Vivelle 100 Mcg

Generic Name: estrogen (Oral route, Parenteral route, Topical application route, Transdermal route)

Commonly used brand name(s)

In the U.S.

• Alora


• Cenestin


• Climara


• Divigel


• Elestrin


• Emcyt


• Enjuvia


• Esclim


• Estinyl


• EstroGel


• Evamist


• Femtrace


• Gynodiol


• Menest


• Menostar


• Ogen .625


• Ogen 1.25


• Ogen 2.5


• Premarin


• Vivelle


• Vivelle-Dot

In Canada

• Estraderm


• Estradot Transdermal


• Estradot Transdermal Therapeutic System


• Estradot Transdermal Therapeutic System


• Estrogel


• Oesclim


• Rhoxal-Estradiol Derm 50


• Rhoxal-Estradiol Derm 75


• Roxal-Estradiol Derm 100


• Vivelle 100 Mcg


• Vivelle 25 Mcg

Available Dosage Forms:

• Tablet


• Patch, Extended Release


• Gel/Jelly


• Spray


• Emulsion


• Tablet, Enteric Coated


• Capsule

Uses For Vivelle 100 Mcg

Estrogens are female hormones. They are produced by the body and are necessary for the normal sexual development of the female and for the regulation of the menstrual cycle during the childbearing years.

The ovaries begin to produce less estrogen after menopause (the change of life). This medicine is prescribed to make up for the lower amount of estrogen. Estrogens help relieve signs of menopause, such as hot flashes and unusual sweating, chills, faintness, or dizziness.

Estrogens are prescribed for several reasons:

• To provide additional hormone when the body does not produce enough of its own, such as during menopause or when female puberty (development of female sexual organs) does not occur on time. Other conditions include a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), or ovary problems (female hypogonadism or failure or removal of both ovaries).


• To help prevent weakening of bones (osteoporosis) in women past menopause.


• In the treatment of selected cases of breast cancer in men and women.


• In the treatment of cancer of the prostate in men.

Estrogens may also be used for other conditions as determined by your doctor.

There is no medical evidence to support the belief that the use of estrogens will keep the patient feeling young, keep the skin soft, or delay the appearance of wrinkles. Nor has it been proven that the use of estrogens during menopause will relieve emotional and nervous symptoms, unless these symptoms are caused by other menopausal symptoms, such as hot flashes or hot flushes.

Estrogens are available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, estrogen is used in certain patients with the following medical conditions:

• Gender identity disorder, male-to-female transsexualism (person who is born as a man but adapts to a woman's lifestyle, sees himself as a woman, and feels like a woman instead of a man.


• Osteoporosis caused by lack of estrogen before menopause.


• Turner's syndrome (a genetic disorder).

Before Using Vivelle 100 Mcg

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to medicines in this group 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 this medicine before puberty is not recommended. Growth of bones can be stopped early. Girls and boys may develop growth of breasts. Girls may have vaginal changes, including vaginal bleeding.

This medicine may be used to start puberty in teenagers with some types of delayed puberty.

Geriatric

Elderly people are especially sensitive to the effects of estrogens. This may increase the chance of side effects during treatment, especially stroke, invasive breast cancer, and memory problems.

Pregnancy

Estrogens are not recommended for use during pregnancy or right after giving birth. Becoming pregnant or maintaining a pregnancy is not likely to occur around the time of menopause.

Certain estrogens have been shown to cause serious birth defects in humans and animals. Some daughters of women who took diethylstilbestrol (DES) during pregnancy have developed reproductive (genital) tract problems and, rarely, cancer of the vagina or cervix (opening to the uterus) when they reached childbearing age. Some sons of women who took DES during pregnancy have developed urinary-genital tract problems.

Breast Feeding

Use of this medicine is not recommended in nursing mothers. Estrogens pass into the breast milk and their possible effect on the baby is not known.

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 taking any of these medicines, 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 medicines in this class with any of the following medicines is not recommended. Your doctor may decide not to treat you with a medication in this class or change some of the other medicines you take.

• Rotavirus Vaccine, Live

Using medicines in this class 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.

• Adenovirus Vaccine Type 4, Live


• Adenovirus Vaccine Type 7, Live


• Bacillus of Calmette and Guerin Vaccine, Live


• Boceprevir


• Felbamate


• Influenza Virus Vaccine, Live


• Isotretinoin


• Measles Virus Vaccine, Live


• Mumps Virus Vaccine, Live


• Paclitaxel


• Paclitaxel Protein-Bound


• Rotavirus Vaccine, Live


• Rubella Virus Vaccine, Live


• Smallpox Vaccine


• St John's Wort


• Theophylline


• Tizanidine


• Tranexamic Acid


• Typhoid Vaccine


• Varicella Virus Vaccine


• Yellow Fever Vaccine

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. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

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

For all patients

• Asthma or


• Calcium, too much or too little in blood or


• Diabetes or


• Epilepsy or seizures or


• Heart problems or


• Kidney problems or


• Liver tumors, benign or


• Lupus erythematosus, systemic or


• Migraine headaches—Estrogens may worsen these conditions.

• Blood clotting problems, or history of during previous estrogen therapy—Estrogens usually are not used until blood clotting problems stop; using estrogens is not a problem for most patients without a history of blood clotting problems due to estrogen use.

• Breast cancer or


• Bone cancer or


• Cancer of the uterus or


• Fibroid tumors of the uterus—Estrogens may interfere with the treatment of breast or bone cancer or worsen cancer of the uterus when these conditions are present.

• Bulging eyes or


• Double vision or


• Migraine headache or


• Vision changes, sudden onset including or


• Vision loss, partial or complete—Estrogens may cause these problems. Tell your doctor if you have had any of these problems, especially while taking estrogen or oral contraceptives (“birth control pills”).

• Changes in genital or vaginal bleeding of unknown causes—Use of estrogens may delay diagnosis or worsen condition. The reason for the bleeding should be determined before estrogens are used.

• Endometriosis or


• Gallbladder disease or gallstones, or history of or


• High cholesterol or triglycerides, or history of or


• Liver disease, or history of or


• Pancreatitis (inflammation of pancreas) or


• Porphyria—Estrogens may worsen these conditions. Although estrogens can improve blood cholesterol, they can worsen blood triglycerides for some people.

• Hypothyroid (too little thyroid hormone)—Dose of thyroid medicine may need to be increased.

For males treated for breast or prostate cancer:

• Blood clots or


• Heart or circulation disease or


• Stroke—Males with these medical problems may be more likely to have clotting problems while taking estrogens; the high doses of estrogens used to treat male breast or prostate cancer have been shown to increase the chances of heart attack, phlebitis (inflamed veins) caused by a blood clot, or blood clots in the lungs.

Proper Use of estrogen

This section provides information on the proper use of a number of products that contain estrogen. It may not be specific to Vivelle 100 Mcg. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it and do not take or use it for a longer time than your doctor ordered. For patients taking any of the estrogens by mouth, try to take the medicine at the same time each day to reduce the possibility of side effects and to allow it to work better.

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

For patients taking any of the estrogens by mouth or by injection:

• Nausea may occur during the first few weeks after you start taking estrogens. This effect usually disappears with continued use. If the nausea is bothersome, it can usually be prevented or reduced by taking each dose with food or immediately after food.

For patients using the transdermal (skin patch):

• Wash and dry your hands thoroughly before and after handling the patch.


• Apply the patch to a clean, dry, non-oily skin area of your lower abdomen, hips below the waist, or buttocks that has little or no hair and is free of cuts or irritation. The manufacturer of the 0.025-mg patch recommends that its patch be applied to the buttocks only. Furthermore, each new patch should be applied to a new site of application. For instance, if the old patch is taken off the left buttock, then apply the new patch to the right buttock.


• Do not apply to the breasts. Also, do not apply to the waistline or anywhere else where tight clothes may rub the patch loose.


• Press the patch firmly in place with the palm of your hand for about 10 seconds. Make sure there is good contact, especially around the edges.


• If a patch becomes loose or falls off, you may reapply it or discard it and apply a new patch.


• Each dose is best applied to a different area of skin on your lower abdomen, hips below the waist, or buttocks so that at least 1 week goes by before the same area is used again. This will help prevent skin irritation.

For patients using the topical emulsion (skin lotion):

• Washing and drying hands thoroughly before each application.


• Apply while you are sitting comfortably. Apply one pouch to each leg every morning.


• Apply the entire contents of one pouch to clean, dry skin on the left thigh. Rub the emulsion into the entire thigh and calf for 3 minutes until thoroughly absorbed.


• Apply entire contents of the second pouch to clean, dry skin on the right thigh. Rub the emulsion into the entire thigh and calf for 3 minutes until thoroughly absorbed.


• Rub any remaining emulsion on both hands on the buttocks.


• Washing and drying hands thoroughly after application.


• To avoid transfer to other individuals, allow the application areas to dry completely before covering with clothing.

If you are using the Evamist® transdermal spray:

• Spray the medicine on your skin on the inside of your forearm, between the elbow and the wrist.


• Do not allow your child to touch the area of the arm where the medicine was sprayed. If you cannot avoid to come nearer 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.

Dosing

The dose medicines in this class 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 these medicines. 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 conjugated estrogens


• For oral dosage form (tablets):
  
  • For treating breast cancer in women after menopause and in men:
    
    • Adults—10 milligrams (mg) three times a day for at least 3 months.
    
    
  
  
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), or symptoms of menopause:
    
    • Adults—0.3 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month. Your doctor may change the dose based on how your body responds to the medication.
    
    
  
  
  • To prevent loss of bone (osteoporosis):
    
    • Adults—0.3 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month. Your doctor may change the dose based on how your body responds to the medication.
    
    
  
  
  • For treating ovary problems (female hypogonadism or for starting puberty):
    
    • Adults and teenagers—0.3 to 0.625 milligram (mg) a day. Your doctor may want you to take the medicine only on certain days of the month.
    
    
  
  
  • For treating ovary problems (failure or removal of both ovaries):
    
    • Adults—1.25 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  
  • For treating prostate cancer:
    
    • Adults—1.25 to 2.5 milligram (mg) three times a day.
    
    
  
  


• For injection dosage form:
  
  • For controlling abnormal bleeding of the uterus:
    
    • Adults—25 milligrams (mg) injected into a muscle or vein. This may be repeated in six to twelve hours if needed.
    
    
  
  

• For esterified estrogens


• For oral dosage form (tablets):
  
  • For treating breast cancer in women after menopause and in men:
    
    • Adults—10 milligrams (mg) three times a day for at least three months.
    
    
  
  
  • For treating a genital skin condition (vulvar atrophy) or inflammation of the vagina (atrophic vaginitis), or to prevent loss of bone (osteoporosis):
    
    • Adults—0.3 to 1.25 mg a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  
  • For treating ovary problems (failure or removal of both ovaries):
    
    • Adults—1.25 mg a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  
  • For treating ovary problems (female hypogonadism):
    
    • Adults—2.5 to 7.5 mg a day. This dose may be divided up and taken in smaller doses. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  
  • For treating symptoms of menopause:
    
    • Adults—0.625 to 1.25 mg a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  
  • For treating prostate cancer:
    
    • Adults—1.25 to 2.5 mg three times a day.
    
    
  
  

• For estradiol


• For oral dosage form:
  
  • For treating breast cancer in women after menopause and in men:
    
    • Adults—10 milligrams (mg) three times a day for at least 3 months.
    
    
  
  
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), ovary problems (female hypogonadism or failure or removal of both ovaries), or symptoms of menopause:
    
    • Adults—At first, 1 to 2 milligrams (mg) one time per day for at least 3 months. Your doctor may want you to take the medicine each day or only on certain days of the month. Your doctor may also need to change the dose based on how your body responds to the medication.
    
    
  
  
  • For treating prostate cancer:
    
    • Adults—1 to 2 milligrams (mg) three times a day.
    
    
  
  
  • To prevent loss of bone (osteoporosis):
    
    • Adults—0.5 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  


• For topical emulsion dosage form (skin lotion):
  
  • For treating symptoms of menopause:
    
    • Adults—1.74 grams (one pouch) applied to the skin of each leg (thigh and calf) once a day in the morning.
    
    
  
  


• For transdermal dosage form (skin patches):
  
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), symptoms of menopause, ovary problems (female hypogonadism or failure or removal of both ovaries), or to prevent loss of bone (osteoporosis):
    
    • For the Climara patches
    
    
    • Adults—0.025 to 0.1 milligram (mg) (one patch) applied to the skin and worn for one week. Then, remove that patch and apply a new one. A new patch should be applied once a week for three weeks. During the fourth week, you may or may not wear a patch. Your health care professional will tell you what you should do for this fourth week. After the fourth week, you will repeat the cycle.
    
    
    • For the Alora, Estraderm, Estradot, Vivelle, or Vivelle-Dot patches
    
    
    • Adults—0.025 to 0.1 mg (one patch) applied to the skin and worn for one half of a week. Then, remove that patch and apply and wear a new patch for the rest of the week. A new patch should be applied two times a week for three weeks. During the fourth week, you may or may not apply new patches. Your health care professional will tell you what you should do for this fourth week. After the fourth week, you will repeat the cycle.
    
    
  
  

• For estradiol cypionate


• For injection dosage form:
  
  • For treating ovary problems (female hypogonadism):
    
    • Adults—1.5 to 2 milligrams (mg) injected into a muscle once a month.
    
    
  
  
  • For treating symptoms of menopause:
    
    • Adults—1 to 5 milligrams (mg) injected into a muscle every 3 to 4 weeks.
    
    
  
  

• For estradiol valerate


• For injection dosage form:
  
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), symptoms of menopause, or ovary problems (female hypogonadism or failure or removal of both ovaries):
    
    • Adults—10 to 20 milligrams (mg) injected into a muscle every 4 weeks as needed.
    
    
  
  
  • For treating prostate cancer:
    
    • Adults—30 milligrams (mg) injected into a muscle every 1 or 2 weeks.
    
    
  
  

• For estrone


• For injection dosage form:
  
  • For controlling abnormal bleeding of the uterus:
    
    • Adults—2 to 5 milligrams (mg) a day, injected into a muscle for several days.
    
    
  
  
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), or symptoms of menopause:
    
    • Adults—0.1 to 0.5 milligram (mg) injected into a muscle 2 or 3 times a week. Your doctor may want you to receive the medicine each week or only during certain weeks of the month.
    
    
  
  
  • For treating ovary problems (female hypogonadism or failure or removal of both ovaries):
    
    • Adults—0.1 to 1 milligram (mg) a week. This is injected into a muscle as a single dose or divided into more than one dose. Your doctor may want you to receive the medicine each week or only during certain weeks of the month.
    
    
  
  
  • For treating prostate cancer:
    
    • Adults—2 to 4 milligrams (mg) injected into a muscle 2 or 3 times a week.
    
    
  
  

• For estropipate


• For oral dosage form (tablets):
  
  • For treating a genital skin condition (vulvar atrophy), inflammation of the vagina (atrophic vaginitis), or symptoms of menopause:
    
    • Adults—0.75 to 6 milligrams (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  
  • For treating ovary problems (female hypogonadism or failure or removal of both ovaries):
    
    • Adults—1.5 to 9 milligrams (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  
  • To prevent loss of bone (osteoporosis):
    
    • Adults—0.75 milligram (mg) a day. Your doctor may want you to take the medicine each day for twenty-five days of a thirty-one–day cycle.
    
    
  
  

• For ethinyl estradiol


• For oral dosage form (tablets):
  
  • For treating breast cancer in women after menopause and in men:
    
    • Adults—1 milligram (mg) three times a day.
    
    
  
  
  • For treating ovary problems (female hypogonadism or failure or removal of both ovaries):
    
    • Adults—0.05 milligram (mg) one to three times a day for 3 to 6 months. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  
  • For treating prostate cancer:
    
    • Adults—0.15 to 3 milligrams (mg) a day.
    
    
  
  
  • For treating symptoms of menopause:
    
    • Adults—0.02 to 0.05 milligram (mg) a day. Your doctor may want you to take the medicine each day or only on certain days of the month.
    
    
  
  

• For ethinyl estradiol and norethindrone


• For oral dosage form (tablets):
  
  • For treating symptoms of menopause:
    
    • Adults—1 tablet (5 mcg ethinyl estradiol and 1 mg of norethindrone) each day.
    
    
  
  
  • To prevent loss of bone (osteoporosis):
    
    • Adults—1 tablet (5 mcg ethinyl estradiol and 1 mg of norethindrone) each day.
    
    
  
  

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.

If you miss a dose of this medicine, apply 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.

If you forget to wear or change a patch, put one on as soon as you can. If it is almost time to put on your next patch, wait until then to apply a new patch and skip the one you missed. Do not apply extra patches to make up for a missed 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 Vivelle 100 Mcg

It is very important that your doctor check your progress at regular visits to make sure this medicine does not cause unwanted effects. These visits will usually be every year, but some doctors require them more often.

In some patients using estrogens, tenderness, swelling, or bleeding of the gums may occur. Brushing and flossing your teeth carefully and regularly and massaging your gums may help prevent this. See your dentist regularly to have your teeth cleaned. Check with your medical doctor or dentist if you have any questions about how to take care of your teeth and gums, or if you notice any tenderness, swelling, or bleeding of your gums.

Although the incidence is low, the use of estrogens may increase you chance of getting cancer of the breast, ovaries, or uterus (womb). Therefore, it is very important that you regularly check your breasts for any unusual lumps or discharge. Report any problems to your doctor. You should also have a mammogram (x-ray pictures of the breasts) done if your doctor recommends it. Because breast cancer has occurred in men taking estrogens, regular breast self-exams and exams by your doctor for any unusual lumps or discharge should be done.

If your menstrual periods have stopped, they may start again. This effect will continue for as long as the medicine is taken. However, if taking the continuous treatment (0.625 mg conjugated estrogens and 2.5 mg medroxyprogesterone once a day), monthly bleeding usually stops within 10 months.

Also, vaginal bleeding between your regular menstrual periods may occur during the first 3 months of use. Do not stop taking your medicine. Check with your doctor if bleeding continues for an unusually long time, if your period has not started within 45 days of your last period, or if you think you are pregnant.

Tell the doctor in charge that you are using this medicine before having any laboratory test because some results may be affected.

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 Evamist® transdermal spray.

Do not allow your pets to lick or touch the arm where Evamist® transdermal spray 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.

Vivelle 100 Mcg Side Effects

Women rarely have severe side effects from taking estrogens to replace estrogen. Discuss these possible effects with your doctor:

The prolonged use of estrogens has been reported to increase the risk of endometrial cancer (cancer of the lining of the uterus) in women after menopause. This risk seems to increase as the dose and the length of use increase. When estrogens are used in low doses for less than 1 year, there is less risk. The risk is also reduced if a progestin (another female hormone) is added to, or replaces part of, your estrogen dose. If the uterus has been removed by surgery (total hysterectomy), there is no risk of endometrial cancer.

Although the incidence is low, the use of estrogens may increase you chance of getting cancer of the breast. Breast cancer has been reported in men taking estrogens.

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.

The following side effects may be caused by blood clots, which could lead to stroke, heart attack, or death. These side effects occur rarely, and, when they do occur, they occur in men treated for cancer using high doses of estrogens.

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

More common

• Breast pain (in females and males)


• fast heartbeat


• fever


• hives


• hoarseness


• increased breast size (in females and males)


• irritation of the skin


• itching of the skin


• joint pain, stiffness, or swelling


• rash


• redness of the skin


• shortness of breath


• swelling of the eyelids, face, lips, hands, or feet


• swelling of the feet and lower legs


• tightness in the chest


• troubled breathing or swallowing


• weight gain (rapid)


• wheezing

Less common or rare

• Changes in vaginal bleeding (spotting, breakthrough bleeding, prolonged or heavier bleeding, or complete stoppage of bleeding)


• chest pain


• chills


• cough


• heavy non-menstrual vaginal bleeding


• lumps in, or discharge from, breast (in females and males)


• pains in the stomach, side, or abdomen


• yellow eyes or skin

Rare - for males being treated for breast or prostate cancer only

• Headache (sudden or severe)


• loss of coordination (sudden)


• loss of vision or change of vision (sudden)


• pains in the chest, groin, or leg, especially in the calf of leg


• shortness of breath (sudden and unexplained)


• slurring of speech (sudden)


• weakness or numbness in the arm or leg

Incidence not known

• Abdominal or stomach bloating


• abdominal or stomach cramps


• acid or sour stomach


• anxiety


• backache


• belching


• blindness


• blistering, peeling, or loosening of the skin


• blue-yellow color blindness


• blurred vision


• change in vaginal discharge


• changes in skin color


• changes in vision


• chest discomfort


• clay-colored stools


• clear or bloody discharge from nipple


• confusion


• constipation


• convulsions


• dark urine


• decrease in the amount of urine


• decreased vision


• depression


• diarrhea


• difficulty with breathing


• difficulty with speaking


• dimpling of the breast skin


• dizziness


• double vision


• dry mouth


• eye pain


• fainting


• fluid-filled skin blisters


• full feeling in upper abdomen or stomach


• full or bloated feeling or pressure in the stomach


• headache


• heartburn


• inability to move the arms, legs, or facial muscles


• inability to speak


• incoherent speech


• increased urination


• indigestion


• inverted nipple


• irregular heartbeats


• light-colored stools


• lightheadedness


• loss of appetite


• loss of bladder control


• lump under the arm


• metallic taste


• migraine headache


• mood or mental changes


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


• muscle pain


• muscle spasm or jerking of all extremities


• muscle weakness


• nausea


• noisy breathing


• numbness or tingling of the hands, feet, or face


• 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, tenderness, swelling of the foot or leg


• painful or tender cysts in the breasts


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


• pains in the chest, groin, or legs, especially calves of the legs


• partial or complete loss of vision in the eye


• pelvic pain


• persistent crusting or scaling of nipple


• pinpoint red or purple spots on the skin


• prominent superficial veins over affected area


• red, irritated eyes


• redness or swelling of the breast


• sensitivity to the sun


• severe headaches of sudden onset


• skin thinness


• skin warmth


• slow speech


• 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 loss of coordination


• sudden onset of shortness of breath for no apparent reason


• sudden onset of slurred speech


• sudden vision changes


• swelling of the abdominal or stomach area


• swelling of the fingers or hands


• thirst


• tremor


• unpleasant breath odor


• unusual tiredness or weakness


• vomiting


• vomiting of blood


• weight loss

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:

More common

• Abnormal growth filled with fluid or semisolid material


• accidental injury


• bladder pain


• bloated full feeling


• bloody or cloudy urine


• body aches or pain


• coating or white patches on tongue


• congestion


• cough producing mucus


• decrease in amount of urine


• difficult, burning, or painful urination


• discouragement


• dryness of the throat


• ear congestion or pain


• excess air or gas in the stomach or intestines


• fear


• feeling of warmth


• feeling sad or empty


• frequent urge to urinate


• general feeling of discomfort or illness


• headache, severe and throbbing


• increased clear or white vaginal discharge


• irritability


• itching of the vaginal, rectal or genital areas


• lack of appetite


• lack or loss of strength


• loss of interest or pleasure


• mild dizziness


• neck pain


• nervousness


• pain


• pain during sexual intercourse


• painful or difficult urination


• pain or tenderness around the eyes and cheekbones


• passing gas


• redness of the face, neck, arms, and occasionally, upper chest


• runny nose


• skin irritation or redness where skin patch was worn


• shivering


• sleeplessness


• sneezing


• sore mouth or tongue


• stuffy nose


• sudden sweating


• tender, swollen glands in the neck


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


• tiredness


• trouble concentrating


• trouble sleeping


• unable to sleep


• voice changes

Less common

• Blemishes on the skin


• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings


• burning or stinging of the skin


• diarrhea (mild)


• difficulty with moving


• dizziness (mild)


• increased hair growth, especially on the face


• lower abdominal or stomach pain or pressure


• mood or mental changes


• muscle stiffness


• painful cold sores or blisters on the lips, nose, eyes, or genitals


• pimples


• pounding in the ears


• problems in wearing contact lenses


• slow heartbeat


• tooth or gum pain


• unusual decrease in sexual desire (in males)


• unusual increase in sexual desire (in females)


• white or brownish vaginal discharge

Incidence not known

• Abnormal turning out of cervix


• changes in appetite


• dull ache or feeling of pressure or heaviness in the legs


• flushed, dry skin


• fruit-like breath odor


• increased hunger


• irritability


• large amount of triglyceride in the blood


• leg cramps


• patchy brown or dark brown discoloration of the skin


• poor insight and judgment


• problems with memory or speech


• trouble recognizing objects


• trouble thinking and planning


• trouble walking


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


• unexpected or excess milk flow from the breasts

Also, many women who are taking estrogens with a progestin (another female hormone) will start having monthly vaginal bleeding, similar to menstrual periods, again. This effect will continue for as long as the medicine is taken. However, monthly bleeding will not occur in women who have had the uterus removed by surgery (total hysterectomy).

This medicine may cause loss or thinning of the scalp hair in some people.

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.

Rapamune 1mg / ml Oral Solution

Rapamune 1mg/ml oral solution.

Sirolimus

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

In this leaflet:

1. What Rapamune is and what it is used for

2. Before you take Rapamune

3. How to take Rapamune

4. Possible side effects

5. How to store Rapamune

6. Further information

What Rapamune Is And What It Is Used For

Rapamune belongs to a group of medicines called immunosuppressants. It helps to control your body’s immune system after you have received an organ transplant. It is used to prevent your body from rejecting transplanted kidneys and is normally used with medicines called corticosteroids and initially with ciclosporin.

Before You Take Rapamune

Do not take Rapamune

• if you are allergic (hypersensitive) to sirolimus or any of the other ingredients of Rapamune.

Take special care with Rapamune

• if you have any liver problems or have had a disease which may have affected your liver, please tell your doctor as this may affect the dose of Rapamune that you receive.


• immunosuppressive medicines may decrease your body’s ability to fight infection, and may increase the risk of developing cancer of the lymphoid tissues and skin.

Your doctor will perform tests to monitor the levels of Rapamune in your blood. Your doctor will also perform tests to monitor your kidney function, your blood fat (cholesterol and/or triglycerides) levels and, possibly, your liver function, during therapy with Rapamune.

Exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor because of the increased risk for skin cancer.

Taking other medicines

Please tell your doctor or pharmacist if you are taking, or have recently taken any other medicines, including those obtained without a prescription. Some medicines can interfere with the action of Rapamune. In particular, you should inform your doctor or pharmacist if you are taking any of the following:

• any other immunosuppressive agents excluding ciclosporin or corticosteroids.


• antibiotics or antifungal medicines used to treat infection e.g. rifampicin, clarithromycin, erythromycin, telithromycin, troleandomycin, rifabutin, clotrimazole, fluconazole, itraconazole, ketoconazole and voriconazole.


• high blood pressure medicines or medicines for heart problems including nicardipine, verapamil and diltiazem.


• anti-epileptic medicines including carbamazepine, phenobarbital, phenytoin.


• medicines used to treat-ulcers or other gastrointestinal disorders such as cisapride, cimetidine, metoclopramide.


• bromocriptine (used in the treatment of Parkinsons’ disease and various hormonal disorders), danazol (used in the treament of gynaecological disorders), or protease inhibitors (used in the treatment of HIV).


• St. John’s Wort (Hypericum perforatum).

The use of Rapamune may lead to increased blood concentrations of cholesterol and triglycerides that may require treatment. Medicines known as “statins” and “fibrates” used to treat elevated cholesterol and triglycerides have been associated with an increased risk of muscle breakdown (rhabdomyolysis). Please inform your doctor if you are taking drugs to lower your blood fats.

Taking Rapamune with food and drink

Rapamune should be taken consistently, either with or without food. Rapamune should be diluted only with water or orange juice. Do not take Rapamune with grapefruit juice.

Pregnancy and breast feeding

You must use effective contraception methods during treatment with Rapamune and for 12 weeks after treatment has stopped. If you are unsure, or think you may have become pregnant, talk to your doctor.

Ask your doctor or pharmacist for advice before taking any medicine.

Decreased sperm count has been associated with the use of Rapamune and usually resolves after discontinuation.

It is not known whether Rapamune passes into breast milk. Patients taking Rapamune should discontinue breast-feeding.

Use in children and adolescents

There is limited experience with the administration of Rapamune in children and adolescents.

Driving and using machines

No specific studies on the effects of Rapamune on the ability to drive and use machines have been conducted. Although Rapamune treatment is not expected to affect your ability to drive, if you have any concerns please consult your doctor.

Important information about one of the ingredients of Rapamune

WARNING: This medicine contains 1.5% to 2.5% ethanol. Each 2 mg dose contains up to 50 mg of alcohol. Alcohol may be harmful for those suffering from alcoholism, epilepsy, brain injury or disease as well as for pregnant women and children. Alcohol may modify or increase the effect of other medicines.

How To Take Rapamune

Rapamune is for oral use only. Always take Rapamune exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Your doctor will decide exactly what dose of Rapamune you must take and how often to take it. Follow your doctor’s instructions exactly and never change the dose yourself. Do not stop taking your medicine unless your doctor tells you to. If you stop taking your medicine, you risk losing your transplant.

Usually for an adult your doctor will give you an initial dose of 6 mg as soon as possible after the kidney transplant operation. Then you will need to take 2 mg of Rapamune each day, unless otherwise directed by your doctor. Your dose will be adjusted depending on the level of Rapamune in your blood. Your doctor will need to perform a blood test to measure Rapamune concentrations.

If you are also taking ciclosporin, then you must take the two medicines approximately 4 hours apart.

Instructions on how to dilute Rapamune

1. Remove the safety cap from the bottle by squeezing the tabs on the cap and twisting. Insert the syringe adapter into the bottle until it is flush with the top of the bottle. Do not attempt to remove the syringe adapter from the bottle once inserted.

2. With the plunger fully depressed, insert one of the dosing syringes into the opening in the adapter.

3. Withdraw the exact amount of Rapamune oral solution as prescribed by your doctor by gently pulling out the plunger of the dosing syringe until the bottom of the black line of the plunger is level with the appropriate mark on the dosing syringe. The bottle should remain in an upright position when withdrawing the solution. If bubbles form in the dosing syringe during withdrawal, empty the Rapamune solution back into the bottle and repeat the withdrawal procedure.

4. You may have been instructed to take your Rapamune oral solution at a particular time of day. If it is necessary to carry your medication with you, fill the dosing syringe to the appropriate mark and place a cap securely on it – the cap should snap into place. Then place the capped dosing syringe in the carrying case provided. Once in the syringe the medication may be kept at room temperature (not exceeding 25°C) or refrigerated and should be used within 24 hours.

Empty the contents of the dosing syringe into only a glass or plastic container holding at least 60 ml of water or orange juice. Stir well for one minute and drink immediately. Refill the glass with at least 120 ml of water or orange juice, stir well, and drink immediately. No other liquids, including grapefruit juice, should be used for dilution. The dosing syringe and cap are to be used once and then discarded.

When refrigerated the solution in the bottle may develop a slight haze. If this occurs, simply bring your Rapamune 1 mg/1 ml oral solution to room temperature and shake gently. The presence of this haze does not affect the quality of Rapamune.

If you take more Rapamune than you should

If you have taken more medicine than you were told contact a doctor or go to the nearest hospital emergency department straight away. Always take the labelled medicine bottle with you, even if it is empty.

If you forget to take Rapamune

If you forget to take Rapamune, take it as soon as you remember, but not within 4 hours of the next dose of ciclosporin. After that, continue to take your medicines as usual. Do not take a double dose to make up for a forgotten dose, and always take Rapamune and ciclosporin approximately 4 hours apart. If you miss a dose of Rapamune completely, you should inform your doctor.

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

Possible Side Effects

Like all medicines, Rapamune can cause side effects, although not everybody gets them. However, since Rapamune is taken in combination with other medicines, the side effects cannot always be attributed with absolute certainty to Rapamune. When taken with medicines called calcineurin inhibitors (ciclosporin or tacrolimus), Rapamune may increase the risk of kidney damage with low blood platelets and low red blood cell counts with or without rash (thrombocytopenic purpura/haemolytic uraemic syndrome).

Immunosuppressants, including Rapamune, reduce your body’s own defence mechanisms to stop you rejecting your transplanted organ. Consequently your body will not be as good as normal at fighting infections. So if you are taking Rapamune you may therefore catch more infections than usual such as infections of the skin, mouth, stomach and intestines, lungs and urinary tract.

Possible side effects of Rapamune are listed according to the following categories:

Very common: more than 1 per 10

Common: less than 1 per 10 but more than 1 per 100

Uncommon: less than 1 per 100 but more than 1 per 1000

Rare: less than 1 per 1000

• Body as a whole:

Very common: Fluid collection around the kidney, swelling of the extremities, fever, pain

Common: Impaired healing (this may include separation of the layers of a surgical wound or suture line), swelling, infections (including life-threatening infections)

• Nervous system disorders:

Very common: Headache

• Cardiac disorders:

Common: Rapid heart rate

Uncommon: Fluid collection in the sac around the heart that, in some cases, may decrease the heart's ability to pump blood

• Blood vessel disorders:

Very common: Increased blood pressure

Common: Blood clots in the legs

Uncommon: Blood clots in the lung

• Gastrointestinal reactions

Very common: Abdominal pain, diarrhea, constipation, nausea

Common: Mouth sores, fluid collection in the abdomen

Uncommon: Inflammation of the pancreas

• Blood and lymph disorders:

Very common: Low red blood cells, low blood platelets

Common: Kidney damage with low blood platelets and low red blood cell counts with or without rash (thrombocytopenic purpura/haemolytic uraemic syndrome), a reduced number of infection fighting cells in the blood (white blood cells), low levels of a type of white blood cells called neutrophils

Uncommon: Cancer of the lymph tissue (lymphoma/post-transplant lympho-proliferative disorder), combined lowering of red blood cells, white blood cells and blood platelets

Rare: Too much fluid collecting in the tissues due to irregular lymph function

• Immune system disorders:

Rare: Allergic reactions including those that are life-threatening

• Metabolism and nutrition disorders:

Very common: Elevated cholesterol, elevated blood sugar, elevated fat in the blood, low blood potassium, low blood phosphorus, elevated lactate dehydrogenase protein in the blood, elevated creatinine in the blood

Common: Diabetes, abnormal tests of liver function, elevated AST and/or ALT liver enzymes

• Bone and joint disorders:

Very common: Joint pain

Common: Deterioration of bone

• Respiratory tract disorders:

Common: Pneumonia and other causes of inflammation that may lead to lung damage, fluid around the lung, nose bleeds

Uncommon: Bleeding from the lung.

Rare: Protein build-up in the air sacs of the lungs that may interfere with breathing

• Skin disorders:

Very common: Acne

Common: Skin cancer, rash

• Kidney disorders:

Very common: Urinary tract infection

Common: Kidney infection; protein in the urine

Uncommon: Protein in the urine, occasionally severe and associated with side effects such as swelling

There is a general tendency for fluid to collect in various tissues.

Serious liver damage has also been reported.

Scarring in the kidney that may reduce kidney function has been reported.

The above side effects may require medical intervention and some may be life-threatening or fatal.

You should see your doctor immediately if you experience symptoms such as swollen face, tongue and/or pharynx (back of the mouth) and/or difficulties in breathing (angioedema), or a skin condition whereby the skin can peel off (exfoliative dermatitis). If you are concerned about any side effect or if you notice any other effects not mentioned in this leaflet, please inform your doctor or pharmacist.

How To Store Rapamune

Keep out of the reach and sight of children.

Do not use Rapamune after the expiry date which is stated on the carton after EXP:. The expiry date refers to the last day of that month.

Keep Rapamune oral solution in its original bottle in order to protect from light. Store in a refrigerator (2°C - 8°C). Once the bottle has been opened, the contents should be kept refrigerated and used within 30 days. If necessary, you may store the bottles at room temperature up to 25°C for a short period of time (no longer than 24 hours).

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 Rapamune contains

The active substance is sirolimus. Each ml of Rapamune contains 1 mg of sirolimus.

The other ingredients are:

Polysorbate 80 and phosal 50 PG (phosphatidylcholine, propylene glycol, monodiglycerides, ethanol (1.5% to 2.5%), soya fatty acids, and ascorbyl palmitate).

What Rapamune looks like and contents of the pack

Rapamune oral solution is supplied in 60 ml amber glass bottles.

Marketing authorisation holder:

Wyeth Europa Ltd

Huntercombe Lane South

Taplow

Maidenhead

Berkshire

SL6 0PH

United Kingdom

Manufacturer:

Wyeth Medica Ireland

Little Connell

Newbridge

Co. Kildare

Ireland

Or

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 1628 415330

Fax:+44 1628 414802

This leaflet was last approved in: 07/2010

Detailed information on this medicine is available on the European Medicines Agency (EMA) website: http://www.emea.europa.eu

Doc ID 61545 (Clean version of 61544)

Mestinon Syrup

Pronunciation: peer-id-oh-STIG-meen
Generic Name: Pyridostigmine
Brand Name: Mestinon

Mestinon Syrup is used for:

Treating myasthenia gravis. It may also be used for other conditions as determined by your doctor.

Mestinon Syrup is a cholinesterase inhibitor. It works by improving nerve impulses in muscles so that the muscles are better able to work.

Do NOT use Mestinon Syrup if:

• you are allergic to any ingredient in Mestinon Syrup


• you are taking quinine or quinidine


• you have a stomach, intestinal, or urinary blockage

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

Before using Mestinon Syrup:

Some medical conditions may interact with Mestinon Syrup. 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, heart block, slow heartbeat), a urinary tract infection, asthma, or kidney problems

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

• Quinine or quinidine because effectiveness of Mestinon Syrup may be decreased


• Succinylcholine because actions and side effects may be increased by Mestinon Syrup

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

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

• Mestinon Syrup may be taken with or without food. Take with food if it upsets your stomach.


• Use a measuring device marked for medicine dosing. Ask your pharmacist for help if you are unsure of how to measure your dose.


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

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

Important safety information:

• Before you have any medical or dental treatments, emergency care, or surgery, tell the doctor or dentist that you are using Mestinon Syrup.


• Use Mestinon Syrup with extreme caution in CHILDREN. Safety and effectiveness have not been confirmed.


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

Possible side effects of Mestinon Syrup:

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); diarrhea; fainting; increased production of saliva; increased sweating; muscle weakness; nausea; small pupils; stomach cramps; trouble breathing; vision changes; vomiting; weakness.

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: Mestinon side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include diarrhea; fainting; increased production of saliva; increased sweating; muscle weakness; nausea; small pupils; stomach cramps; trouble breathing; vision changes; vomiting; weakness.

Proper storage of Mestinon Syrup:

Store Mestinon Syrup between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Mestinon Syrup out of the reach of children and away from pets.

General information:

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


• Mestinon Syrup 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 Mestinon Syrup. 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 Mestinon resources

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

Compare Mestinon with other medications

• Dysautonomia
• Myasthenia Gravis
• Nerve Agent Pretreatment
• Reversal of Nondepolarizing Muscle Relaxants

Cytovene oral and injectable

Generic Name: ganciclovir (oral and injectable) (gan SYE kloe veer)

Brand Names: Cytovene

What is ganciclovir?

Ganciclovir is an antiviral drug. It slows the growth and spread of the cytomegalovirus.

Ganciclovir is used to treat and prevent infections caused by cytomegalovirus. This infection usually occurs in patients who have suppressed immune systems such as patients with AIDS and organ transplant patients.

Ganciclovir may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about ganciclovir?

If you are injecting ganciclovir at home, your healthcare provider will give you detailed instructions on how and where to inject the medication. If you do not understand these directions, do not attempt to inject the medication. Contact your healthcare provider for further instructions.

Serious side effects affecting the blood have been reported with the use of ganciclovir. Decreased levels of blood cells (white blood cells, red blood cells, and platelets) have occurred. Your doctor may monitor your blood with blood tests.

Ganciclovir has caused birth defects in animals, and it is generally not recommended for use during pregnancy. Women should use an effective form of birth control during treatment with ganciclovir. Also, men should use a form of barrier contraception (e.g., condom) during and for at least 90 days following treatment with ganciclovir.

Take all of the ganciclovir that has been prescribed, even if you begin to feel better. Your symptoms may start to improve before the infection is completely treated. Take oral ganciclovir with food to increase its absorption by the body.

What should I discuss with my healthcare provider before taking ganciclovir?

Before taking ganciclovir, tell your doctor if you have

• 
  

  had an allergic reaction to ganciclovir or acyclovir (Zovirax);

  
  


• kidney disease; or


• 
  

  blood problems or low blood counts.

  
  

You may not be able to take ganciclovir, or you may need a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.

Ganciclovir is in the FDA pregnancy category C. This means that it is not known whether ganciclovir will be harmful to an unborn baby. Ganciclovir has caused birth defects in animals, and it is generally not recommended for use during pregnancy. Women should use an effective form of birth control during treatment with ganciclovir. Also, men should use a form of barrier contraception (e.g., condom) during and for at least 90 days following treatment with ganciclovir. It is not known whether ganciclovir passes into breast milk. Generally, breast-feeding should be avoided during treatment with ganciclovir. Do not take ganciclovir without first talking to your doctor if you are breast-feeding a baby.

How should I take ganciclovir?

Take ganciclovir exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each oral dose with a full glass of water. Take each oral dose with food to increase the absorption of the drug in your body.

Your healthcare provider will administer injectable ganciclovir as an intravenous (into a vein) infusion.

If you are injecting ganciclovir at home, your healthcare provider will give you detailed instructions on how and where to inject the medication. If you do not understand these directions, do not attempt to inject the medication. Contact your healthcare provider for further instructions.

Do not use any ganciclovir that is discolored, has particles in it, or looks different from your previous doses. Throw away any unused ganciclovir after the amount of time determined by your pharmacist or doctor.

Take all of the ganciclovir that has been prescribed for you even if you begin to feel better. Your symptoms may start to improve before the infection is completely treated.

Your doctor may want you to have blood tests, eye exams, or other evaluations during treatment with ganciclovir to monitor progress and side effects.

Store oral ganciclovir at room temperature away from moisture and heat.

Dispose of used needles and syringes in a puncture resistant container out of the reach of children.

Your healthcare provider will store injectable ganciclovir as directed by the manufacturer or give you detailed storage instructions if you are storing the medication at home.

What happens if I miss a dose?

If a dose of oral ganciclovir is missed, take the missed dose as soon as you remember. If it is almost time for the next dose, skip that dose and take only your next regularly scheduled dose. Do not take a double dose of this medication.

Contact your healthcare provider if you miss a dose of injectable ganciclovir.

What happens if I overdose?

Seek emergency medical attention if an overdose is suspected.

Symptoms of a ganciclovir overdose include seizures, diarrhea, kidney damage (decreased urine production), liver damage (yellowing of the skin or eyes, abdominal pain), and bone marrow damage (paleness, increased chance of infection, fever and chills).

What should I avoid while taking ganciclovir?

There are no restrictions on food, beverages, or activity during treatment with ganciclovir unless otherwise directed by your doctor.

Ganciclovir side effects

Serious side effects affecting the blood have been reported with the use of ganciclovir. Decreased levels of blood cells (white blood cells, red blood cells, and platelets) have occurred. Your doctor may monitor your blood with blood tests.

Stop taking ganciclovir and seek emergency medical attention if you experience any of the following serious side effects:

• 
  

  an allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives);

  
  


• 
  

  paleness and fatigue that may be signs of anemia (a low level of red blood cells);

  
  


• 
  

  unusual bleeding or bruising;

  
  


• 
  

  fever or signs of infection; or

  
  


• 
  

  numbness or tingling in a part of your body.

  
  

Other, less serious side effects may be more likely to occur. Continue to take ganciclovir and talk to your doctor if you experience

• 
  

  nausea, vomiting, diarrhea, or decreased appetite;

  
  


• 
  

  increased sweating;

  
  


• 
  

  itching; or

  
  


• 
  

  decreased sperm production or infertility.

  
  

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect ganciclovir?

Before taking ganciclovir, tell your doctor if you are taking any of the following drugs:

• 
  

  zidovudine (Retrovir, AZT);

  
  


• 
  

  didanosine (Videx);

  
  


• 
  

  probenecid (Benemid); or

  
  


• 
  

  imipenem-cilastatin (Primaxin).

  
  

You may not be able to take ganciclovir, or you may require a dosage adjustment or special monitoring if you are taking any of the medicines listed above.

Drugs other than those listed here may also interact with ganciclovir. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines, including herbal products.

More Cytovene resources

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

Compare Cytovene with other medications

• CMV Retinitis
• Cytomegalovirus Infection

Where can I get more information?

• Your pharmacist has additional information about ganciclovir written for health professionals that you may read.

See also: Cytovene side effects (in more detail)

Marcain Polyamp Steripack 0.25% and 0.5%

1. Name Of The Medicinal Product

Marcain Polyamp Steripack 0.25%.

Marcain Polyamp Steripack 0.5%.

2. Qualitative And Quantitative Composition

Marcain Polyamp Steripack 0.25% contains Bupivacaine Hydrochloride BP 2.64mg/ml equivalent to bupivacaine hydrochloride anhydrous 2.5mg/ml.

Marcain Polyamp Steripack 0.5% contains Bupivacaine Hydrochloride BP 5.28mg/ml equivalent to bupivacaine hydrochloride anhydrous 5.0mg/ml.

See section 6.1 for list of excipients.

3. Pharmaceutical Form

Injection.

4. Clinical Particulars

4.1 Therapeutic Indications

Marcain 0.25% and 0.5% solutions are used for the production of local anaesthesia by percutaneous infiltration, peripheral nerve block(s) and central neural block (caudal or epidural), that is, for specialist use in situations where prolonged anaesthesia is required. Because sensory nerve block is more marked than motor block, Marcain is especially useful in the relief of pain, e.g. during labour.

A list of indications and the suggested dose and strength of solution appropriate for each are shown in the table below.

4.2 Posology And Method Of Administration

Adults and children above 12 years of age

The following table is a guide to dosage for the more commonly used techniques in the average adult. The figures reflect the expected average dose range needed. Standard textbooks should be consulted for factors affecting specific block techniques and for individual patient requirements.

N.B. When prolonged blocks are used, either by continuous infusion or by repeated bolus administration, the risks of reaching a toxic plasma concentration or inducing a local neural injury must be considered.

The clinician's experience and knowledge of the patient's physical status is important in calculating the required dose. The lowest dose required for adequate anaesthesia should be used. Individual variations in onset and duration occur.

Table 1 Dosage recommendations for adults

	Conc mg/ml	Volume ml	Dose mg	Onset min	Duration of effect hours
SURGICAL ANAESTHESIA
Lumbar Epidural Administration 1)
Surgery	5.0	15-30	75-150	15-30	2-3
Lumbar Epidural Administration 1)
Caesarean Section	5.0	15-30	75-150	15-30	2-3
Thoracic Epidural Administration 1)
Surgery	2.5	5-15	12.5-37.5	10-15	1.5-2
	5.0	5-10	25-50	10-15	2-3
Caudal Epidural Block 1)
	2.5	20-30	50-75	20-30	1-2
	5.0	20-30	100-150	15-30	2-3
Major Nerve Block 2)
(e.g. brachial plexus, femoral, sciatic)	5.0	10-35	50-175	15-30	4-8
Field block
(e.g. minor nerve blocks and infiltration)	2.5	<60	<150	1-3	3-4
	5.0			1-10	3-8

ACUTE PAIN MANAGEMENT
Lumbar Epidural Administration
Intermittent injections 3) (e.g. post-operative pain relief)	2.5	6-15; minimum interval 30 minutes	15-37.5; minimum interval 30 minutes	2-5	1-2
Lumbar Epidural Administration
Continuous infusion 4)	1.25	10-15/h	12.5-18.8/h	-	-
	2.5	5-7.5/h	12.5-18.8/h	-	-
Lumbar Epidural Administration
Continuous infusion, labour pain relief 4)	1.25	5-10/h	6.25-12.5/h	-	-
Thoracic Epidural Administration
Continuous infusion	1.25	5-10/h	6.3-12.5/h	-	-
	2.5	4-7.5/h	10-18.8/h	-	-
Intra-Articular Block 6)
(e.g. single injection following knee arthroscopy)	2.5		5)	5-10	2-4 h after wash out
Field Block
(e.g. minor nerve blocks and infiltration)	2.5			1-3	3-4

1) Dose includes test dose

2) The dose for a major nerve block must be adjusted according to site of administration and patient status. Interscalene and supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anaesthetic used, see also section 4.4.

3) In total

4) This solution is often used for epidural administration in combination with a suitable opioid for pain management. In total

5) If additional bupivacaine is used by any other techniques in the same patient, an overall dose limit of 150 mg should not be exceeded.

6) There have been post-marketing reports of chondrolysis in patients receiving post-operative intra-articular continuous infusion of local anaesthetics. Marcain is not approved for this indication (see also section 4.4).

In general, surgical anaesthesia (e.g. epidural administration) requires the use of higher concentrations and doses. When a less intense block is required (e.g. in the relief of labour pain), the use of a lower concentration is indicated. The volume of drug used will affect the extent of spread of anaesthesia.

In order to avoid intravascular injection, aspiration should be repeated prior to and during administration of the main dose, which should be injected slowly or in incremental doses, at a rate of 25-50 mg/min, while closely observing the patient's vital functions and maintaining verbal contact. An inadvertent intravascular injection may be recognised by a temporary increase in heart rate and an accidental intrathecal injection by signs of a spinal block. If toxic symptoms occur, the injection should be stopped immediately. (See section 4.8.1)

Experience to date indicates that 400 mg administered over 24 hours is well tolerated in the average adult.

Paediatric patients 1 to 12 years of age

The doses in the table should be regarded as guidelines for use in paediatrics. Individual variations occur. In children with a high body weight a gradual reduction of the dosage is often necessary and should be based on the ideal body weight. Standard textbooks should be consulted for factors affecting specific block techniques and for individual patient requirements.

Table 2 Dosage recommendations for children

	Conc. mg/ml	Volume ml/kg	Dose mg/kg	Onset min	Duration of effect hours
ACUTE PAIN MANAGEMENT (per- and postoperative)
Caudal Epidural Administration	2.5	0.6-0.8	1.5-2	20-30	2-6
Lumbar Epidural Administration	2.5	0.6-0.8	1.5-2	20-30	2-6
Thoracic Epidural Administration	2.5	0.6-0.8	1.5-2	20-30	2-6

In children the dosage should be calculated on a weight basis up to 2 mg/kg.

4.3 Contraindications

Bupivacaine hydrochloride solutions are contra-indicated in patients with hypersensitivity to local anaesthetic agents of the amide type or to any of the excipients.

Solutions of bupivacaine hydrochloride are contra-indicated for intravenous regional anaesthesia (Bier's-block).

Epidural anaesthesia, regardless of the local anaesthetic used, has its own contra-indications which include:

Active disease of the central nervous system such as meningitis, poliomyelitis, intracranial haemorrhage, sub-acute combined degeneration of the cord due to pernicious anaemia and cerebral and spinal tumours; tuberculosis of the spine; pyogenic infection of the skin at or adjacent to the site of lumbar puncture; cardiogenic or hypovolaemic shock; coagulation disorders or ongoing anticoagulation treatment.

4.4 Special Warnings And Precautions For Use

There have been reports of cardiac arrest during the use of bupivacaine for epidural anaesthesia or peripheral nerve blockade where resuscitative efforts have been difficult, and were required to be prolonged before the patient responded. However, in some instances resuscitation has proven impossible despite apparently adequate preparation and appropriate management.

Like all local anaesthetic drugs, bupivacaine may cause acute toxicity effects on the central nervous and cardiovascular systems if utilised for local anaesthetic procedures resulting in high blood concentrations of the drug. This is especially the case after unintentional intravascular administration or injection into highly vascular areas. Ventricular arrhythmia, ventricular fibrillation, sudden cardiovascular collapse and death have been reported in connection with high systemic concentrations of bupivacaine.

Adequate resuscitation equipment should be available whenever local or general anaesthesia is administered. The clinician responsible should take the necessary precautions to avoid intravascular injection (see 4.2).

Before any nerve block is attempted, intravenous access for resuscitation purposes should be established. Clinicians should have received adequate and appropriate training in the procedure to be performed and should be familiar with the diagnosis and treatment of side effects, systemic toxicity or other complications (see 4.9 & 4.8).

Major peripheral nerve blocks may require the administration of a large volume of local anaesthetic in areas of high vascularity, often close to large vessels where there is an increased risk of intravascular injection and/or systemic absorption. This may lead to high plasma concentrations.

Overdosage or accidental intravenous injection may give rise to toxic reactions.

Injection of repeated doses of bupivacaine hydrochloride may cause significant increases in blood levels with each repeated dose due to slow accumulation of the drug. Tolerance varies with the status of the patient.

Although regional anaesthesia is frequently the optimal anaesthetic technique, some patients require special attention in order to reduce the risk of dangerous side effects:

• The elderly and patients in poor general condition should be given reduced doses commensurate with their physical status.

• Patients with partial or complete heart block – due to the fact that local anaesthetics may depress myocardial conduction

• Patients with advanced liver disease or severe renal dysfunction

• Patients in the late stages of pregnancy

• Patients treated with anti-arrhythmic drugs class III (e.g. amiodarone) should be under close surveillance and ECG monitoring, since cardiac effects may be additive.

Patients allergic to ester-type local anaesthetic drugs (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to agents of the amide type such as bupivacaine.

Certain local anaesthetic procedures may be associated with serious adverse reactions, regardless of the local anaesthetic drug used.

• Local anaesthetics should be used with caution for epidural anaesthesia in patients with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs.

• The physiological effects generated by a central neural blockade are more pronounced in the presence of hypotension. Patients with hypovolaemia due to any cause can develop sudden and severe hypotension during epidural anaesthesia. Epidural anaesthesia should therefore be avoided or used with caution in patients with untreated hypovolaemia or significantly impaired venous return.

• Retrobulbar injections may very rarely reach the cranial subarachnoid space causing temporary blindness, cardiovascular collapse, apnoea, convulsions etc.

• Retro- and peribulbar injections of local anaesthetics carry a low risk of persistent ocular muscle dysfunction. The primary causes include trauma and/or local toxic effects on muscles and/or nerves. The severity of such tissue reactions is related to the degree of trauma, the concentration of the local anaesthetic and the duration of exposure of the tissue to the local anaesthetic. For this reason, as with all local anaesthetics, the lowest effective concentration and dose of local anaesthetic should be used.

• Vasoconstrictors may aggravate tissue reactions and should be used only when indicated.

• Small doses of local anaesthetics injected into the head and neck, including retrobulbar, dental and stellate ganglion blocks, may produce systemic toxicity due to inadvertent intra-arterial injection.

• Paracervical block may have a greater adverse effect on the foetus than other nerve blocks used in obstetrics. Due to the systemic toxicity of bupivacaine special care should be taken when using bupivacaine for paracervical block.

• There have been post-marketing reports of chondrolysis in patients receiving post-operative intra-articular continuous infusion of local anaesthetics. The majority of reported cases of chondrolysis have involved the shoulder joint. Due to multiple contributing factors and inconsistency in the scientific literature regarding mechanism of action, causality has not been established. Intra-articular continuous infusion is not an approved indication for Marcain.

Epidural anaesthesia with any local anaesthetic can cause hypotension and bradycardia which should be anticipated and appropriate precautions taken. These may include pre-loading the circulation with crystalloid or colloid solution. If hypotension develops it should be treated with a vasopressor such as ephedrine 10-15mg intravenously. Severe hypotension may result from hypovolaemia due to haemorrhage or dehydration, or aorto-caval occlusion in patients with massive ascites, large abdominal tumours or late pregnancy. Marked hypotension should be avoided in patients with cardiac decompensation.

Patients with hypovolaemia due to any cause can develop sudden and severe hypotension during epidural anaesthesia.

Epidural anaesthesia can cause intercostal paralysis and patients with pleural effusions may suffer respiratory embarrassment. Septicaemia can increase the risk of intraspinal abscess formation in the postoperative period.

When bupivacaine is administered as intra-articular injection, caution is advised when recent major intra-articular trauma is suspected or extensive raw surfaces within the joint have been created by the surgical procedure, as that may accelerate absorption and result in higher plasma concentrations.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Bupivacaine should be used with caution in patients receiving other local anaesthetics or agents structurally related to amide-type local anaesthetics, e.g. certain anti-arrhythmics, such as lidocaine and mexiletine, since the systemic toxic effects are additive. Specific interaction studies with bupivacaine and anti-arrhythmic drugs class III (e.g. amiodarone) have not been performed, but caution should be advised. (see also 4.4)

4.6 Pregnancy And Lactation

There is no evidence of untoward effects in human pregnancy. In large doses there is evidence of decreased pup survival in rats and an embryological effect in rabbits if Marcain is administered in pregnancy. Marcain should not therefore be given in early pregnancy unless the benefits are considered to outweigh the risks.

Foetal adverse effects due to local anaesthetics, such as foetal bradycardia, seem to be most apparent in paracervical block anaesthesia. Such effects may be due to high concentrations of anaesthetic reaching the foetus. (see also Section 4.4)

Bupivacaine enters the mother's milk, but in such small quantities that there is no risk of affecting the child at therapeutic dose levels.

4.7 Effects On Ability To Drive And Use Machines

Besides the direct anaesthetic effect, local anaesthetics may have a very mild effect on mental function and co-ordination even in the absence of overt CNS toxicity, and may temporarily impair locomotion and alertness.

4.8 Undesirable Effects

Accidental sub-arachnoid injection can lead to very high spinal anaesthesia possibly with apnoea and severe hypotension.

The adverse reaction profile for Marcain is similar to those for other long acting local anaesthetics. Adverse reactions caused by the drug per se are difficult to distinguish from the physiological effects of the nerve block (e.g. decrease in blood pressure, bradycardia), events caused directly (e.g. nerve trauma) or indirectly (e.g. epidural abscess) by needle puncture.

Neurological damage is a rare but well recognised consequence of regional and particularly epidural and spinal anaesthesia. It may be due to several causes, e.g. direct injury to the spinal cord or spinal nerves, anterior spinal artery syndrome, injection of an irritant substance, or an injection of a non-sterile solution. These may result in localised areas of paraesthesia or anaesthesia, motor weakness, loss of sphincter control and paraplegia. Occasionally these are permanent.

The adverse reactions considered at least possibly related to treatment with Marcain from clinical trials with related products and post-marketing experience are listed below by body system organ class and absolute frequency. Frequencies are defined as very common ( 1/10), common ( 1/100, < 1/10), uncommon ( 1/1,000, < 1/100), rare ( 1/10,000, < 1/1,000) including isolated reports, or not known (identified through post-marketing safety surveillance and the frequency cannot be estimated from the available data).

Table 3

Table of Adverse Drug Reactions (ADR)

System Organ Class	Frequency Classification	Adverse Drug Reaction
Immune system disorders	Rare	Allergic reactions, anaphylactic reaction/shock (see section 4.4)
Nervous system disorders	Common	paraesthesia, dizziness
	Uncommon	Signs and symptoms of CNS toxicity (convulsions, circumoral paraesthesia, numbness of the tongue, hyperacusis, visual disturbances, loss of consciousness, tremor, light headedness, tinnitus, dysarthria, muscle twiching)
	Rare	Neuropathy, peripheral nerve injury, arachnoiditis, paresis and paraplegia
Eye disorders	Rare	Diplopia
Cardiac disorders	Common	Bradycardia (see section 4.4)
	Rare	Cardiac arrest (see section 4.4), cardiac arrhythmias
Vascular disorders	Very Common	Hypotension (see section 4.4)
	Common	Hypertension (see section 4.5)
Respiratory disorders	Rare	Respiratory depression
Gastrointestinal disorders	Very Common	Nausea
	Common	Vomiting
Renal and Urinary	Common	Urinary retention

Hepatic dysfunction, with reversible increases of SGOT, SGPT, alkaline phosphates and bilirubin, has been observed following repeated injections or long-term infusions of bupivacaine. If signs of hepatic dysfunction are observed during treatment with bupivacaine, the drug should be discontinued.

4.8.1 Acute systemic toxicity

Systemic toxic reactions primarily involve the central nervous system (CNS) and the cardiovascular system. Such reactions are caused by high blood concentrations of a local anaesthetic, which may appear due to (accidental) intravascular injection, overdose or exceptionally rapid absorption from highly vascularised areas (see section 4.4). CNS reactions are similar for all amide local anaesthetics, while cardiac reactions are more dependent on the drug, both quantitatively and qualitatively.

Central nervous system toxicity is a graded response with symptoms and signs of escalating severity. The first symptoms are usually light-headedness, circumoral paraesthesia, numbness of the tongue, hyperacusis, tinnitus and visual disturbances. Dysarthria, muscular twitching or tremors are more serious and precede the onset of generalised convulsions. These signs must not be mistaken for neurotic behaviour. Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercarbia occur rapidly following convulsions due to the increased muscular activity, together with the interference with respiration and possible loss of functional airways. In severe cases apnoea may occur. Acidosis, hyperkalaemia and hypoxia increase and extend the toxic effects of local anaesthetics.

Recovery is due to redistribution of the local anaesthetic drug from the central nervous system and subsequent metabolism and excretion. Recovery may be rapid unless large amounts of the drug have been injected.

Cardiovascular system toxicity may be seen in severe cases and is generally preceded by signs of toxicity in the central nervous system. In patients under heavy sedation or receiving a general anaesthetic, prodromal CNS symptoms may be absent. Hypotension, bradycardia, arrhythmia and even cardiac arrest may occur as a result of high systemic concentrations of local anaesthetics, but in rare cases cardiac arrest has occurred without prodromal CNS effects.

4.8.2 Treatment of acute toxicity

If signs of acute systemic toxicity appear, injection of the local anaesthetic should be immediately stopped.

Treatment of a patient with systemic toxicity consists of arresting convulsions and ensuring adequate ventilation with oxygen, if necessary by assisted or controlled ventilation (respiration).

Once convulsions have been controlled and adequate ventilation of the lungs ensured, no other treatment is generally required

If circulatory arrest should occur, immediate cardiopulmonary resuscitation should be instituted. Optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance.

Cardiac arrest due to bupivacaine can be resistant to electrical defibrillation and resuscitation must be continued energetically for a prolonged period.

High or total spinal blockade causing respiratory paralysis and hypotension during epidural anaesthesia should be treated by ensuring and maintaining a patent airway and giving oxygen by assisted or controlled ventilation.

If cardiovascular depression occurs (hypotension, bradycardia) appropriate treatment with intravenous fluids, vasopressor, and or inotropic agents should be considered. Children should be given doses commensurate with age and weight.

4.9 Overdose

Accidental intravascular injections of local anaesthetics may cause immediate (within seconds to a few minutes) systemic toxic reactions. In the event of overdose, systemic toxicity appears later (15-60 minutes after injection) due to the slower increase in local anaesthetic blood concentration. (See sections 4.8.1 & 4.8.2)

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Phamacotherapeutic group (ATC code): N01B B51

Bupivacaine hydrochloride (Marcain) is a long acting local anaesthetic of the amide type with both anaesthetic and analgesic effects. At high doses it produces surgical anaesthesia, while at lower doses it produces sensory block (analgesia) with less pronounced motor block.

Onset and duration of the local anaesthetic effect of bupivacaine depends on the dose and site of administration.

Bupivacaine, like other local anaesthetics, causes a reversible blockade of impulse propagation along nerve fibres by preventing the inward movement of sodium ions through the cell membrane of the nerve fibres. The sodium channels of the nerve membrane are considered a receptor for local anaesthetic molecules.

Local anaesthetics may have similar effects on other excitable membranes e.g. in the brain and myocardium. If excessive amounts of drug reach the systemic circulation, symptoms and signs of toxicity may appear, emanating from the central nervous and cardiovascular systems.

Central nervous system toxicity (See section 4.8.1) usually precedes the cardiovascular effects as central nervous system toxicity occurs at lower plasma concentrations. Direct effects of local anaesthetics on the heart include slow conduction, negative inotropism and eventually cardiac arrest.

Indirect cardiovascular effects (hypotension, bradycardia) may occur after epidural administration depending on the extent of the concomitant sympathetic block.

5.2 Pharmacokinetic Properties

Bupivacaine has a pKa of 8.2 and a partition coefficient of 346 (25°C n-octanol/ phosphate buffer pH 7.4). The metabolites have a pharmacological activity that is less than that of bupivacaine.

The plasma concentration of bupivacaine depends upon the dose, the route of administration and the vascularity of the injection site.

Bupivacaine shows complete and biphasic absorption from the epidural space with half-lives in the order of 7 min and 6 h respectively. The slow absorption is rate-limiting in the elimination of bupivacaine, which explains why the apparent half-life after epidural administration is longer than that after intravenous administration.

Bupivacaine has a total plasma clearance of 0.58 l/min, a volume of distribution at steady state of 73 l, a terminal half-life of 2.7 h and an intermediate hepatic extraction ratio of 0.38 after IV administration. It is mainly bound to alpha-l-acid glycoprotein with plasma binding of 96%. Clearance of bupivacaine is almost entirely due to liver metabolism and more sensitive to changes in intrinsic hepatic enzyme function that to liver perfusion.

In children between 1 to 7 years the pharmacokinetics is similar to that in adults.

An increase in total plasma concentration has been observed during continuous epidural infusion. This is related to a postoperative increase in alpha 1-acid glycoprotein. The unbound, i.e. pharmacologically active, concentration is similar before and after surgery.

Bupivacaine readily crosses the placenta and equilibrium with regard to the unbound concentration is rapidly reached. The degree of plasma protein binding in the foetus is less than in the mother, which results in lower total plasma concentrations in the foetus.

Bupivacaine is extensively metabolised in the liver, predominately by aromatic hydroxylation to 4-hydroxy-bupivacaine and N-dealkylation to PPX, both mediated by cytochrome P4503A4. About 1% of bupivacaine is excreted in the urine as unchanged drug in 24 h and approximately 5% as PPX. The plasma concentrations of PPX and 4-hydroxy-bupivacaine during and after continuous administration of bupivacaine are low as compared to the parent drug.

5.3 Preclinical Safety Data