pregnant could harm your unborn baby. If you think you have become pregnant while using the medicine, tell your doctor right away.

Using large doses of this medicine over a long period of time may increase your risk of heart attack, stroke, blood clots, dementia, breast cancer, or uterine cancer. Talk with your doctor about this risk. If you still have your uterus (womb), ask your doctor if you should also use a progestin medicine.

Your risk of heart disease or stroke from this medicine is higher if you smoke. Your risk is also increased if you have diabetes or high cholesterol, or if you are overweight. Talk with your doctor about ways to stop smoking. Keep your diabetes under control. Ask your doctor about diet and exercise to control your weight and blood cholesterol level.

Tell the medical doctor or dentist in charge that you are using this medicine before any kind of surgery (including dental surgery) or emergency treatment. Your doctor will decide whether you should continue using this medicine.

This medicine may also increase your risk of certain types of cancer. Talk to your doctor if you have concerns about this risk.

Using this medicine alone may increase your risk of getting cancer of the uterus (womb). Check with your doctor right away if you have unusual vaginal bleeding while you are using this medicine.

Stop using this medicine and check with your doctor immediately if severe headache or sudden loss of vision or any other change in vision occurs while you are using this medicine. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

Check with your child's doctor right away if your child starts to have the following symptoms: nipple or breast swelling or tenderness in females, or enlargement of the breasts in males. Your child may have been exposed to this medicine.

Do not allow your pets to lick or touch the arm where this medicine was applied. Small pets may be sensitive to this medicine. Call your pet's veterinarian if your pet starts to have the following symptoms: nipple or breast enlargement, swelling of the vulva, or any signs of illness.

Before you have any medical tests, tell the medical doctor in charge that you are taking this medicine. The results of some tests may be affected by this medicine.

Do not take other medicines or drink grapefruit juice unless you discuss it with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (e.g., St. John's wort) or vitamin supplements.

Estraderm Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

Incidence not known

• Abdominal or stomach cramps or pain


• acid or sour stomach


• anxiety


• backache


• belching


• blistering, peeling, or loosening of the skin


• bloating


• blurred vision


• breast tenderness, enlargement, pain, or discharge


• change in vaginal discharge


• changes in skin color


• changes in vision


• chest pain or discomfort


• chills


• clay-colored stools


• clear or bloody discharge from the nipple


• confusion


• constipation


• convulsions


• cough


• darkening of the urine


• diarrhea


• difficulty with breathing


• difficulty with swallowing


• dimpling of the breast skin


• dizziness or lightheadedness


• double vision


• fainting


• fast heartbeat


• fever


• fluid-filled skin blisters


• full or bloated feeling or pressure in the stomach


• headache


• headache, severe and throbbing


• heartburn


• hives


• indigestion


• inverted nipple


• irregular heartbeats


• itching of the skin


• itching of the vagina or genital area


• joint or muscle pain


• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs


• light-colored stools


• loss of appetite


• loss of bladder control


• lump in the breast or under the arm


• migraine headache


• mood or mental changes


• muscle cramps in the hands, arms, feet, legs, or face


• muscle spasm or jerking of all extremities


• nausea


• noisy breathing


• numbness and tingling around the mouth, fingertips, or feet


• pain during sexual intercourse


• pain in the ankles or knees


• pain or discomfort in the arms, jaw, back, or neck


• pain or feeling of pressure in the pelvis


• pain, redness, or swelling in the arm, foot, or leg


• painful, red lumps under the skin, mostly on the legs


• pains in the stomach, side, or abdomen, possibly radiating to the back


• persistent crusting or scaling of the nipple


• poor insight and judgment


• problems with memory or speech


• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue


• rash


• red, irritated eyes


• redness or swelling of the breast


• sensitivity to the sun


• shortness of breath


• skin thinness


• sore on the skin of the breast that does not heal


• sore throat


• sores, ulcers, or white spots in the mouth or on the lips


• stomach discomfort, upset, or pain


• sudden loss of consciousness


• sudden shortness of breath or troubled breathing


• sweating


• swelling


• swelling of the abdominal or stomach area


• thick, white vaginal discharge with no odor or with a mild odor


• tightness in the chest


• tremor


• trouble recognizing objects


• trouble thinking and planning


• trouble walking


• unexpected or excess milk flow from the breasts


• unpleasant breath odor


• unusual tiredness or weakness


• unusually heavy or unexpected menstrual bleeding


• vaginal bleeding or spotting


• vomiting


• vomiting of blood


• wheezing


• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

• Back pain


• difficulty with moving


• muscle aches


• muscle pain or stiffness


• stuffy or runny nose

Incidence not known

• Decreased interest in sexual intercourse


• heavy bleeding


• hives or welts


• inability to have or keep an erection


• increased hair growth, especially on the face


• increased in sexual ability, desire, drive, or performance


• increased interest in sexual intercourse


• irritability


• leg cramps


• loss in sexual ability, desire, drive, or performance


• loss of scalp hair


• mental depression


• mood disturbances


• patchy brown or dark brown discoloration of the skin


• redness of the skin


• twitching, uncontrolled movements of the tongue, lips, face, arms, or legs


• weight changes

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

Lactobacillus Granules

Pronunciation: LACT-o-bah-sill-us
Generic Name: Lactobacillus
Brand Name: Lactinex

Lactobacillus Granules are used for:

Aiding digestion, preventing diarrhea, and alleviating symptoms of irritable bowel syndrome (IBS). It may also be used for other conditions as determined by your doctor.

Lactobacillus Granules are a dietary supplement. It introduces "friendly bacteria" into the digestive tract, which helps many different conditions.

Do NOT use Lactobacillus Granules if:

• you are allergic to any ingredient in Lactobacillus Granules


• you are sensitive to milk or soy products

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

Before using Lactobacillus Granules:

Some medical conditions may interact with Lactobacillus Granules. 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

Some MEDICINES MAY INTERACT with Lactobacillus Granules. However, no specific interactions with Lactobacillus Granules are known at this time.

This may not be a complete list of all interactions that may occur. Ask your health care provider if Lactobacillus Granules 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 Lactobacillus Granules:

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

• The contents of 1 packet of Lactobacillus Granules should be added to cereal, food, or milk 3 or 4 times a day.


• If you miss a dose of Lactobacillus Granules, 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 Lactobacillus Granules.

Important safety information:

• PREGNANCY and BREAST-FEEDING: If you become pregnant while taking Lactobacillus Granules, discuss with your doctor the benefits and risks of using Lactobacillus Granules during pregnancy. It is unknown if Lactobacillus Granules are excreted in breast milk. If you are or will be breast-feeding while you are using Lactobacillus Granules, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Lactobacillus Granules:

All medicines may cause side effects, but many people have no, or minor, side effects. When used in small doses, no COMMON side effects have been reported with this product. 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.

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 Lactobacillus Granules:

Store Lactobacillus Granules in the refrigerator, between 36 and 46 degrees F (2 and 8 degrees C). Do not freeze. Keep Lactobacillus Granules out of the reach of children and away from pets.

General information:

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


• Lactobacillus Granules are 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 Lactobacillus Granules. 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.

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• Lactobacillus Support Group
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Chlorpromazine Hydrochloride 100mg / 5ml Oral Syrup

Chlorpromazine Hydrochloride 100mg/5ml Oral Syrup

Read all of this leaflet carefully before you start taking this medicine.

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


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


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


• If any of these side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet

• 1. What Chlorpromazine Syrup is and what it is used for


• 2. Before you take Chlorpromazine Syrup


• 3. How to take Chlorpromazine Syrup


• 4. Possible side effects


• 5. How to store Chlorpromazine Syrup


• 6. Further information

What Chlorpromazine Syrup is and what it is used for

The name of your medicine is Chlorpromazine Hydrochloride 100mg/5ml Oral Syrup (referred to as Chlorpromazine Syrup in this leaflet). It contains chlorpromazine hydrochloride. This belongs to a group of medicines called neuroleptics.

Chlorpromazine acts on the brain to calm your emotions.

Chlorpromazine can be used to treat:

• schizophrenia


• feeling and being sick, when you have a terminal illness


• persistent hiccups


• schizophrenia and autism in children


• or to calm your emotions particularly if you feel anxious, agitated, over-excited, violent or dangerously impulsive.

Before you take Chlorpromazine Syrup

Do not take Chlorpromazine Syrup and tell your doctor if:

• you are allergic (hypersensitive) to chlorpromazine or any other ingredients in this liquid (listed in section 6). The signs of allergic reaction can include a rash, itching or shortness of breath


• you are pregnant or breast-feeding


• you have a history of blood problems


• you have severe heart disease


• you have dulled senses such as feeling sleepy or uncoordinated, having blurred vision, slurred speech or being less aware of your surroundings (CNS depression).

Do not take this medicine if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before taking Chlorpromazine Syrup.

Take special care with Chlorpromazine Syrup.

Before you take Chlorpromazine Syrup, tell your doctor if:

• you have heart problems including unusual heart beats, heart disease or heart failure


• you have lung and breathing problems


• you have kidney problems


• you have Parkinson’s Disease


• you have or have had in the past narrow angle glaucoma (this is abnormal pressure in the eye accompanied by pain and blurred vision)


• you have an enlarged prostate gland


• you have epilepsy or have had epilepsy in the past


• you have a condition that causes muscle weakness with tiredness, called myasthenia gravis


• you have a tumour of your adrenal gland that causes high blood pressure (phaeochromocytoma)


• you have liver problems


• you have an underactive thyroid


• you are feeling depressed


• you or someone else in your family has a history of blood clots, as medicines like these have been associated with formation of blood clots


• you have had a stroke or you have any of the following that can increase your risk of having a stroke
  
  
  • a heart attack
  
  
  • a TIA (transient ischaemic attack). This is a type of stroke where symptoms last less than 24 hours
  
  
  • an artificial heart valve
  
  
  • uncontrolled high blood pressure
  
  
  • diabetes
  
  
  • high cholesterol
  
  
  • a family history of strokes
  
  
  • you smoke
  
  
  • you drink excess alcohol (this tends to weaken blood vessels and can raise blood pressure)
  
  



• Older people should take chlorpromazine with caution in very hot or cold weather. This is because there is a risk of having a higher body temperature than usual in hot weather (hyperthermia) and a lower body temperature in cold weather (hypothermia) if you take this medicine


• If you are having anaesthetic, tell your doctor or dentist that you are taking chlorpromazine.

Other important information to take into account before you take this medicine:

• if you or members of your family have heart problems (including heart failure, heart attack or uneven heart beats) or you have low potassium or magnesium in your blood, your doctor may do some tests on your heart and blood before giving you this medicine


• your doctor may also want to give you regular blood tests in the first few months of your treatment


• do not go into direct sunlight if you are taking high doses of this medicine. This is because you may become more sensitive to strong sunlight while taking this medicine


• do not put this medicine in contact with your skin as it may cause a skin problem called dermatitis (a skin rash with itching). If the medicine does have contact with your skin, wash the area thoroughly.

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Chlorpromazine Syrup.

Taking other medicines:

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines.

This includes medicines you buy without a prescription, including herbal medicines. This is because chlorpromazine can affect the way some other medicines work. Also some medicines can affect the way chlorpromazine works.

Tell your doctor if you are taking any of these medicines:

• heart medicines such as quinidine, disopyramide, procainamide, amiodarone, sotalol, dofetilide, bretylium, calcium channel blockers such as verapamil, ACE inhibitors such as captopril


• medicines to treat high blood pressure such as propranolol, guanethidine, methyldopa, metirosine, clonidine


• medicines that control your emotions such as anxiety medicines, antidepressants such as amitriptyline and maprotiline, pimozide, sertindole, haloperidol, lithium, trazodone


• medicines that help you sleep such as sedatives or hypnotics such as temazepam


• medicines to treat epilepsy such as barbiturates or phenytoin


• medicines used to treat malaria such as quinine and mefloquine


• antibiotics such as sparfloxacin, moxifloxacin and intravenous erythromycin


• medicines used to treat Parkinson’s Disease such as levodopa, bromocriptine, lisuride and pergolide


• medicines to treat allergies such as hayfever (antihistamines) for example terfenadine and astemizole


• medicines to treat stomach problems such as cimetidine or cisapride


• medicines to treat diabetes


• strong painkillers such as codeine


• medicine used to treat cancer


• tetrabenazine, used to treat disorders that cause unnatural movements


• medicines that help the body get rid of water and affect electrolyte balance (diuretics) such as furosemide or indapamide


• prochlorperazine, used to treat nausea (feeling sick) and vomiting


• desferrioxamine, used to treat some types of anaemia, a type of blood problem


• phenylpropranolamine, used to treat a blocked stuffy nose


• adrenaline.

If you are taking antacids, you should take these at least two hours after taking chlorpromazine.

Taking Chlorpromazine Syrup with food and drink

You must not drink alcohol whilst taking this medicine. This is because this medicine may make you feel drowsy and drinking alcohol will make you even more drowsy. Drinking alcohol may also affect the condition you are suffering from.

Pregnancy and Breast-feeding:

Talk to your doctor before taking this medicine if you are pregnant, planning to become pregnant or are breast-feeding.

You should not use this medicine if you are pregnant or breast-feeding unless your doctor feels it is absolutely necessary.

Driving and using machines:

Do not drive or use tools or machines if this medicine makes you drowsy or if it has affected your eyesight.

Important information about what is in this medicine:

This medicine contains:

• ethanol (alcohol). This product contains a small amount of alcohol, less than 100mg per dose


• methyl, ethyl and propyl parahydroxybenzoates. These may cause an allergic reaction. This allergy may happen some time after starting the medicine


• sorbitol and sucrose. If your doctor has told you that you cannot tolerate some sugars, see your doctor before taking this medicine. In large doses it can have a laxative effect.
  
  
  • The number of calories provided by sorbitol in the maximum daily dose is 36Kcal.
  
  
  • There are 2.25grams of sucrose in each 5ml dose. You should take this into account if you have diabetes. It may be harmful to your teeth.
  
  

How to take Chlorpromazine Syrup

Take this medicine as your doctor or pharmacist has told you. Look on the label and ask the doctor or pharmacist if you are not sure.

Taking this medicine

• this medicine contains 100mg of chlorpromazine hydrochloride in each 5ml


• take this medicine by mouth


• if you feel that the effect of your medicine is too strong or too weak, do not change the dose yourself, but talk to your doctor or pharmacist.

Adults

• The usual dose for adults is 40mg to 300mg daily in divided doses


• The dose prescribed and how often you should take the doses will depend upon the condition being treated and on your response. You will start treatment on a low dose which will be increased as necessary by your doctor


• Older people will need to take one third or half the usual adult dose. Your doctor will gradually increase this dose.

Children

• Children under 1 year should not take this medicine


• Children aged 1 to 5 years: the maximum dose should be no more than 40mg a day.
  
  You must split this dose over the day.


• Children aged 6 to 12 years: the maximum dose should be no more than 75mg a day.
  
  You must split this dose over the day.

Your doctor will work out the dose for your child according to their age and weight.

If you take more Chlorpromazine Syrup than you should

Talk to a doctor or go to a hospital straight away. Take the medicine pack with you so the doctor knows what you have taken. Signs of an overdose may include quick and shallow breaths, low body temperature, low blood pressure, restlessness, twisting of your limbs, fits, unusual heart beats and coma.

If you forget to take Chlorpromazine Syrup

• Do not take a double dose (two doses at the same time) to make up for forgotten doses.


• Skip the missed dose then go on as before.

If you stop taking Chlorpromazine Syrup

Keep taking Chlorpromazine Syrup until your doctor tells you to stop. The doctor will lower your dose gradually.

If you stop taking the medicine suddenly you may get withdrawal symptoms. Signs include:

• feeling or being sick, sweating and difficulty sleeping (insomnia)


• your original symptoms becoming worse


• movements that you can’t control.

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

Possible side effects

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

Stop taking the medicine straight away and see your doctor, if:

• you have an allergic reaction to chlorpromazine syrup
  
  An allergic reaction may include any kind of skin rash, flaking skin, boils or sore lips and mouth, sudden wheezing, fluttering or tightness of the chest or collapse



• you have any of the following symptoms:
  
  
  • unusually fast heart beat, unstable blood pressure (feeling dizzy, light-headed or faint) and sweating. These are early warning signs of a disorder caused by the type of medicine you are taking
  
  
  • very high body temperature, muscle stiffness or a change in consciousness leading to coma
  
  



• a prolonged painful erection. If this happens to you, go to your nearest hospital


• yellowing of the skin and whites of your eyes (jaundice) with fever and possible liver damage.

If you get any of the following side effects, see your doctor as soon as possible:

• blood clots in the veins especially in the legs (symptoms include swelling, pain and redness in the leg), which may travel through blood vessels to the lungs causing chest pain and difficulty in breathing. If you notice any of these symptoms seek medical advice immediately


• feeling depressed, agitated, lack of emotion


• fits


• blood problems. You may notice signs such as high temperature or chills, sore throat, ulcers in your mouth or throat and unusual tiredness


• heart changes including fast heart beats, unusual heart beats, heart attack. Symptoms of a heart attack are chest pain which may spread to the shoulders, neck or arms and shortness of breath. If you get these see a doctor straight away. Unexplained deaths have been reported but it is not proven that they were caused by chlorpromazine


• low body temperature


• low blood pressure. You may feel dizzy when standing up. This may affect older people more


• unusual movements, often of the mouth, lips, eyes and tongue. These movements can also include trembling and shaking of the hands and feet, twisting of the body, shuffling walk and stiffness of the arms and legs and unable to sit still.


• eye changes, such as problems with your eyesight or change in eye colour


• hyperglycaemia (high levels of glucose in the blood). The symptoms of this are feeling thirsty, urinating more often and tiredness


• changes in bowel habits.

Tell your doctor if you get any of these side effects:

• unable to sleep, nightmares


• dry mouth, blocked nose


• pale skin


• skin rash caused by medicine spilt on your skin, skin rashes, skin reaction to direct sunlight


• swelling of the breasts (particularly in men) and breast milk production


• light periods or absence of periods


• decrease in sexual performance


• weight gain


• high cholesterol levels


• changes in your level of alertness.

In elderly people with dementia, a small increase in the number of deaths has been reported for patients taking antipsychotics compared with those not receiving antipsychotics.

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How to store Chlorpromazine Syrup

• Keep out of the reach and sight of children


• Store below 25°C. Do not allow to freeze


• Take any unused medicine back to the pharmacy 6 months after you first open it


• Do not use after the expiry date which stated on the label and carton.(exp: month, year)


• The expiry date refers to the last day of that month


• Do not use Chlorpromazine Syrup if you notice that the appearance or smell of your medicine has changed. Talk to your pharmacist


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

Further information

What Chlorpromazine Syrup contains

• The active ingredient is chlorpromazine hydrochloride.


• The other ingredients are ascorbic acid (E330), sorbitol solution 70% (E420), sucrose, methyl hydroxybenzoate (E218), ethyl hydroxybenzoate (E214), propyl hydroxybenzoate (E216), propylene glycol (E1520), caramel (E150), apricot flavour, garden mint flavour, isopropyl alcohol and purified water.

What Chlorpromazine Syrup looks like and contents of the pack

A pale to dark red-brown syrup with an odour of apricot and mint.

It comes in a brown glass bottle holding 150ml of syrup.

Marketing Authorisation Holder and Manufacturer

Rosemont Pharmaceuticals Ltd

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

UK

This leaflet was last approved in January 2010

P0489

Artiss

Dosage Form: kit
FULL PRESCRIBING INFORMATION

Indications and Usage for Artiss

Artiss is indicated to adhere autologous skin grafts to surgically prepared wound beds resulting from burns in adult and pediatric populations greater than or equal to 1 year of age.

Artiss is not indicated for hemostasis.

Artiss Dosage and Administration

FOR TOPICAL USE ONLY – DO NOT INJECT.

The required dose of Artiss depends on the size of the surface to be covered. The approximate surface areas covered by each package size of Artiss are:

Table 1.

Approximate area requiring skin graft fixation	Required package size of Artiss
100 cm2	2 mL
200 cm2	4 mL
500 cm2	10 mL

It is recommended that every time a patient receives a dose of Artiss the name and lot number (batch number) of the product are documented in order to maintain a record of the batches used.

Preparation of Artiss Kit (Freeze-Dried)

During preparation of Artiss Kit:

DO NOT EXPOSE TO TEMPERATURES ABOVE 37°C

DO NOT REFRIGERATE OR FREEZE AFTER RECONSTITUTION

Do not use iodine or heavy metal containing preparations such as betadine for disinfection of vial stoppers. Allow alcohol-based disinfectants to evaporate before puncturing stopper.

After reconstitution, the product must be used within 4 hours.

Use separate syringes for reconstituting Sealer Protein and Thrombin solutions and for application to prevent premature clotting.

Artiss Kit contains the following substances in four separate vials:

 

-Sealer Protein Concentrate (Human)

 

-Fibrinolysis Inhibitor Solution (Synthetic)

 

-Thrombin (Human)

 

-Calcium Chloride Solution

Freeze-dried Sealer Protein Concentrate and Thrombin are reconstituted in Fibrinolysis Inhibitor Solution and Calcium Chloride Solution, respectively. The Sealer Protein Solution and Thrombin Solution are then combined using the DUPLOJECT Preparation and Application System, or an equivalent delivery device cleared by FDA for use with Artiss to form the Fibrin Sealant.

Prewarming Artiss Kit with FIBRINOTHERM

If a FIBRINOTHERM device is not available, contact Baxter (1-800-423-2090) for assistance. See FIBRINOTHERM manual for complete operating instructions.

1. Plug the FIBRINOTHERM Heating and Stirring Device into an electrical socket and activate the warmer (amber switch). Ensure that the stirring mechanism of the FIBRINOTHERM device is initially switched off (green switch).


2. Place all four vials from the Artiss Kit into the prewarmed wells of the FIBRINOTHERM, using the appropriately sized adapter rings, and allow the vials to warm for up to 5 minutes (room temperature product may take less time).

Preparation of Sealer Protein Solution with FIBRINOTHERM

1. Remove the flip-off caps from the vial containing the Sealer Protein Concentrate and the vial containing the Fibrinolysis Inhibitor Solution, disinfect the rubber stoppers of both vials with a germicidal solution and allow to dry.


2. Transfer the Fibrinolysis Inhibitor Solution into the vial containing the freeze-dried Sealer Protein Concentrate using the sterile reconstitution components provided with the DUPLOJECT Preparation and Application System, or an equivalent device cleared by FDA for use with Artiss (see directions provided with the device system for specific reconstitution instructions). Gently swirl the vial to ensure that the freeze-dried material is completely soaked.


3. Place the vial into the largest opening of the FIBRINOTHERM device with the appropriate adaptor. Switch on the stirrer (green switch) and allow the vial contents to stir until all Sealer Protein Concentrate is dissolved.


4. Reconstitution of the freeze-dried Sealer Protein Concentrate is complete as soon as no undissolved particles are visible. Otherwise, return the vial to the FIBRINOTHERM device and agitate for a few more minutes until the solution appears homogeneous.

Notes:

• Do not use the Sealer Protein Concentrate until it has fully dissolved. If the Sealer Protein Concentrate has not dissolved within 20 minutes using the FIBRINOTHERM device, discard the vial and prepare a fresh kit. Excessive stirring (20 minutes or more) may compromise product quality.


• If not used promptly, keep the Sealer Protein Solution at 37°C without stirring. To ensure homogeneity, switch on the stirrer of the FIBRINOTHERM device shortly before drawing up the solution.

Preparation of Thrombin Solution with FIBRINOTHERM

1. Remove the flip-off caps from the vial containing Thrombin and the vial containing Calcium Chloride Solution, disinfect the rubber stoppers of both vials with a germicidal solution and allow to dry.


2. Transfer the contents of the vial with Calcium Chloride Solution into the vial containing the freeze-dried Thrombin using the sterile reconstitution components provided with the DUPLOJECT Preparation and Application System, or an equivalent device cleared by FDA for use with Artiss (see directions provided with the device system for specific reconstitution instructions).


3. Swirl briefly.


4. Place the vial into the adapted opening of the FIBRINOTHERM device.


5. Reconstitution of Thrombin is complete when all of the Thrombin concentrate is dissolved.


6. Keep the Thrombin Solution at 37°C until used.

Transferring to the Sterile Field

For transfer of the Sealer Protein Solution and the Thrombin Solution to the sterile field, the scrub nurse should withdraw the solutions while the circulating nurse holds the non-sterile vials. The solutions should be withdrawn slowly by firm constant aspiration to reduce the risk of large air bubbles.

See DOSAGE AND ADMINISTRATION, Method of Application (2.3).

Preparation of Artiss Pre-filled Syringe (Frozen)

During preparation of Artiss (frozen):

DO NOT EXPOSE TO TEMPERATURES ABOVE 37°C

DO NOT MICROWAVE

DO NOT REFRIGERATE OR RE-FREEZE AFTER THAWING

Do not use Artiss (frozen) unless it is completely thawed and warmed (liquid consistency).

Do not remove the protective syringe cap until thawing is complete and the application tip is ready to be attached.

Artiss (frozen) can be prepared (thawed) using one of two options:

Room Temperature Thawing

Approximate thawing times when using this method are:

Pack Size	Room Temperature (In Pouches)
2 mL	60 minutes
4 mL	110 minutes
10 mL	160 minutes

Unopened pouches, thawed at room temperature, may be stored for up to 14 days at 15-25°C.

Prior to use, the product should be warmed to 33-37°C:

Pack Size	33°C to 37°C Incubator (In Pouches)
2 mL	15 minutes
4 mL	25 minutes
10 mL	35 minutes

Quick Thawing

Thawing on the sterile field using a water bath

33°C to 37°C sterile water bath - transfer the inner pouch to the sterile field, remove pre-filled syringe from inner pouch and place directly into sterile water bath. Ensure the contents of the pre-filled syringe are completely immersed under the water.

Approximate thawing times when using this method are:

Pack Size	33°C to 37°C Sterile Water Bath (Pouches Removed)
2 mL	5 minutes
4 mL	5 minutes
10 mL	12 minutes

Thawing off the sterile field using a water bath

33°C to 37°C non-sterile water bath in two pouches - maintain the pre-filled syringe in both pouches and place into a water bath off the sterile field for appropriate time. Ensure the pouches remain submerged throughout thawing. Remove from the water bath after thawing, dry external pouch and transfer inner pouch with pre-filled syringe onto the sterile field.

Approximate thawing times when using this method are:

Pack Size	33°C to 37°C Non-Sterile Water Bath (In Pouches)
2 mL	30 minutes
4 mL	40 minutes
10 mL	80 minutes

Thawing off the sterile field using an incubator

33°C to 37°C incubator in pouches – maintain the pre-filled syringe in both pouches and place into an incubator for appropriate time. Remove from incubator after thawing and transfer inner pouch with pre-filled syringe onto the sterile field.

Approximate thawing times when using this method are:

Pack Size	33°C to 37°C Incubator (In Pouches)
2 mL	40 minutes
4 mL	85 minutes
10 mL	105 minutes

Maintain the product at 33-37°C until use. If product is removed from original pouch or warmed to 33-37°C it must be used within 12 hours.

See DOSAGE AND ADMINISTRATION, Method of Application (2.3).

Method of Application

Apply Artiss using the Easyspray and Spray Set, or an equivalent device cleared by FDA for application of Artiss. See additional instructions for use provided with the spray set.

The wound surface should be as dry as possible before application.

Apply Artiss as a thin layer to avoid the formation of excess granulation tissue and to ensure gradual absorption of the polymerized fibrin sealant. The aerosolized sealant should be applied to the wound in a painting motion from side to side to achieve a single thin application. The wound bed will glisten in the area to which fibrin sealant has been applied. Any areas not covered by fibrin sealant will be clearly visible. The skin graft should be attached to the wound bed immediately after Artiss has been sprayed. The surgeon has approximately 60 seconds to manipulate and position the graft prior to polymerization. To prevent adherence, wet gloves with normal saline before product contact.

After the graft has been applied, hold in the desired position by gentle compression for at least 3 minutes to ensure Artiss sets properly and adheres firmly to the surrounding tissue. The solidified fibrin sealant reaches its final strength in approximately 2 hours after application.

The cannulas included with the DUPLOJECT Preparation and Application System or DUO Set may be used for small wounds or for edges of a skin graft that did not adhere to the wound bed  (see WARNINGS/PRECAUTIONS Application Precautions (5.2)). Immediately before application, expel and discard the first several drops from the application cannula to ensure adequate mixing of the Sealer Protein and Thrombin solutions.

 

Freeze-Dried: Refer to instructions for use provided with the DUPLOJECT Preparation and Application System.

 

Frozen: DUO Set Instructions (see Figure 1 below):

1. Insert plunger into syringe barrel.


2. Firmly connect the two syringe nozzles to the joining piece and secure it by fastening the tether strap to the syringe.


3. Fit an application cannula to the joining piece.
   

   If application of Artiss is interrupted, replace the cannula immediately before application is resumed.

   
   

Figure 1 DUO SET A

Vials and pre-filled syringes are for single use only. Discard unused contents.

Dosage Forms and Strengths

Presentations and Pack Sizes

Artiss Kit (Freeze-Dried) is supplied as 2 mL, 4 mL and 10 mL (total volume) pack sizes with and without the DUPLOJECT Preparation and Application System.

Artiss Pre-filled Syringe (Frozen) is supplied as 2 mL, 4 mL and 10 mL (total volume) pack sizes with the DUO Set.

Package Contents

Artiss Kit (Freeze-Dried)

1. Sealer Protein Concentrate (Human), Vapor Heated, Solvent/Detergent Treated, Freeze-Dried, Sterile


2. Fibrinolysis Inhibitor Solution (Synthetic), Sterile


3. Thrombin (Human), Vapor Heated, Solvent/Detergent Treated, Freeze-Dried, Sterile


4. Calcium Chloride Solution, Sterile


5. DUPLOJECT Preparation and Application System (if indicated on the carton)

Artiss Pre-filled Syringe (Frozen)

1. (1) Sealer Protein Solution, Vapor Heated, Solvent/Detergent Treated, Sterile


2. (2) Thrombin Solution, Vapor Heated, Solvent/Detergent Treated, Sterile


3. Sterile accessory devices (DUO Set: 1 plunger, 2 joining pieces and 4 application cannulas) are included with each pre-filled syringe

The reconstituted solution or pre-filled syringe contains:

Sealer Protein Solution

	Total protein:	96 – 125 mg/mL
	Fibrinogen:	67 – 106 mg/mL
	Fibrinolysis Inhibitor (Synthetic):	2250 – 3750 KIU/mL
	Other ingredients include: human albumin, tri-sodium citrate, histidine, niacinamide, polysorbate 80 and water for injection (WFI).

Thrombin Solution

* The potency expressed in units is determined using a clotting assay against an internal reference standard for potency that has been calibrated against the World Health Organization (WHO) Second International Standard for Thrombin, 01/580. Therefore, a unit (U) is equivalent to an International Unit (IU).
	Thrombin (Human):	2.5 – 6.5 units/mL*
	Calcium Chloride:	36 – 44 µmol/mL
	Other ingredients include: human albumin, sodium chloride and water for injection (WFI).

Contraindications

Intravascular Application

Do not inject Artiss directly into blood vessels. Intravascular application of Artiss may result in life-threatening thromboembolic events.

Aprotinin Hypersensitivity

Do not use Artiss in individuals with a known hypersensitivity to aprotinin and/or hypersensitivity to any of the active substances or excipients (see WARNINGS/PRECAUTIONS, Hypersensitivity/Allergic/Anaphylactic Reactions (5.1) and ADVERSE REACTIONS, Overall Adverse Reactions (6.1)).

Warnings and Precautions

Hypersensitivity/Allergic/Anaphylactic Reactions

Hypersensitivity or allergic/anaphylactoid reactions may occur with the use of Artiss. Cases (<1/10,000) have been reported in post marketing experience with Baxter's fibrin sealant (see ADVERSE REACTIONS, Post Marketing (6.3)). In specific cases, these reactions have progressed to severe anaphylaxis. Such reactions may especially be seen if Artiss is applied repeatedly over time or in the same setting, or if systemic aprotinin has been administered previously. Even if the first treatment was well tolerated, a subsequent administration of Artiss or systemic aprotinin may not exclude the occurrence of an allergic reaction. Symptoms associated with allergic anaphylactic reactions include: flush, urticaria, pruritus, nausea, drop in blood pressure, tachycardia or bradycardia, dyspnea, severe hypotension and anaphylactic shock. Such reactions may also occur in patients receiving Artiss for the first time.

Discontinue administration of Artiss in the event of hypersensitivity reactions. Remove the already applied, polymerized product from the surgical field. Mild reactions can be managed with antihistamines. Severe hypotensive reactions require immediate intervention using current principles of shock therapy.

Application Precautions

Apply Artiss as a thin layer. Excessive clot thickness may negatively interfere with the product’s efficacy and the wound healing process.

Air or gas embolism has occurred with the use of spray devices employing pressure regulator to administer fibrin sealants. This event appears to be related to the use of the spray device at higher than recommended pressures and in close proximity to the tissue surface.

When applying Artiss using a spray device, be sure to use the pressure within the pressure range recommended by the spray device manufacturer. In the absence of a specific recommendation avoid using pressure above 20-25 psi. Do not spray closer than the distance recommended by the spray device manufacturer. In the absence of a specific recommendation avoid spraying closer than 10-15 cm from the surface of the tissue. When spraying Artiss, changes in blood pressure, pulse, oxygen saturation and end tidal CO2 should be monitored because of the possibility of occurrence of air or gas embolism.

The sealer protein and thrombin solutions can be denatured by alcohol, iodine or heavy metal ions (e.g. antiseptic solutions). If any of these substances have been used to clean the wound area, the area must be thoroughly rinsed before application of Artiss and made as dry as possible.

Infection Risk from Human Plasma

Artiss is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and removing certain viruses (see CLINICAL PHARMACOLOGY, Other Clinical Pharmacology Information (12.4)). Despite these measures, such products can still potentially transmit disease. Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. This also applies to unknown or emerging viruses or other pathogens. All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Baxter Healthcare Corporation, telephone # 1-866-888-2472.

Some viruses, such as parvovirus B19, are particularly difficult to remove or inactivate at this time. Parvovirus B19 most seriously affects pregnant women (fetal infection), immune-compromised individuals or individuals with an increased erythropoiesis (e.g., hemolytic anemia) (see USE IN SPECIFIC POPULATIONS, Pregnancy (8.1) and PATIENT COUNSELING INFORMATION (17)).

Adverse Reactions

Overall Adverse Reactions

Adverse reactions occurring in greater than 1% of patients treated with Artiss were skin graft failure and pruritus.

Hypersensitivity/Allergic/Anaphylactic Reactions: Hypersensitivity or allergic/anaphylactoid reactions may occur (see WARNINGS/PRECAUTIONS, Hypersensitivity/Allergic/Anaphylactic Reactions (5.1)). No adverse events of this type were reported during clinical trials.

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.

The following adverse reactions have been reported from a clinical trial where Artiss was used to affix split thickness sheet skin grafts to excised burn wounds (see CLINICAL STUDIES (14)). A total of 8 non-serious adverse reactions were deemed related to the use of Artiss by the investigator. Of the 8 related non-serious adverse reactions, 5 were incidences of skin graft failure: 4 were graft detachment/non-adherence and 1 was graft necrosis. The graft detachment in 2 patients may have been related to the maximum thawing temperature (40°C) being exceeded during study product preparation. The 3 other non-serious adverse reactions considered related to Artiss were 2 incidences of pruritus and 1 incidence of dermal cyst. The graft necrosis and the 2 cases of pruritus considered related to Artiss each had an equivalent adverse reaction with the exact start date and severity reported at a control wound where skin grafts were affixed with staples. Therefore, these events are most likely not related to Artiss, but instead are expected outcomes for any grafted wound regardless of the method of attachment.

Overall, the data collected and analyzed during this study demonstrated that Artiss is safe for the attachment of sheet skin grafts in subjects with deep partial thickness or full thickness burn wounds.

The adverse reactions and their frequencies are summarized in Table 2:

Table 2.

Adverse reactions (Preferred Term)	Number of events/ Number of patients treated
Dermal cyst	1/138
Pruritus	2/138
Skin graft failure	5/138

Post Marketing

The following adverse reactions reflect what has been reported in post marketing experience with Baxter's fibrin sealant that could reasonably be expected to occur with Artiss:

Immune system disorders: anaphylactic responses, hypersensitivity

Cardiac disorders: bradycardia, tachycardia

Respiratory, thoracic and mediastinal disorders: dyspnea

Gastrointestinal disorders: nausea

Skin and subcutaneous tissue disorders: urticaria

General disorders and administration site conditions: flushing, impaired healing, edema, pyrexia

Injury, poisoning and procedural complication: seroma

Air embolism associated with misapplication of fibrin sealant using the spray device, Class Effect: A postmarketing fatality was reported in association with the use of another fibrin sealant when applied using a spray device. The case involved an attempt to stop active bleeding by applying the fibrin sealant using a spray device attached to a wall unit at a higher than recommended pressure for the spray device. In addition, the spray head was placed at a distance from the bleeding site that was closer than the recommended distance guidelines for the application of the sealant. The patient suffered a fatal air embolism.

Because these reactions are 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

No interaction studies have been performed.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with Artiss. It is also not known whether Artiss can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Some viruses, such as parvovirus B19, are particularly difficult to remove or inactivate at this time. Parvovirus B19 most seriously affects pregnant women (fetal infection). Artiss should be given to a pregnant woman only if deemed medically necessary.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Artiss is administered to a lactating woman.

Pediatric Use

Thirty six pediatric subjects aged 1–16 years old were included in the prospective, randomized, controlled, evaluator-blinded, multicenter burn clinical study. There was no exclusion criterion for age. Overall, the efficacy of Artiss was demonstrated in subjects less than or equal to?18 years old (Nineteen (13.8%) subjects were less than or equal to 6 years old, 21 (15.2%) subjects were 7 to 18 years old, and 98 (71.0%) were greater than 18 years old) [ITT] (see CLINICAL STUDIES (14)).

Geriatric Use

Clinical studies of Artiss did not include any subjects aged 65 and over.

Overdosage

To avoid the formation of excess granulation tissue and to ensure gradual absorption of the polymerized fibrin sealant, apply only a thin layer of Artiss (see METHOD OF APPLICATION (2.3)).

Artiss Description

Artiss [Fibrin Sealant], Vapor Heated, Solvent Detergent Treated, (Artiss) is a two-component fibrin sealant made from pooled human plasma. When combined, the two components, Sealer Protein (Human) and Thrombin (Human), mimic the final stage of the blood coagulation cascade.

Sealer Protein (Human)

Sealer Protein (Human) is a sterile, non-pyrogenic, vapor-heated and solvent/detergent treated preparation made from pooled human plasma. Sealer Protein (Human) is provided either as a freeze-dried powder [Sealer Protein Concentrate (Human)] for reconstitution with Fibrinolysis Inhibitor Solution (Synthetic) or as a frozen liquid solution pre-filled into one side of a dual-chambered syringe (1). The active ingredient in Sealer Protein (Human) is fibrinogen. A Fibrinolysis Inhibitor, Aprotinin (Synthetic) is included in the Sealer Protein (Human) component to delay fibrinolysis. Aprotinin (Synthetic) is manufactured by solid phase synthesis from materials completely of non-human/non-animal origin.

To obtain Sealer Protein (Human), cryoprecipitate derived from the plasma is dissolved in buffer solution, solvent/detergent treated, vapor heat treated, sterile filtered and either freeze-dried in vials or frozen in pre-filled syringes.

Thrombin (Human)

Thrombin (Human) is a sterile, non-pyrogenic, vapor-heated and solvent/detergent treated preparation made from pooled human plasma. Thrombin (Human) is also provided either as a freeze-dried powder for reconstitution with Calcium Chloride Solution or as a frozen liquid solution pre-filled into one side of a dual-chambered syringe (2).

Thrombin is prepared from plasma through a series of separation and filtration steps followed by incubation of the solution with calcium chloride to activate prothrombin to thrombin. The solution subsequently undergoes ultra/diafiltration, vapor heat treatment, solvent/detergent treatment, sterile filtration and either freeze-drying in vials or frozen in pre-filled syringes.

Sealer Protein (Human) and Thrombin (Human) are made from pooled human plasma collected at US licensed collection centers. The vapor heat and solvent/detergent treatment steps used in the manufacturing process have been shown to be capable of significant viral reduction. No procedure, however, has been shown to be completely effective in removing viral infectivity from derivatives of human plasma (see CLINICAL PHARMACOLOGY, Other Clinical Pharmacology Information (12.4) and WARNINGS/PRECAUTIONS, Infection Risk from Human Plasma (5.3).

See DOSAGE FORMS AND STRENGTHS (3).

Artiss - Clinical Pharmacology

Mechanism of Action

Upon mixing Sealer Protein (Human) and Thrombin (Human), soluble fibrinogen is transformed into fibrin that adheres to the wound surface and to the skin graft to be affixed. Due to the low thrombin concentration, polymerization of Artiss will take approximately 60 seconds.

Pharmacodynamics

Thrombin is a highly specific protease that transforms the fibrinogen contained in Sealer Protein (Human) into fibrin (see Pharmacokinetics (12.3)). Fibrinolysis Inhibitor, Aprotinin (Synthetic), is a polyvalent protease inhibitor that prevents premature degradation of fibrin. Free Aprotinin and its metabolites have a half-life of 30 to 60 minutes and are eliminated by the kidney. Preclinical studies with different fibrin sealant preparations simulating the fibrinolytic activity generated by extracorporeal circulation in patients during cardiovascular surgery have shown that incorporation of aprotinin in the product formulation increases resistance of the fibrin sealant clot to degradation in a fibrinolytic environment.

Pharmacokinetics

Pharmacokinetic studies were not conducted. Because Artiss is applied only topically, systemic exposure or distribution to other organs or tissues is not expected.

Other Clinical Pharmacology Information

Viral Clearance

The manufacturing procedure for Artiss includes processing steps designed to further reduce the risk of viral transmission. In particular, vapor heating and solvent/detergent treatment processes are included in the manufacturing of Sealer Protein Concentrate and Thrombin. Validation studies were conducted using samples drawn from manufacturing intermediates for each of the two human plasma derived components. These samples were spiked with stock virus suspensions of known titers followed by further processing under conditions equivalent to those in the respective manufacturing steps. The stock virus suspensions represent HIV, HBV, HCV, HAV and Human Parvovirus B19.

The virus reduction factors (expressed as log10) of independent manufacturing steps are shown in Table 3 for each of the viruses tested:

Table 3.

n.d. = not determined HIV-1: Human immunodeficiency virus 1; HAV: Hepatitis A virus; BVDV: Bovine viral diarrhea virus, a model for Hepatitis C virus; PRV: Pseudorabies virus, a model for enveloped DNA viruses, among those Hepatitis B virus; MMV: Mice minute virus, a model for B19V.
Reduction Factors for Virus Removal and/or Inactivation Sealer Protein Component
	Mean Reduction Factors [log10] of Virus Tested
Manufacturing Step	HIV-1	HAV	BVDV	PRV	MMV
Early Manufacturing Steps	n.d.	n.d.	n.d.	n.d.	2.7
Solvent/Detergent Treatment	>5.3	n.d.	>5.7	>5.9	n.d.
Vapor Heat Treatment	>5.5	>5.6	>5.7	>6.7	1.2
Overall Reduction Factor (ORF)	>10.8	>5.6	>11.4	>12.6	3.9
Reduction Factors for Virus Removal and/or Inactivation Thrombin Component
	Mean Reduction Factors [log10] of Virus Tested
Manufacturing Step	HIV-1	HAV	BVDV	PRV	MMV
Thrombin precursor mass capture	3.2	1.5	1.8	2.5	1.2
Vapor Heat Treatment	>5.5	>4.9	>5.3	>6.7	1.0
Solvent/Detergent Treatment	>5.3	n.d.	>5.5	>6.4	n.d.
Ion Exchange Chromatography	n.d.	n.d.	n.d.	n.d.	3.6
Overall Reduction Factor (ORF)	>14.0	>6.4	>12.6	>15.6	5.8

In addition, Human Parvovirus B19 was used to investigate the upstream Thrombin precursor mass capture step, the Sealer Protein early manufacturing steps and the Thrombin and Sealer Protein vapor heating steps. Using quantitative PCR assays, the estimated log reduction factors obtained were 1.7 and 3.4 for the Thrombin precursor mass capture step and Sealer Protein early manufacturing steps and >4 / 1.0 for the Thrombin / Sealer Protein vapor heating steps, respectively.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Artiss or studies to determine the effect of Artiss on fertility have not been performed.

Clinical Studies

Artiss was investigated for adherence of split thickness sheet skin grafts in burn patients in a prospective, randomized, controlled, evaluator- blinded, multicenter clinical study. In each of the 138 patients, two comparable test sites were identified after burn wound excision. Skin grafts were adhered at one test site using Artiss, and at the other test site using staples (control). The study product was applied once to the wound bed of the allocated test site during skin grafting surgery.

Of the 138 treated subjects, 94 (68.1%) were male and 44 (31.9%) were female. The mean ± SD age was 30.8 ± 17.6 years; 19 (13.8%) subjects were less than or equal to 6 years old, 21 (15.2%) subjects were 7 to 18 years old, and 98 (71.0%) were greater than 18 years old. The mean ± SD estimated total body surface area (TBSA) for all burn wounds was 13.6 ± 9.2%. The mean ± SD estimated TBSA requiring skin grafting was 8.0 ± 6.9%. The mean ± SD estimated TBSA for Artiss test sites was 1.7 ± 0.8% and for the stapled test sites was 1.7 ± 0.7%. Burn wound thickness was classified as full thickness in 106 (76.8%) of the 138 treated subjects, and partial thickness in 32 (23.2%) subjects. The mean ± SD volume applied was 2.7 ± 1.9 mL (range: 0.2 to 12.0 mL). The mean ± SD surface area treated was 166.4 ± 95.0 cm2 (range: 26.1 to 602. cm2). The mean ± SD calculated dosing volume was 1.8 ± 1.1 mL/100 cm2 (range: 0.2 to 6.0 mL/100 cm2).

The safety population contained all 138 treated subjects; however, 11 subjects did not have an available primary endpoint assessment, leaving a modified intent-to-treat (ITT) set of 127 patients. Complete wound closure by Day 28 was achieved in 43.3% of the Artiss test sites and 37.0% of the stapled test sites in the 127 ITT patients. Rate of wound closure decreased with increasing age. Wound closure at Day 28 was complete for 72.2% of the 1-?6 years old group (N=18) and 31.6% of the 7-18 years old group (N=19) [ITT]. The lower limit of the 97.5% confidence interval of the difference between Artiss and staples was –0.029. A similar result was obtained in the per protocol (PP) population: complete wound closure by Day 28 was achieved in 45.3% of the Artiss test sites and 39.6% of the stapled test sites in the 106 PP patients. The lower limit of the 97.5% confidence interval of the difference between Artiss and staples was –0.041. Therefore, Artiss was found to be non-inferior to staples in the ITT and PP populations at the 97.5% one-sided level for complete wound closure by Day 28 because the lower limit of the confidence interval of the difference between Artiss and staples success rates was greater than the predefined limit of –0.1.

How Supplied/Storage and Handling

Artiss is supplied in the following pack sizes and presentations:

Table 4.

Pack Size	NDC Number
	Artiss Kit (Freeze-Dried)	Artiss Kit (Freeze-Dried) with DUPLOJECT System	Artiss Pre-Filled Syringe (Frozen) with DUO Set
2 mL	0944-4351-03	0944-4351-04	0944-8503-02