WebSite Israel: October 2016

Saturday, October 29, 2016

Imiquimod topical

Generic Name: imiquimod topical (i MI kwi mod TOP ik al)

Brand Names: Aldara, Zyclara

What is imiquimod topical?

Imiquimod is an immune response modifier. Imiquimod topical is used to treat actinic keratosis (a condition caused by too much sun exposure) on the face and scalp.

Imiquimod topical (for the skin) is also used to treat a minor form of skin cancer called superficial basal cell carcinoma, when surgery would not be an appropriate treatment.

Imiquimod topical also treats genital warts that appear on the outside of the body, but this medicine is not a cure for genital warts. Imiquimod may be used in adults and children who are at least 12 years.

Imiquimod topical may also be used for purposes not listed in this medication guide.

What is the most important information I should know about imiquimod topical?

Using too much of this medicine, or using it for too long can increase your risk of severe skin reactions. Follow your doctor's instructions.

Do not use imiquimod topical on areas of broken, wounded, or burned skin. Wait until these conditions have healed before using imiquimod topical.

Before using this medication, tell your doctor if you have a weak immune system, an autoimmune disorder, graft-versus-host disease, or if you have recently received a bone marrow transplant or cord blood transplant.

When treating genital warts around the vagina, avoid getting the cream on the more sensitive inner layers of vaginal tissue. This could result in vaginal swelling or irritation and painful urination. Avoid exposure to sunlight or tanning beds. Imiquimod topical can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Imiquimod topical is not a cure for genital warts and it may not keep you from spreading this condition to others through vaginal, anal, or oral sex. You may develop new lesions during treatment with imiquimod topical. For best results, keep using the medicine for the entire length of time prescribed by your doctor.

Imiquimod will not protect against sexually transmitted diseases such as chlamydia, gonorrhea, herpes, HIV, syphilis, and trichomoniasis.

If you are treating the genital or rectal area with imiquimod topical, avoid sexual activity while the medicine is on your skin. Imiquimod topical can weaken the rubber that condoms or diaphragms are made out of. If you use a condom or diaphragm for birth control, these items could break if the rubber weakens and an unplanned pregnancy could result.

What should I discuss with my healthcare provider before using imiquimod topical?

To make sure you can safely take imiquimod topical, tell your doctor if you have any of these other conditions:

sunburn or other skin problems;

a weak immune system or autoimmune disorder;

graft-versus-host disease;

if you have recently been treated for actinic keratosis or genital warts with surgery or other medications; or

if you have recently received a bone marrow transplant or cord blood transplant.

FDA pregnancy category C. It is not known whether imiquimod topical will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. If you are treating the genital or rectal area with imiquimod topical, avoid sexual activity while the medicine is on your skin. Imiquimod topical can weaken the rubber that condoms or diaphragms are made out of. If you use a condom or diaphragm, these items could break if the rubber weakens, and an unplanned pregnancy could result. It is not known whether imiquimod topical passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Do not use this medicine on a child younger than 12 years old. Imiquimod topical is for use in treating genital warts in patients who are at least 12 years old. All other uses of this medication are for adults over 18 only.

How should I apply imiquimod topical?

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

Using too much of this medicine, or using it for too long can increase your risk of severe skin reactions.

Before applying imiquimod topical, wash your hands and wash the skin area to be treated. Allow the skin to dry for at least 10 minutes before applying the medicine. Always wash your hands after applying the medicine also. Do not use imiquimod topical on areas of broken, wounded, or burned skin. Wait until these conditions have healed before using imiquimod topical.

Imiquimod topical is normally used 2 to 5 times per week for up to 16 weeks. How you use this medication will depend on the condition you are treating. Follow your doctor's instructions.

Actinic keratosis:

Aldara is usually applied 2 times per week (such as Monday and Thursday, or Tuesday and Friday) for a full 16 weeks. Zyclara is applied once daily for 2 weeks followed by 2 weeks without treatment. Apply the cream to the treatment area in a thin layer, and rub in the cream until it disappears. Use the medicine before going to bed and leave it on for 8 hours. In the morning, wash off the medicine with water and a mild soap.

Superficial basal cell carcinoma:

Usually applied 5 times per week (such as Monday through Friday) for a full 6 weeks. Apply the cream from one imiquimod topical packet to the treatment area and the border of skin around it, and rub in the cream until it disappears. Use the medicine before going to bed and leave it on for 8 hours. In the morning, wash off the medicine with water and a mild soap.

Genital warts:

Usually applied 3 times per week (such as Monday, Wednesday, and Friday) for no longer than 16 weeks. Apply the cream from one imiquimod topical packet to the treatment area, and rub in the cream until it disappears. Do not cover the treated skin areas with any type of plastic bandaging, and avoid nylon underwear. You may wear cotton gauze or underwear over the treated area. Use the medicine before going to bed and leave it on for 6 to 10 hours. Then wash off the medicine with water and a mild soap.

When treating genital warts under the foreskin of an uncircumcised penis, pull back the foreskin and wash it with mild soap and water before applying imiquimod topical. Clean this area daily during treatment. When treating genital warts around the vagina, avoid getting the cream on the more sensitive inner layers of vaginal tissue. This could result in vaginal swelling or irritation and painful urination.

All conditions:

Your doctor will need to check your skin on a regular basis, especially if you have a more severe skin reaction to the medication. Do not miss any scheduled appointments.

Call your doctor if your skin condition does not improve or if it gets worse during treatment.

Do not use imiquimod topical to treat any skin condition that has not been checked by a doctor. Do not share this medication with anyone else, even if they have the same symptoms you have.

Each packet of imiquimod topical is for a single application only. Throw away the packet after one use, even if there is medicine left in it. If you treat more than one skin area at a time, ask your doctor how many packets to use.

Store at room temperature away from moisture and heat. Do not freeze. Keep each packet unopened until you are ready to use it.

What happens if I miss a dose?

Skip the missed dose and wait until the next time you are getting ready for bed to use the medicine. Do not use extra medicine to make up the missed dose.

What happens if I overdose?

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

Overdose symptoms may include severe skin irritation, feeling light-headed, or fainting.

What should I avoid while using imiquimod topical?

Avoid getting this medication in your eyes, mouth, and nose, or on your lips. Do not place the cream in your rectum, vagina, or urethra. If it does get into any of these areas, rinse with water. Do not use imiquimod topical on sunburned, windburned, dry, chapped, irritated, or broken skin.

Avoid using other medications on the areas you treat with imiquimod topical unless you doctor tells you to.

Avoid exposure to sunlight or tanning beds. Imiquimod topical can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Avoid having unprotected sex. Imiquimod is not a cure for genital warts, and it will not protect against sexually transmitted diseases such as chlamydia, gonorrhea, herpes, HIV, syphilis, and trichomoniasis. Talk with your doctor about safe ways to prevent transmission during sex.

Imiquimod topical side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Wash off the medicine and call your doctor at once if you have a serious skin reaction such as severe itching, burning, oozing, bleeding, or skin changes where the medicine is applied. Stop using imiquimod topical and call your doctor at once if you have a serious side effect such as flu symptoms such as fever, chills, body aches, tired feeling, swollen glands. When treating genital warts around the vagina, if you have severe swelling or urination problems, stop using imiquimod topical and call your doctor right away.

Less serious side effects may include:

mild skin irritation, itching, dryness, flaking, scabbing, crusting, redness, or hardening of the skin where the medicine was applied;

changes in the color of treated skin;

headache, dizziness, chest pain, back pain;

cold sores, fever blisters;

cold symptoms such as stuffy nose, sneezing, sore throat;

nausea, diarrhea, loss of appetite; or

vaginal itching or discharge.

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

Imiquimod topical Dosing Information

Usual Adult Dose for Keratosis:

Actinic Keratosis:
3.75% cream: Apply topically to the affected area (either the face or balding scalp) once a day prior to bedtime. Up to 2 packets may be applied to the treatment area at each application.

Treatment should continue for two 2-week treatment cycles separated by a 2-week no-treatment period. Neither 2-week treatment cycle should be extended due to rest periods or missed doses.

5% cream: Apply topically to defined treatment area 2 times per week prior to bedtime. The treatment area should be one contiguous area of approximately 5 cm by 5 cm on the face or scalp, but not both concurrently. No more than 1 packet should be applied to the contiguous treatment area at each application.

Treatment should continue for a full 16 weeks. The treatment period should not be extended beyond 16 weeks due to rest periods or missed doses.

3.75% and 5% cream: The cream should be applied as a thin layer to the entire treatment area and rubbed in until it disappears. It should be left on for approximately 8 hours and then removed by washing with mild soap and water.

Usual Adult Dose for Condylomata Acuminata:

3.75% cream: Apply a thin layer topically to external genital/perianal warts once a day prior to bedtime. Up to 1 packet may be applied to the treatment area at each application. The cream should be left on for approximately 8 hours and then removed by washing with mild soap and water.

Treatment should continue until total clearance of genital/perianal warts or for up to 8 weeks. The treatment period should not be extended beyond 8 weeks due to rest periods or missed doses.

5% cream: Apply topically to external genital/perianal warts 3 times per week prior to bedtime. The cream should be applied as a thin layer to the wart area and rubbed in until it disappears. The cream should be left on for 6 to 10 hours and then removed by washing with mild soap and water.

Treatment should continue until total clearance of genital/perianal warts or for a maximum of 16 weeks.

Usual Adult Dose for Basal Cell Carcinoma:

Biopsy-confirmed superficial basal cell carcinoma:
5% cream: Apply topically to target tumor 5 times per week prior to bedtime for a full 6 weeks. Sufficient cream should be applied to cover the treatment area (including a 1 cm margin of skin around the tumor) and it should be rubbed in until the cream disappears. The cream should be left on for approximately 8 hours and then removed by washing with mild soap and water.

Amount of imiquimod topical 5% cream to use:
Target tumor diameter 0.5 to less than 1 cm: 4 mm (diameter) droplet of cream (approximately 10 mg of 5% cream)

Target tumor diameter greater than or equal to 1 to less than 1.5 cm: 5 mm (diameter) droplet of cream (approximately 25 mg of 5% cream)

Target tumor diameter greater than or equal to 1.5 to 2 cm: 7 mm (diameter) droplet of cream (approximately 40 mg of 5% cream)

The target tumor should have a maximum diameter of 2 cm and be located on the trunk (excluding anogenital skin), neck, or extremities (excluding hands and feet). Treatment area should include a 1 cm margin of skin around the tumor.

Usual Adult Dose for Molluscum Contagiosum:

Study (n=15)
Apply to lesion once a day, rub in and leave on for 24 hours, for 5 days or until mollusca no longer visible. Wash with soap and water before applying next dose.

Usual Pediatric Dose for Condylomata Acuminata:

12 years or older:
3.75% cream: Apply a thin layer topically to external genital/perianal warts once a day prior to bedtime. Up to 1 packet may be applied to the treatment area at each application. The cream should be left on for approximately 8 hours and then removed by washing with mild soap and water.

Treatment should continue until total clearance of genital/perianal warts or for up to 8 weeks. The treatment period should not be extended beyond 8 weeks due to rest periods or missed doses.

5% cream: Apply topically to external genital/perianal warts 3 times per week prior to bedtime. The cream should be applied as a thin layer to the wart area and rubbed in until it disappears. The cream should be left on for 6 to 10 hours and then removed by washing with mild soap and water.

Treatment should continue until total clearance of genital/perianal warts or for a maximum of 16 weeks.

Usual Pediatric Dose for Molluscum Contagiosum:

Case Reports (5, 7, 8 year(s)):
Apply to lesions once or twice a day, rub in and leave on. At the end of 8 weeks of therapy, all lesions had resolved in two of the cases, and 75% of the lesions in the third case.

Case Report (4 to 11 years) n=13:
Apply to lesions three times a week at bedtime. Rub in until cream disappears. Leave on for approximately 8 hours. Then, remove the cream by washing with mild soap and water. Treatment continued for up to 16 weeks, at which point there was a 69% response rate.

What other drugs will affect imiquimod topical?

It is not likely that other drugs you take orally or inject will have an effect on topically applied imiquimod topical. But many drugs can interact with each other. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Compare imiquimod topical with other medications

Actinic Keratosis
Basal Cell Carcinoma
Condylomata Acuminata
Human Papilloma Virus
Molluscum Contagiosum

Where can I get more information?

Your pharmacist can provide more information about imiquimod topical.

See also: imiquimod side effects (in more detail)

IsoDitrate

Generic Name: isosorbide dinitrate (Oral route, Sublingual route)

eye-soe-SOR-bide dye-NYE-trate

Commonly used brand name(s)

In the U.S.

Dilatrate-SR

Isochron

IsoDitrate

Isordil Titradose

In Canada

Apo-Isdn

Isordil

Available Dosage Forms:

Tablet, Chewable

Tablet

Capsule, Extended Release

Tablet, Extended Release

Therapeutic Class: Antianginal

Chemical Class: Nitrate

Uses For IsoDitrate

Isosorbide dinitrate is used to prevent angina (chest pain) caused by coronary artery disease. It does not work fast enough to relieve the pain of an angina attack that has already started.

Isosorbide dinitrate belongs to the group of medicines called nitrates. It works by relaxing the blood vessels and increasing the supply of blood and oxygen to the heart while reducing its work load. When used regularly on a long-term basis, this helps prevent angina attacks from occurring.

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

Before Using IsoDitrate

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

Appropriate studies have not been performed on the relationship of age to the effects of isosorbide dinitrate in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of isosorbide dinitrate in the elderly. However, elderly patients are more likely to have age-related liver, kidney, or heart problems, which may require caution and an adjustment in the dose for patients receiving isosorbide dinitrate.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

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 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 not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

Sildenafil

Tadalafil

Vardenafil

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.

Proper Use of isosorbide dinitrate

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

Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This form of nitrate is used to reduce the number of angina attacks over a long time. It will not relieve an attack that has already started because it works too slowly. The extended-release form releases medicine gradually to provide its effect for 8 to 10 hours. Check with your doctor if you also need a fast-acting medicine to relieve the pain of an angina attack.

You should take this medicine first thing in the morning and follow the same schedule each day. This medicine works best if you have a "drug-free" period of time every day when you do not take it. Your doctor will schedule your doses during the day to allow for a drug-free time. Follow the schedule of dosing carefully so the medicine will work properly.

Sublingual tablets should not be chewed, crushed, or swallowed. They work much faster when absorbed through the lining of the mouth. Place the tablet under the tongue and let it dissolve there. Do not eat, drink, smoke, or use chewing tobacco while a tablet is dissolving.

Swallow the extended-release tablet or capsule whole. Do not split, crush, or chew it.

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 angina prevention:
- For oral dosage form (extended-release tablets, sustained-release capsules):
  - Adults—At first, 40 milligrams (mg) two times a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 160 mg per day.
  - Children—Use and dose must be determined by your doctor.
- For oral dosage form (tablets):
  - Adults—At first, 5 to 20 milligrams (mg) two or three times a day. Your doctor may increase your dose as needed.
  - Children—Use and dose must be determined by your doctor.
- For sublingual dosage form (tablets):
  - Adults—2.5 to 5 milligrams (mg) about 15 minutes before expected physical or emotional stress.
  - Children—Use and dose must be determined by your doctor.

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.

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 IsoDitrate

If you will be taking this medicine for a long time, it is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Blood tests may be needed to check for unwanted effects.

Do not take sildenafil (Viagra®), tadalafil (Cialis®), or vardenafil (Levitra®) while you are using this medicine. Using these medicines together may cause blurred vision, dizziness, lightheadedness, or fainting. If you are taking these medicines and you experience an angina attack, you must go to the hospital right away.

This medicine may cause headaches. These headaches are a sign that the medicine is working. Do not stop using the medicine or change the time you use it in order to avoid the headaches. If you have severe pain, talk with your doctor.

Dizziness, lightheadedness, or faintness may occur, especially when you get up quickly from a lying or sitting position. Getting up slowly may help.

Dizziness, lightheadedness, or fainting is also more likely to occur if you drink alcohol, stand for long periods of time, exercise, or if the weather is hot. While you are taking this medicine, be careful to limit the amount of alcohol you drink. Also, use extra care during exercise or hot weather or if you must stand for long periods of time.

Do not stop using this medicine without checking first with your doctor. Your doctor may want you to gradually reduce the amount you are using before stopping it completely.

IsoDitrate 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:

Rare

Bluish-colored lips, fingernails, or palms

dark urine

difficulty with breathing

dizziness or lightheadedness

fever

headache

pale skin

rapid heart rate

shortness of breath

sore throat

unusual bleeding or bruising

unusual tiredness or weakness

Incidence not known

Arm, back, or jaw pain

blurred vision

chest pain or discomfort

chest tightness or heaviness

confusion

dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly

fainting

fast or irregular heartbeat

sweating

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

Blurred or loss of vision

bulging soft spot on the head of an infant

change in consciousness

change in the ability to see colors, especially blue or yellow

cold, clammy skin

convulsions

disturbed color perception

double vision

fast, irregular, pounding, or racing heartbeat or pulse

feeling of constant movement of self or surroundings

halos around lights

headache, severe and throbbing

increased sweating

loss of appetite

loss of consciousness

nausea

night blindness

overbright appearance of lights

paralysis

sensation of spinning

slow heartbeat

tunnel vision

vomiting

wheezing

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.

See also: IsoDitrate side effects (in more detail)

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.

More IsoDitrate resources

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

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Angina
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Friday, October 28, 2016

Paracetamol Caplets 500mg (Boots Company plc)

1. Name Of The Medicinal Product

Paracetamol Tablets BP 500 mg or Paracetamol Caplets 500mg.

2. Qualitative And Quantitative Composition

Active ingredient	mg/tab
Paracetamol Pdr Ph Eur	500.00

3. Pharmaceutical Form

Tablet

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of headache, rheumatic pains, neuralgia and relief of symptoms of colds and influenza.

For oral administration.

4.2 Posology And Method Of Administration

Adults and children over 12 years

One to two tablets to be taken three or four times daily at intervals of not less than four hours, up to a maximum of eight tablets in 24 hours.

Children 6 to 12 years

Half to one tablet to be taken three or four times daily at intervals of not less than four hours, up to a maximum of four tablets in 24 hours.

Elderly

There is no need for dosage reduction in the elderly.

4.3 Contraindications

Hypersensitivity to any of the ingredients. Severe liver disease.

4.4 Special Warnings And Precautions For Use

Should be taken with caution in patients with impaired liver and kidney function.

The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease.

Do not exceed the stated dose.

Not to be given to children under 6 years, without medical advice.

Dosage should not be continued for more than three days without consulting your doctor.

If symptoms persist, consult your doctor.

Do not take with any other paracetamol-containing products.

Keep all medicines out of the reach of children.

Label:

Immediate medical advice should be sought in the event of an overdose, even if you feel well.

Leaflet or combined label/leaflet:

Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine.

The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

4.6 Pregnancy And Lactation

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol when used in the recommended dosage but patients should follow the advice of their doctor regarding its use.

Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast feeding.

4.7 Effects On Ability To Drive And Use Machines

No adverse effects known.

4.8 Undesirable Effects

Side-effects are usually mild and may include skin rashes and other allergic reactions occasionally.

Very rarely there have been reports of blood dyscrasias including thrombocytopenia and agranulocytoosis, but these were not necessarily causally related to paracetamol.

4.9 Overdose

Symptoms of paracetamol overdosage in the first 24 hours include pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion as liver function tests become abnormal. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe cases liver failure may lead to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop with or without severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Liver damage is likely in adults who have taken 10g or more of paracetamol. It is considered that excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested), become irreversibly bound to liver tissue.

Immediate treatment is essential in the management of paracetamol overdosage. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention and any patient who has ingested around 7.5g or more of paracetamol in the preceding 4 hours should undergo gastric lavage. Administration of oral methionine or intravenous N-acetylcysteine which may have a beneficial effect up to at least 48 hours after the overdose, may be required. General supportive measures must be available.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Paracetamol is a peripherally acting analgesic with antipyretic activity.

5.2 Pharmacokinetic Properties

Paracetamol is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring about 30 minutes to 2 hours after ingestion. Paracetamol is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates, with about 10% as glutathione conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half-life varies from about 1-4 hours. Plasma protein binding is negligible at usual therapeutic concentrations, although this is dose-dependent.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Maize starch Pdr Ph Eur

Pregelatinised maize starch BP

Stearic acid Pdr BP

Purified water Ph Eur

6.2 Incompatibilities

None known

6.3 Shelf Life

PVC/PVDC Blister: 36 months

PVC Blister: 36 months

Glass Bottle 36 months

HDPE bottle: 36 months

6.4 Special Precautions For Storage

None

6.5 Nature And Contents Of Container

A child-resistant push through pack of opaque 250 micron PVC/40gsm PVdC blisters, heat sealed to 35gsm Glassine paper/9 micron soft temper aluminium foil.

Pack sizes: 6, 8, 10, 12, 16, 18, 20, 24, 25, 30, 32, 36, 48, 96

A child-resistant push through pack of opaque 250 micron PVC blisters, heat sealed to 35gsm Glassine paper/9 micron soft temper aluminium foil.

Pack sizes: 6, 8, 10, 12, 16, 18, 20, 24, 25, 30, 32, 36, 48, 96

Amber glass bottle with a child-resistant polyethylene/polypropylene cap fitted with a tamper evident heat sealed liner of surlyn/aluminium or aluminium/polyethylene or a child resistant polyethylene/polypropylene cap fitted with a waxed aluminium faced liner.

Pack sizes: 30, 32, 36, 50, 100

Amber glass bottle with a tinplate cap, fitted with a waxed aluminium faced pulpboard liner.

Pack sizes: 1,000

White pigmented high density polyethylene bottle fitted with a polypropylene cap with an induction heat sealable liner including aluminium and surlyn or aluminium/polyethylene.

Pack size: 30, 32, 36, 50, 100

6.6 Special Precautions For Disposal And Other Handling

Not applicable

7. Marketing Authorisation Holder

The Boots Company PLC

1 Thane Road West

Nottingham NG2 3AA

8. Marketing Authorisation Number(S)

PL 00014/5072R

9. Date Of First Authorisation/Renewal Of The Authorisation

19 May 1981 / 14 February 2002

10. Date Of Revision Of The Text

November 2004

Gadobutrol Intravenous

gad-oh-BUE-trol

Intravenous route(Solution)

Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) in patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. The risk for NSF appears highest among patients with chronic, severe kidney disease (GFR less than 30 mL/min/1.73 m(2) or acute kidney injury. Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (eg, age greater than 60 years, hypertension, or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing .

Commonly used brand name(s)

In the U.S.

Gadavist

Available Dosage Forms:

Solution

Therapeutic Class: Diagnostic Agent, Radiological Contrast Media

Uses For gadobutrol

Gadobutrol injection is a magnetic resonance imaging (MRI) contrast agent. Contrast agents are used to help create a clear picture of the body during MRI scans. MRI scans are a special kind of procedure that let a doctor look at the inside of the body, such as the brain. They use magnets and computers to create images or “pictures” of the body. Unlike x-rays, MRI scans do not involve radiation. Gadobutrol is a gadolinium-based contrast agent (GBCA) that is given by injection before the MRI to help diagnose problems in the brain, spine, and other parts of your body.

gadobutrol is to be used only by or under the direct supervision of a doctor.

Before Using gadobutrol

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 gadobutrol, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to gadobutrol 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

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of gadobutrol injection in children 2 years of age and older. However, safety and efficacy have not been established in children younger than 2 years of age.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of gadobutrol injection in the elderly. However, elderly patients are more likely to have age-related kidney problems, which may require caution in patients receiving gadobutrol.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

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. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Proper Use of gadobutrol

A doctor or other trained health professional will give you gadobutrol. gadobutrol is given through a needle placed in one of your veins just before you have an MRI scan.

Precautions While Using gadobutrol

It is very important that your doctor check the progress of you or your child while you are receiving gadobutrol and during the MRI scan. This will allow your doctor to see if the medicine is working properly and to check for unwanted effects.

Check with your doctor or nurse right away if you or your child have burning or itching of the skin; deep bone pain in the hips or ribs; joint stiffness; a limited range of motion in the arms and legs; muscle weakness; red or dark patches on the skin of the arms or legs; or skin swelling, hardening, or tightening within the first few days or weeks after you receive gadobutrol. These may be symptoms of a very serious disease called nephrogenic systemic fibrosis (NSF).

gadobutrol may cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Check with your doctor or nurse right away if you or your child have chest pain; cold, clammy skin; confusion; dizziness; lightheadedness; a skin rash; itching; sweating; swelling of the face, tongue, and throat; or trouble with breathing after you receive the medicine.

Tell your doctor right away if you or your child have burning pain; feeling of warmth or coldness; redness or swelling at the injection site.

gadobutrol 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 or nurse immediately if any of the following side effects occur:

Rare

Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site

blurred vision

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

confusion

convulsions

difficult or labored breathing

dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position

fast, pounding, or irregular heartbeat or pulse

feeling of warmth

general feeling of discomfort or illness

hives or welts

itching

loss of consciousness

paleness of the skin

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

redness of the skin

shortness of breath

skin rash

sweating

tightness in the chest

unusual tiredness or weakness

wheezing

Incidence not known

Bluish color of the fingernails, lips, skin, palms, or nail beds

burning sensation

burning, dry, or itching eyes

chest pain

cough

deep bone pain

difficulty with swallowing

discharge or excessive tearing

hoarseness

increased sweating

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

muscle stiffness or weakness

no blood pressure or pulse

no breathing

noisy breathing

redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid

skin rash, swelling, hardness, tightness, burning, itching, or red or dark patches

slow or irregular breathing

sneezing

stiff joints or trouble moving

stopping of the heart

swelling of the mouth or throat

unconsciousness

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

Headache

nausea

Rare

Change in sense of smell

change in taste

dizziness

dry mouth

feeling hot or cold

loss of taste

unusually warm skin

vomiting

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.

See also: gadobutrol Intravenous side effects (in more detail)

More gadobutrol Intravenous resources

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

Compare gadobutrol Intravenous with other medications

CNS Magnetic Resonance Imaging
Vascular Magnetic Resonance Imaging

Glimepiride and pioglitazone

Generic Name: glimepiride and pioglitazone (glye MEP ir ide and PYE oh GLI ta zone)

Brand Names: Duetact

What is glimepiride and pioglitazone?

Glimepiride and pioglitazone is a combination of two oral diabetes medicines that help control blood sugar levels.

Glimepiride and pioglitazone is for people with type 2 diabetes who do not use daily insulin injections. Glimepiride and pioglitazone is sometimes given with other diabetes medications when greater blood sugar control is needed.

This medication is not for treating type 1 diabetes.

Glimepiride and pioglitazone may also be used for purposes not listed in this medication guide.

What is the most important information I should know about glimepiride and pioglitazone?

Do not take glimepiride and pioglitazone for longer than recommended. Taking this medication for longer than 1 year (12 months) may increase your risk of developing bladder cancer. Talk with your doctor about your specific risk.

Before taking glimepiride and pioglitazone, tell your doctor if you have congestive heart failure or heart disease, a history of bladder cancer, a history of heart attack or stroke, liver disease, or kidney disease.

Take care not to let your blood sugar get too low. Low blood sugar (hypoglycemia) can occur if you skip a meal, exercise too long, drink alcohol, or are under stress. Symptoms include headache, hunger, weakness, sweating, tremor, irritability, or trouble concentrating. Carry hard candy or glucose tablets with you in case you have low blood sugar. Other sugar sources include orange juice and milk. Be sure your family and close friends know how to help you in an emergency.

What should I discuss with my health care provider before taking glimepiride and pioglitazone?

You should not use this medication if you are allergic to glimepiride (Amaryl, Avandaryl) or pioglitazone (Actos), or if you have:

severe heart failure;

active bladder cancer; or

if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

To make sure you can safely take glimepiride and pioglitazone, tell your doctor if you have any of these other conditions:

congestive heart failure or heart disease;

a history of heart attack or stroke; or

liver or kidney disease.

Certain oral diabetes medications may increase your risk of serious heart problems. However, not treating your diabetes can damage your heart and other organs. Talk to your doctor about the risks and benefits of treating your diabetes with glimepiride and pioglitazone. Some women using glimepiride and pioglitazone have started having menstrual periods, even after not having a period for a long time due to a medical condition. You may be able to get pregnant if your periods restart. Talk with your doctor about the need for birth control. Women may also be more likely than men to have bone fractures in the upper arm, hand, or foot while taking medicine that contains pioglitazone. Talk with your doctor if you are concerned about this possibility. Do not take glimepiride and pioglitazone for longer than recommended. Taking this medication for longer than 1 year (12 months) may increase your risk of developing bladder cancer. Talk with your doctor about your specific risk. FDA pregnancy category C. It is not known whether glimepiride and pioglitazone will harm an unborn baby. Similar diabetes medications have caused severe hypoglycemia in newborn babies whose mothers had used the medication near the time of delivery. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether this medication passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are taking glimepiride and pioglitazone.

How should I take glimepiride and pioglitazone?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results

Take glimepiride and pioglitazone with your first meal of the day.

Glimepiride and pioglitazone is only part of a complete program of treatment that also includes diet, exercise, and weight control. Use this medication regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Your blood sugar will need to be checked often, and you may need other blood tests at your doctor's office. Visit your doctor regularly.

Know the signs of low blood sugar (hypoglycemia) and how to recognize them: headache, hunger, weakness, sweating, tremor, irritability, or trouble concentrating.

Always keep a source of sugar available in case you have symptoms of low blood sugar. Sugar sources include orange juice, glucose gel, candy, or milk. If you have severe hypoglycemia and cannot eat or drink, use an injection of glucagon. Your doctor can give you a prescription for a glucagon emergency injection kit and tell you how to give the injection.

Also watch for signs of blood sugar that is too high (hyperglycemia). These symptoms include increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin, blurred vision, and weight loss.

Check your blood sugar carefully during a time of stress or illness, if you travel, exercise more than usual, drink alcohol, or skip meals. These things can affect your glucose levels and your dose needs may also change. Your doctor may want you to stop taking the medicine for a short time if you become ill, have a fever or infection, or if you have surgery or a medical emergency.

Ask your doctor how to adjust your glimepiride and pioglitazone dose if needed. Do not change your medication dose or schedule without your doctor's advice. Store at room temperature, protected from moisture, heat, and light.

See also: Glimepiride and pioglitazone dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember (be sure to take the medicine with food). Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. A glimepiride and pioglitazone overdose can cause life-threatening hypoglycemia. Symptoms of severe hypoglycemia include extreme weakness, blurred vision, sweating, trouble speaking, tremors, stomach pain, confusion, and seizure (convulsions).

What should I avoid while taking glimepiride and pioglitazone?

Avoid drinking alcohol. It lowers blood sugar and may interfere with your diabetes treatment. Avoid exposure to sunlight or tanning beds. Glimepiride and pioglitazone can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Glimepiride and pioglitazone side effects

Stop using glimepiride and pioglitazone and get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects:

stomach pain, blood in your urine, painful urination;

swelling in your feet, rapid weight gain, feeling short of breath (even with mild exertion);

pale skin, easy bruising or bleeding;

pain or burning when you urinate; or

dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

nausea, vomiting, weakness, loss of appetite, feeling restless or irritable, confusion, hallucinations, muscle pain or weakness, and/or seizure.

Less serious side effects may include:

sneezing, stuffy nose, cough, sore throat, or other cold symptoms;

gradual weight gain;

mild nausea, diarrhea;

headache, dizziness, blurred vision; or

tooth problems.

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

Glimepiride and pioglitazone Dosing Information

Usual Adult Dose for Diabetes Mellitus Type II:

The initial dosage of glimepiride recommended for this patient with diabetes mellitus type II is based on the patient's current regime of pioglitazone and /or sulfonylurea.

For patients currently on glimepiride monotherapy, glimepiride-pioglitazone may be initiated at 30 mg/2 mg or 30 mg/4 mg tablet strengths once daily, and adjusted after assessing adequacy of therapeutic response.

For patients currently on pioglitazone monotherapy, glimepiride-pioglitazone may be initiated at 30 mg-2 mg or 30 mg-4 mg tablet strengths once daily, and adjusted after assessing adequacy of therapeutic response.

For patients currently on a different sulfonylurea monotherapy or switching from combination therapy of pioglitazone plus a different sulfonylurea (e.g. glyburide, glipizide, chlorpropamide, tolbutamide, acetohexamide), glimepiride-pioglitazone should be limited initially to a starting dose of 30 mg/2 mg once daily, and adjusted after assessing adequacy of therapeutic response.

For patients switching from combination therapy of pioglitazone plus glimepiride as separate tablets, glimepiride-pioglitazone may be initiated with 30 mg/2 mg or 30 mg/4 mg tablet strengths based on the dose of pioglitazone and glimepiride already being taken. Patients who are not controlled with 15 mg of pioglitazone in combination with glimepiride should be carefully monitored when switched to glimepiride-pioglitazone.

What other drugs will affect glimepiride and pioglitazone?

Tell your doctor about all other medicines you use, especially:

gemfibrozil (Lopid);

rifampin (Rifadin, Rimactane, Rifater); or

fluconazole (Diflucan), ketoconazole (Nizoral).

Using certain medicines can make it harder for you to tell when you have low blood sugar. Tell your doctor if you use any of the following:

albuterol (Proventil, Ventolin);

clonidine (Catapres);

reserpine; or

beta-blockers such as atenolol (Tenormin), carvedilol (Coreg), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal, InnoPran), sotalol (Betapace), and others.

You may be more likely to have hyperglycemia (high blood sugar) if you take glimepiride and pioglitazone with:

isoniazid;

diuretics (water pills);

steroids (prednisone and others);

niacin (Advicor, Niaspan, Niacor, Niaspan, Simcor, Slo-Niacin, and others);

phenothiazines (Compazine and others);

thyroid medicine (Synthroid and others);

birth control pills and other hormones;

seizure medicines (Dilantin and others); and

diet pills or medicines to treat asthma, colds or allergies.

You may be more likely to have hypoglycemia (low blood sugar) if you take glimepiride and pioglitazone with:

exenatide (Byetta);

probenecid (Benemid);

some nonsteroidal anti-inflammatory drugs (NSAIDs);

aspirin or other salicylates (including Pepto-Bismol);

a blood thinner such as warfarin (Coumadin, Jantoven);

sulfa drugs (Bactrim, Gantanol, Gantrisin, Septra, SMX-TMP, and others);

a monoamine oxidase inhibitor (MAOI); and

other oral diabetes medications, especially acarbose (Precose), metformin (Glucophage), miglitol (Glyset), pioglitazone (Actos), or rosiglitazone (Avandia).

These lists are not complete and there are many other medicines that can increase or decrease the effects of glimepiride and pioglitazone on lowering your blood sugar. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More glimepiride and pioglitazone resources

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

Compare glimepiride and pioglitazone with other medications

Diabetes, Type 2

Where can I get more information?

Your pharmacist can provide more information about glimepiride and pioglitazone.

See also: glimepiride and pioglitazone side effects (in more detail)

Thursday, October 27, 2016

Insulin Isophane Pens

Pronunciation: IN-su-lin EYE-soe-fane
Generic Name: Insulin Isophane
Brand Name: Examples include Humulin N and Novolin N

Insulin Isophane Pens are used for:

Treating diabetes mellitus.

Insulin Isophane Pens are an intermediate-acting form of the hormone insulin. It works by helping your body to use sugar properly. This lowers the amount of glucose in the blood, which helps to treat diabetes.

Do NOT use Insulin Isophane Pens if:

you are allergic to any ingredient in Insulin Isophane Pens

you are having an episode of low blood sugar

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

Before using Insulin Isophane Pens:

Some medical conditions may interact with Insulin Isophane Pens. 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 drink alcoholic beverages or smoke

if you have kidney or liver problems; nerve problems; adrenal, pituitary, or thyroid problems; or diabetic ketoacidosis

if you use 3 or more insulin injections per day

if you are fasting, have high blood sodium levels, or are on a low-salt (sodium) diet

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

Beta-blockers (eg, propranolol), clonidine, guanethidine, lithium, or reserpine because they may increase the risk of high or low blood sugar, or may hide the signs and symptoms of low blood sugar, if it occurs

Angiotensin-converting enzyme (ACE) inhibitors (eg, enalapril), disopyramide, fenfluramine, fibrates (eg, clofibrate, gemfibrozil), fluoxetine, monoamine oxidase inhibitors (MAOIs) (eg, phenelzine), oral medicines for diabetes (eg, glipizide, metformin, nateglinide), pentamidine, propoxyphene, salicylates (eg, aspirin), somatostatin analogs (eg, octreotide), or sulfonamide antibiotics (eg, sulfamethoxazole) because the risk of low blood sugar may be increased

Corticosteroids (eg, prednisone), danazol, diuretics (eg, furosemide, hydrochlorothiazide), estrogen, hormonal contraceptives (eg, birth control pills), isoniazid, niacin, phenothiazines (eg, chlorpromazine), progesterones (eg, medroxyprogesterone), somatropin, sympathomimetics (eg, albuterol, epinephrine, terbutaline), or thyroid hormones (eg, levothyroxine) because they may decrease Insulin Isophane Pens's effectiveness, resulting in high blood sugar

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

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

An extra patient leaflet is available with Insulin Isophane Pens. Talk to your pharmacist if you have questions about this information.

Check with your doctor about how you should use Insulin Isophane Pens with regard to meals.

If you will be using Insulin Isophane Pens at home, a health care provider will teach you how to use it. Be sure you understand how to use Insulin Isophane Pens. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.

Carefully rotate the vial or container as directed before each injection. This will ensure that the contents are evenly mixed. This insulin should look uniformly cloudy or milky.

Do not use Insulin Isophane Pens if it contains particles or clumps, is discolored, or if the vial or container is cracked or damaged.

If you are mixing Insulin Isophane Pens with another insulin, draw the other insulin into the syringe first. Inject the dose immediately after mixing, as directed by your doctor.

Do NOT use Insulin Isophane Pens in an insulin pump.

Use the proper technique taught to you by your doctor. Inject deep under the skin, NOT into a vein or muscle.

Injection sites within an injection area (abdomen, thigh, upper arm) must be rotated from one injection to the next.

Be sure you have purchased the correct insulin. Insulin comes in a variety of containers, including vials, cartridges, and pens. Make sure that you understand how to properly measure and prepare your dose. If you have any questions about measuring and preparing your dose, contact your doctor or pharmacist for information.

Insulin Isophane Pens begins lowering blood sugar within 30 to 90 minutes after an injection. The peak effect occurs within 4 to 12 hours after a dose. The effect may last for up to 24 hours.

Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.

It is very important to follow your insulin regimen exactly. Do NOT miss any doses. Ask your doctor for specific instructions to follow in case you ever miss a dose of insulin.

Ask your health care provider any questions you may have about how to use Insulin Isophane Pens.

Important safety information:

Drowsiness, dizziness, lightheadedness, or blurred vision may occur while you use Insulin Isophane Pens. These effects may be worse if you take it with alcohol or certain medicines. Use Insulin Isophane Pens with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.

Do not drink alcohol without discussing it with your doctor. Drinking alcohol may increase the risk of developing high or low blood sugar.

Do NOT take more than the recommended dose, use Insulin Isophane Pens more often than prescribed, or change the type or dose of insulin you are using without checking with your doctor.

Any change of insulin should be made cautiously and only under medical supervision. Changes in purity, strength, brand (manufacturer), type (regular, NPH, lente), species (beef, pork, beef-pork, human), and/or method of manufacture may require a change in dose.

Illness, especially with nausea and vomiting, may cause your insulin requirements to change. Even if you are not eating, you still require insulin. You and your doctor should establish a sick day plan to use in case of illness. When you are sick, test your blood/urine frequently and call your doctor as instructed.

Tell your doctor or dentist that you take Insulin Isophane Pens before you receive any medical or dental care, emergency care, or surgery.

If you will be traveling across time zones, consult your doctor concerning adjustments in your insulin schedule.

Carry an ID card at all times that says you have diabetes.

An insulin reaction resulting from low blood sugar levels (hypoglycemia) may occur if you take too much insulin, skip a meal, or exercise too much. Low blood sugar may make you anxious, sweaty, weak, dizzy, drowsy, or faint. It may also make your heart beat faster; make your vision change; give you a headache, chills, or tremors; or make you more hungry. It is a good idea to carry a reliable source of glucose (eg, tablets or gel) to treat low blood sugar. If this is not available, you should eat or drink a quick source of sugar like table sugar, honey, candy, orange juice, or non-diet soda. This will raise your blood sugar level quickly. Tell your doctor right away if this happens. To prevent low blood sugar, eat meals at the same time each day and do not skip meals.

Developing a fever or infection, eating significantly more than prescribed, or missing your dose of insulin may cause high blood sugar (hyperglycemia). High blood sugar may make you feel confused, drowsy, or thirsty. It can also make you flush, breathe faster, or have a fruit-like breath odor. If these symptoms occur, tell you doctor right away.

Check with your doctor if you notice a depression in the skin or skin thickening at the injection site. You may need to change your injection technique.

Proper diet, regular exercise, and regular testing of blood sugar are important for best results when using Insulin Isophane Pens.

Lab tests, including fasting blood glucose and hemoglobin A_1c levels, may be performed while you use Insulin Isophane Pens. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.

Use Insulin Isophane Pens with caution in the ELDERLY; if low blood sugar occurs, it may be more difficult to recognize in these patients.

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

Possible side effects of Insulin Isophane Pens:

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

Redness, swelling, itching, or mild pain at the injection site.

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; wheezing; muscle pain); changes in vision; chills; confusion; dizziness; drowsiness; fainting; fast or irregular heartbeat; headache; loss of consciousness; mood changes; seizures; slurred speech; swelling; tremor; trouble breathing; trouble concentrating; unusual hunger; unusual sweating; 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: Insulin Isophane 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 chills; dizziness; drowsiness; fainting; fast or irregular heartbeat; headache; loss of consciousness; nervousness; seizures; shakiness; sweating; tremor; vision changes; weakness.

Proper storage of Insulin Isophane Pens:

VIALS: Store new (unopened) vials in the refrigerator between 36 and 46 degrees F (2 and 8 degrees C). Do not freeze. Certain brands of the medicine may be stored at room temperature, below 77 degrees F (25 degrees C) for up to 6 weeks (42 days), if refrigeration is not possible. Check with your pharmacist to see if your brand can be stored at room temperature. Keep Insulin Isophane Pens in the carton to protect from light.

Store used (open) vials as directed in the extra patient leaflet or by your health care provider. Check with your pharmacist to see how long unrefrigerated or opened vials may be used. Store away from heat and light. If Insulin Isophane Pens has been frozen or overheated, throw it away.

INNOLETS, PENS, and PENFILL CARTRIDGES: Store new (unopened) InnoLets, pens, or PenFill cartridges in a refrigerator, between 36 and 46 degrees F (2 and 8 degrees C). Do not freeze. Store used (open) InnoLets, pens, or PenFill cartridges at room temperature, below 86 degrees F (30 degrees C). Do NOT store used (open) InnoLets, pens, or PenFill cartridges in the refrigerator. Store away from heat and light. If Insulin Isophane Pens has been frozen or overheated, throw it away. Throw away unrefrigerated or used InnoLets, pens, or PenFill cartridges after 14 days, even if they still contain medicine.

Do not leave Insulin Isophane Pens in a car on a warm or sunny day. Do not use Insulin Isophane Pens after the expiration date stamped on the label. Keep Insulin Isophane Pens, as well as syringes and needles, out of the reach of children and away from pets. If Insulin Isophane Pens has been mixed with other medicines, you may need to store it differently. Ask your doctor, pharmacist, or other health care provider how to store Insulin Isophane Pens.

General information:

If you have any questions about Insulin Isophane Pens, please talk with your doctor, pharmacist, or other health care provider.

Insulin Isophane Pens 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 Insulin Isophane Pens. 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

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Primacor Injection

1. Name Of The Medicinal Product

Primacor 1mg/ml Solution for Injection

2. Qualitative And Quantitative Composition

Each ampoule contains 1mg/ml of the active substance Milrinone.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for Injection.

Clear, colourless to pale yellow liquid.

4. Clinical Particulars

4.1 Therapeutic Indications

Primacor Injection is indicated for the short-term treatment of severe congestive heart failure unresponsive to conventional maintenance therapy, and for the treatment of patients with acute heart failure, including low output states following cardiac surgery.

In paediatric population Primacor is indicated for the short-term treatment (up to 35 hours) of severe congestive heart failure unresponsive to conventional maintenance therapy (glycosides, diuretics, vasodilators and/or angiotensin converting enzyme (ACE) inhibitors), and for the short-term treatment (up to 35 hours) of paediatric patients with acute heart failure, including low output states following cardiac surgery.

4.2 Posology And Method Of Administration

For intravenous administration.

Adults: Primacor Injection should be given as a loading dose of 50µg/kg administered over a period of 10 minutes usually followed by a continuous infusion at a dosage titrated between 0.375µg/kg/min and 0.75µg/kg/min according to haemodynamic and clinical response, but should not exceed 1.13mg/kg/day total dose.

The following provides a guide to maintenance infusion delivery rate based upon a solution containing milrinone 200µg/ml prepared by adding 40ml diluent per 10ml ampoule (400ml diluent per 100ml Primacor Injection). 0.45% saline, 0.9% saline or 5% glucose may be used as diluents.

Primacor Injection Dose

(µg /kg/min)

Infusion

Delivery Rate (ml/kg/hr)

0.375

0.400

0.500

0.600

0.700

0.750

0.11

0.12

0.15

0.18

0.21

0.22

Solutions of different concentrations may be used according to patient fluid requirements. The duration of therapy should depend upon the patient's response. In congestive cardiac failure, patients have been maintained on the infusion for up to 5 days, although the usual period is 48 to 72 hours. In acute states following cardiac surgery, it is unlikely that treatment need be maintained for more than 12 hours.

Renal Impairment: Dosage adjustment required. Data obtained from patients with severe renal impairment but without heart failure have demonstrated that the presence of renal impairment significantly increases the terminal elimination half-life of milrinone. For patients with clinical evidence of renal impairment, the loading dose is not affected, but the following maintenance infusion rates are recommended using the infusion solution described above.

Creatinine Clearance

(ml/min/1.73m²)

Primacor Injection Dose

(µg/kg/min)

Maintenance Infusion Delivery Rate

(ml/kg/hr)

0.20

0.23

0.28

0.33

0.38

0.43

0.06

0.07

0.08

0.10

0.11

0.13

The infusion rate should be adjusted according to haemodynamic response.

Elderly: Experience so far suggests that no special dosage recommendations are necessary.

Paediatric population:

In published studies selected doses for infants and children were:

• Intravenous loading dose: 50 to 75 µg/kg administered over 30 to 60 minutes.

• Intravenous continuous infusion: To be initiated on the basis of hemodynamic response and the possible onset of undesirable effects between 0.25 to 0.75 µg/kg/min for a period up to 35 hours.

In clinical studies on low cardiac output syndrome in infants and children under 6 years of age after corrective surgery for congenital heart disease 75 µg/kg loading dose over 60 minutes followed by a 0.75 µg/kg/min infusion for 35 hours significantly reduced the risk of development of low cardiac output syndrome.

Results of pharmacokinetic studies (see section 5.2) have to be taken into consideration.

Renal impairment:

Due to lack of data the use of milrinone is not recommended in paediatric population with renal impairment (for further information please see section 4.4).

Patent ductus arteriosus:

If the use of milrinone is desirable in preterm or term infants at risk of/with patent ductus arteriosus, the therapeutic need must be weighed against potential risks (see section 4.4, 4.8, 5.2, and 5.3).

4.3 Contraindications

• Hypersensitivity to milrinone or any of the excipients

• Severe hypovolaemia.

4.4 Special Warnings And Precautions For Use

The use of inotropic agents such as milrinone during the acute phase of a myocardial infarction may lead to an undesirable increase in myocardial oxygen consumption (MVO2). Primacor Injection is not recommended immediately following acute myocardial infarction until safety and efficacy have been established in this situation.

Careful monitoring should be maintained during Primacor Injection therapy including blood pressure, heart rate, clinical state, electro-cardiogram, fluid balance, electrolytes and renal function (i.e. serum creatinine).

In patients with severe obstructive aortic or pulmonary valvular disease, or hypertrophic subaortic stenosis, Primacor Injection should not be used in place of surgical relief of the obstruction. In these conditions it is possible that a drug with inotropic / vasodilator properties might aggravate outflow obstruction.

Supraventricular and ventricular arrhythmias have been observed in the high risk population treated with milrinone. In some patients, an increase in ventricular ectopy including non-sustained ventricular tachycardia has been observed which did not affect patient safety or outcome.

The potential for arrhythmia, present in heart failure itself, may be increased by many drugs or a combination of drugs. Patients receiving Primacor Injection should be closely monitored during infusion and the infusion should be stopped if arrhythmias develop.

As milrinone produces a slight enhancement in A-V node conduction, there is a possibility of an increased ventricular response rate in patients with uncontrolled atrial flutter / fibrillation. Consideration should therefore be given to digitalisation or treatment with other agents to prolong A-V node conduction time prior to starting Primacor Injection therapy, and to discontinuing the therapy if arrhythmias occur.

Milrinone may induce hypotension as a consequence of its vasodilatory activity; therefore caution should be exercised when Primacor Injection is administered to patients who are hypotensive prior to treatment. The rate of infusion should be slowed or stopped in patients showing excessive decreases in blood pressure.

If prior vigorous diuretic therapy is suspected of having caused significant decreases in cardiac filling pressure Primacor Injection should be cautiously administered while monitoring blood pressure, heart rate and clinical symptomatology.

Improvement in cardiac output with resultant diuresis may necessitate a reduction in the dose of diuretic. Potassium loss due to excessive diuresis may necessitate a reduction in the dose of diuretic. Potassium loss due to excessive diuresis may predispose digitalised patients to arrhythmias. Therefore, hypokalaemia should be corrected by potassium supplementation in advance of, or during, the use of Primacor Injection.

Decrease in haemoglobin, including anaemia, often takes place in the setting of cardiac failure. Due to the risk of thrombocytopenia or anaemia, careful monitoring of the corresponding laboratory parameters is required in patients with decreased platelet count or decreased haemoglobin

There is no experience in controlled trials with infusions of milrinone for periods exceeding 48 hours.

Cases of infusion site reaction have been reported with Primacor Injection (see Section 4.8 Undesirable effects). Consequently, careful monitoring of the infusion site should be maintained so as to avoid possible extravasation.

Use in the elderly: There are no special recommendations for elderly patients. No age-related effects on the incidence of adverse reactions have been observed. Controlled pharmacokinetic studies have not shown changes in the pharmacokinetic profile of milrinone in the elderly.

In patients with severe renal impairment dosage adjustment is required (see section 4.2 Posology and method of administration).

Paediatric population:

The following should be considered in addition to the warnings and precautions described for adults:

In neonates, following open heart surgery during Primacor therapy, monitoring should include heart rate and rhythm, systemic arterial blood pressure via umbilical artery catheter or peripheral catheter, central venous pressure, cardiac index, cardiac output, systemic vascular resistance, pulmonary artery pressure, and atrial pressure. Laboratory values that should be followed are platelet count, serum potassium, liver function, and renal function. Frequency of assessment is determined by baseline values, and it is necessary to evaluate the neonate's response to changes in therapy.

Literature revealed that in paediatric patients with impaired renal function, there were marked impairment of milrinone clearance and clinically significant side effects, but the specific creatinine clearance at which doses must be adjusted in paediatric patients is still not clear, therefore the use of milrinone is not recommended in this population (see section 4.2).

In paediatric patients milrinone should be initiated only if the patient is hemodynamically stable.

Caution should be exercised in neonates with risk factors of intraventricular haemorrhage (i.e. preterm infant, low birth weight) since milrinone may induce thrombocytopenia. In clinical studies in paediatric patients, risk of thrombocytopenia increased significantly with duration of infusion. Clinical data suggest that milrinone-related thrombocytopenia is more common in children than in adults (see section 4.8).

In clinical studies milrinone appeared to slow the closure of the ductus arteriosus in paediatric population. Therefore, if the use of milrinone is desirable in preterm or term infants at risk of/with patent ductus arteriosus, the therapeutic need must be weighed against potential risks (see section 4.2, 4.8, 5.2, and 5.3).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Furosemide or bumetanide should not be administered in intravenous lines containing milrinone lactate in order to avoid precipitation.

Milrinone should not be diluted in sodium bicarbonate intravenous infusion.

Whilst there is a theoretical potential interaction with calcium channel blockers, there has been no evidence of a clinically significant interaction to date.

Milrinone has a favourable inotropic effect in fully digitalised patients without causing signs of glycoside toxicity.

Fluid and electrolyte changes, as well as serum creatinine levels should be carefully monitored during treatment with milrinone. Improvement in cardiac output and consequently, diuresis, may require reduction in the dose of a diuretic agent. Potassium loss due to excessive diuresis may predispose digitalised patients to arrhythmias. Therefore, hypokalaemia should be corrected by potassium supplementation in advance of, or during milrinone use.

4.6 Pregnancy And Lactation

Use in Pregnancy

Although animal studies have not revealed evidence of drug-induced foetal damage or other deleterious effects on reproductive function, the safety of milrinone in human pregnancy has not yet been established. It should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Use in Lactation

There is insufficient information on the excretion of milrinone in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue milrinone therapy taking into account the benefit of breast feeding for a child and the benefit of therapy for the woman.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effect on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

Adverse reactions have been ranked under heading of system-organ class and frequency using the following convention: very common (

Blood and the lymphatic system disorders:

• Uncommon: Thrombocytopenia*

• Not known: reduction of red blood count and/or haemoglobin concentration

*In infants and children, risk of thrombocytopenia increased significantly with duration of infusion. Clinical data suggest that milrinone-related thrombocytopenia is more common in children than in adults (see section 4.4).

Immune system disorders:

• Very rare: Anaphylactic shock

Metabolism and nutrition disorders:

• Uncommon: Hypokalaemia

Nervous system disorders:

• Common: Headaches, usually mild to moderate in severity

• Uncommon: Tremor

Cardiac disorders:

• Common:

- Ventricular ectopic activity

- Non sustained or sustained ventricular Tachycardia (see section 4.4)

- Supraventricular arrhythmias

- Hypotension

• Uncommon:

- Ventricular fibrillation

- Angina/chest pain

• Very rare: Torsades de pointes

The incidence of arrhythmias has not been related to dose or plasma levels of milrinone. These arrhythmias are rarely life threatening. If present, they are often associated with certain underlying factors such as pre-existing arrhythmias, metabolic abnormalities (e.g. hypokalaemia) abnormal digoxin levels and catheter insertion. . Clinical data suggest that milrinone-related arrhythmias are less common in children than in adults.

Respiratory, thoracic and mediastinal disorders:

• Very rare: Bronchospasm

Hepato-biliary disorders:

• Uncommon: Liver function tests abnormal

Skin and subcutaneous tissue disorders:

• Very rare: Skin reactions such as rash

General disorders and administration site conditions:

• Not known: Infusion site reaction

Paediatric population:

Nervous system disorders

Not known: intraventricular haemorrhage (see section 4.4)

Congenital, familial, and genetic disorders

Not known: patent ductus arteriosus*** (see section 4.2, 4.4, 5.2, and 5.3)

***The critical consequences of the patent ductus arteriosus are related to a combination of pulmonary overcirculation with consecutive pulmonary oedema and haemorrhage and of reduced organ perfusion with consecutive intraventricular haemorrhage and necrotizing enterocolitis with possible fatal outcome as described in literature.

Long-term safety data for paediatric population are not yet available.

4.9 Overdose

Overdose of intravenous Primacor may produce hypotension (because of its vasodilatory effect) and cardiac arrhythmia. If this occurs, Primacor Injection administration should be reduced or temporarily discontinued until the patient's condition stabilises. No specific antidote is known, but general measures for circulatory support should be taken.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Cardiac therapy; Phosphodiesterase inhibitor, ATC code: C01CE02

Milrinone is a positive inotrope and vasodilator, with little chronotropic activity. It also improves left ventricular diastolic relaxation. It differs in structure and mode of action from the digitalis glycosides, catecholamines or angiotensin converting enzyme inhibitors. It is a selective inhibitor of peak III phosphodiesterase isoenzyme in cardiac and vascular muscle. It produces slight enhancement of A-V node conduction, but no other significant electro-physiological effects.

In clinical studies Primacor Injection has been shown to produce prompt improvements in the haemodynamic indices of congestive heart failure, including cardiac output, pulmonary capillary wedge pressure and vascular resistance, without clinically significant effect on heart rate or myocardial oxygen consumption. Haemodynamic improvement during intravenous Primacor therapy is accompanied by clinical symptomatic improvement in congestive cardiac failure, as measured by change in New York Heart Association classification.

Paediatric population:

Literature review identified clinical studies with patients treated for low cardiac output syndrome following cardiac surgery, septic shock or pulmonary hypertension. The usual dosages were a loading dose of 50 to 75 μg/kg administered over 30 to 60 minutes followed by an intravenous continuous infusion of 0.25 to 0.75 μg/kg/min for a period up to 35 hours. In these studies, milrinone demonstrated an increase of cardiac output, a decrease in cardiac filling pressure, a decrease in systemic and pulmonary vascular resistance, with minimal changes in heart rate and in myocardial oxygen consumption.

Studies of a longer use of milrinone are not sufficient to recommend an administration of milrinone during a period of more than 35 hours.

Some studies explored the paediatric use of milrinone in patients with nonhyperdynamic septic shock (Barton et al., 1996; Lindsay et al., 1998); the effect of milrinone on postbypass pulmonary hypertension after tetralogy of Fallot repair (Chu et al., 2000); the combined effect of nitric oxide and milrinone on pulmonary circulation after Fontan-type procedure (Cai et al., 2008).

The results of these studies were inconclusive. Therefore, the use of milrinone in these indications cannot be recommended.

5.2 Pharmacokinetic Properties

Following intravenous injections of 12.5 to 125mcg/kg to congestive heart failure patients, Primacor Injection had a volume of distribution of 0.38 l/kg/hr, a mean terminal elimination half-life of 2.3 hours, and a clearance of 0.13 l/kg/hr. Following intravenous infusions of 0.2 to 0.7mcg/kg/min to congestive heart failure patients, the drug had a volume of distribution of about 0.45 l/kg, a mean terminal elimination half-life of 2.4 hours, and a clearance of 0.14 l/kg/hr. These pharmacokinetic parameters were not dose-dependent, and the area under the plasma concentration versus time curve following injection was significantly dose-dependent.

The primary route of excretion of milrinone in man is via the urine. Elimination in normal subjects via the urine is rapid, with approximately 60% recovered within the first two hours following dosing, and approximately 90% recovered within the first eight hours following dosing. The mean renal clearance of milrinone is approximately 0.3 l/min, indicative of active secretion.

Paediatric population:

Milrinone is cleared more rapidly in children than in adults, but infants have significantly lower clearance than children, and preterm infants have even lower clearance. As a consequence of this more rapid clearance compared to adults, steady-state plasma concentrations of milrinone were lower in children than in adults. In paediatric population with normal renal function steady-state milrinone plasma concentrations after 6 to 12 hours continuous infusion of 0.5 to 0.75 µg/kg/min were about of 100 to 300 ng/ml.

Following intravenous infusion of 0.5 to 0.75 µg/kg/min to neonates, infants and children after open heart surgery, milrinone has a volume of distribution ranging from 0.35 to 0.9 litres/kg with no significant difference across age groups. Following intravenous infusion of 0.5 µg/kg/min to very preterm infants to prevent low systemic outflow after birth, milrinone has a volume of distribution of about 0.5 litres/kg.

Several pharmacokinetic studies showed that, in paediatric population, clearance increases with increasing age. Infants have significantly lower clearance than children (3.4 to 3.8 ml/kg/min versus 5.9 to 6.7 ml/kg/min). In neonates milrinone clearance was about 1.64 ml/kg/min and preterm infants have even lower clearance (0.64 ml/kg/min).

Milrinone has a mean terminal half-life of 2 to 4 hours in infants and children and a mean terminal elimination half-life of 10 hours in preterm infants.

It was concluded that the optimal dose of milrinone in paediatric patients in order to obtain plasma levels above the threshold of pharmacodynamic efficacy appeared higher than in adults, but that optimal dose in preterms in order to obtain plasma levels above the threshold of pharmacodynamic efficacy appeared lower than in children.

Patent ductus arteriosus:

Milrinone is cleared by renal excretion and has a volume of distribution that is restricted to extracellular space which suggests that the fluid overload and hemodynamic changes associated with patent ductus arteriosus may have an effect on distribution and excretion of milrinone (see section 4.2, 4.4, 4.8, and 5.3).

5.3 Preclinical Safety Data

Juvenile animals:

A preclinical study was performed to clarify the ductus-dilating effects of PDE 3 inhibitors in near-term rat pups and their differential effects in near-term and preterm foetal rats. Postnatal ductus arteriosus dilatation by milrinone was studied with three doses (10, 1 and 0.1mg/kg). The dilating effects of milrinone in the foetal ductus constricted by indomethacin were studied by simultaneous administration of milrinone (10, 1 and 0.1mg/kg) and indomethacin (10 mg/kg) to the mother rat at D21 (near-term) and D19 (preterm). This in vivo study has shown that milrinone induces dose-dependent dilation of the foetal and the postnatal constricted ductus arteriosus. Dilating effects were more potent with injection immediately after birth than at 1 hour after birth. In addition, study showed that the premature ductus arteriosus is more sensitive to milrinone than the mature ductus arteriosus (see section 4.2, 4.4, 4.8, and 5.2).

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactic Acid

Glucose Anhydrous

Water for Injection

Sodium Hydroxide (for pH adjustment)

6.2 Incompatibilities

Furosemide or bumetanide should not be administered in intravenous lines containing Primacor Injection since precipitation occurs on admixture. Sodium Bicarbonate Intravenous infusion should not be used for dilution.

Other drugs should not be mixed with Primacor Injection until further compatibility data are available.

6.3 Shelf Life

48 months when unopened. A diluted solution of Primacor Injection should be used within 24 hours.

6.4 Special Precautions For Storage

Store below 25°C. Do not freeze.

6.5 Nature And Contents Of Container

Type 1 colourless, glass ampoules 10ml packed in lots of 10.

6.6 Special Precautions For Disposal And Other Handling

Infusion solutions diluted as recommended with 0.45% saline, 0.9% saline or 5% glucose should be freshly prepared before use. Parenteral drug products should be examined visually and should not be used if particulate matter or discolouration are present.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

8. Marketing Authorisation Number(S)

PL 04425/0646

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 11 October 1989

Date of latest renewal: 7 April 2004

10. Date Of Revision Of The Text

19 July 2011

LEGAL STATUS

POM

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1. Name Of The Medicinal Product

2. Qualitative And Quantitative Composition

3. Pharmaceutical Form

4. Clinical Particulars

4.1 Therapeutic Indications

4.2 Posology And Method Of Administration

4.3 Contraindications

4.4 Special Warnings And Precautions For Use

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

4.6 Pregnancy And Lactation

4.7 Effects On Ability To Drive And Use Machines

4.8 Undesirable Effects

4.9 Overdose

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

5.2 Pharmacokinetic Properties

5.3 Preclinical Safety Data

6. Pharmaceutical Particulars

6.1 List Of Excipients

6.2 Incompatibilities

6.3 Shelf Life

6.4 Special Precautions For Storage

6.5 Nature And Contents Of Container

6.6 Special Precautions For Disposal And Other Handling

7. Marketing Authorisation Holder

8. Marketing Authorisation Number(S)

9. Date Of First Authorisation/Renewal Of The Authorisation

10. Date Of Revision Of The Text

Commonly used brand name(s)

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