L.M.X.4

Ingredient matches for L.M.X.4

Lidocaine

Lidocaine is reported as an ingredient of L.M.X.4 in the following countries:

• United States

International Drug Name Search

Bronchotussine

Bronchotussine may be available in the countries listed below.

Ingredient matches for Bronchotussine

Bromhexine

Bromhexine hydrochloride (a derivative of Bromhexine) is reported as an ingredient of Bronchotussine in the following countries:

• Greece


• Malta

International Drug Name Search

Mirena

Generic Name: levonorgestrel (Intrauterine route)

lee-voe-nor-JES-trel

Commonly used brand name(s)

In the U.S.

• Mirena

Available Dosage Forms:

• Insert, Extended Release

Therapeutic Class: Contraceptive, Local

Pharmacologic Class: Progestin

Uses For Mirena

Levonorgestrel-releasing intrauterine system is a device that contains the female hormone, levonorgestrel. It is placed in the uterus (womb) where it slowly releases the hormone to prevent pregnancy for up to five years. It works by stopping a woman's egg from fully developing each month. The egg can no longer accept a sperm and fertilization (pregnancy) is prevented.

Levonorgestrel-releasing intrauterine system is also used to treat heavy menstrual bleeding in women. It works best in women who have had at least one child.

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

Before Using Mirena

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 performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of levonorgestrel in teenage females. This medicine may be used for birth control in teenage females but is not recommended before the start of menstruation.

Geriatric

Appropriate studies on the relationship of age to the effects of levonorgestrel have not been performed in the geriatric population. This medicine is not recommended for use in elderly women.

Pregnancy

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

Breast Feeding

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 receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

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

• Isotretinoin


• Theophylline


• Tizanidine


• Tranexamic Acid

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

• Acitretin


• Alprazolam


• Amoxicillin


• Ampicillin


• Amprenavir


• Aprepitant


• Atazanavir


• Bacampicillin


• Betamethasone


• Bexarotene


• Bosentan


• Carbamazepine


• Colesevelam


• Cyclosporine


• Darunavir


• Delavirdine


• Doxycycline


• Efavirenz


• Etravirine


• Fosamprenavir


• Fosaprepitant


• Fosphenytoin


• Griseofulvin


• Lamotrigine


• Licorice


• Minocycline


• Modafinil


• Mycophenolate Mofetil


• Mycophenolic Acid


• Nelfinavir


• Nevirapine


• Oxcarbazepine


• Oxytetracycline


• Phenobarbital


• Phenytoin


• Pioglitazone


• Prednisolone


• Primidone


• Rifabutin


• Rifampin


• Rifapentine


• Ritonavir


• Rosuvastatin


• Rufinamide


• Selegiline


• St John's Wort


• Tacrine


• Telaprevir


• Tetracycline


• Topiramate


• Troglitazone


• Troleandomycin


• Voriconazole


• Warfarin

Interactions with Food/Tobacco/Alcohol

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

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

• Caffeine

Other Medical Problems

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

• Abnormal or unusual vaginal bleeding or


• Abnormally-shaped uterus or uterine fibroids or


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


• Cancer of the uterus or cervix, known or suspected or


• Infection (e.g., pneumonia, HIV/AIDS) or


• Liver disease, including tumors or cancer or


• Pelvic infection (active or untreated), history of or


• Pelvic inflammatory disease (a serious pelvic infection), or history of—Should not be used in patients with these conditions.

• Bleeding problems or


• Blood clots or


• Diabetes or


• Heart attack, history of or


• Heart disease or other heart problems (e.g., congenital heart disease, heart valve problems) or


• Hypertension (high blood pressure), severe or


• Migraine headaches, severe or


• Stroke, history of—Use with caution. May make these conditions worse.

Proper Use of Mirena

Your doctor will give you this medicine in a hospital or clinic. The intrauterine device (IUD) is inserted into your uterus.

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

Your doctor may want to do tests to make sure you do not have an infection before putting in an IUD. The IUD is usually inserted during your monthly period or immediately after a miscarriage or an abortion in the first trimester of your pregnancy. Putting an IUD in during a monthly period also helps to make sure that you are not pregnant. You will also need to see your doctor within four to twelve weeks of having your IUD placed and then once a year.

Levonorgestrel IUD has a string or "tail" which is made of plastic thread. About one or two inches of this string hangs into your vagina. You cannot see this string, and it will not cause problems when you have sex. Check your IUD string every few days during the first few months that you have your IUD. After that, check the string after each monthly period. You may not be protected against pregnancy if you cannot feel the string or if you feel plastic. Do the following to check the placement of your IUD:

• Wash your hands with soap and warm water. Dry them with a clean towel.


• Bend your knees and squat low to the ground.


• Gently put your index (pointing) finger high inside your vagina. The cervix is at the top of the vagina and feels like the tip of your nose. Find the IUD string coming from your cervix. Never pull on the string. You should not be able to feel the firm plastic of the IUD itself.


• Wash your hands after you are finished checking your IUD.

You will need to have your levonorgestrel-releasing IUD replaced every five years, or sooner if it comes out of your uterus.

Precautions While Using Mirena

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and does not cause unwanted effects. These visits will usually be every 4 to 12 weeks after insertion, but some doctors require them more often.

Call your doctor right away if you think you have become pregnant while you are using this medicine. You may have a higher risk of an ectopic pregnancy if you get pregnant while your IUD is in place. An ectopic pregnancy can be a serious and life-threatening condition. It can also cause problems that may make it harder for you to become pregnant in the future.

An IUD can slip partly or all of the way out of your uterus without you knowing it. If this happens, you will have no protection against getting pregnant or you may have an increased risk for serious problems. This is more likely during the first year that you have your IUD, but can happen at any time. Regularly checking the string of your IUD can tell you if your IUD is still in place.

You may have some blood spotting and cramping during the first few weeks after the IUD has been inserted. These symptoms should go away within a few months. Rarely, the IUD may make a hole in the wall of your uterus when it is inserted. If this happens, check with your doctor right away.

An IUD increases your risk of a serious infection of the female organs called pelvic inflammatory disease (PID). PID can be serious, even life threatening. This infection could cause scarring of the female organs, which may make it hard for you to become pregnant in the future, and can increase your risk of ectopic pregnancy.

Call your doctor right away if you have flu-like symptoms, fever, chills, cramps, pain, bleeding, or fluid leaking from your vagina. These may be signs that you have an infection.

This device will not protect you from getting HIV/AIDS, herpes, or other sexually transmitted diseases. Tell your doctor if you or your partner begin to have sexual intercourse with other people, or you or your partner tests positive for a sexually transmitted disease. If this is a concern for you, talk with your doctor.

This medicine may cause changes in your blood sugar levels. Also, this medicine may cover up signs of low blood sugar, such as a rapid pulse rate. Check with your doctor if you have these problems or if you notice a change in the results of your blood or urine sugar tests.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Mirena 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:

More common

• Abdominal or pelvic pain


• absent, missed, or irregular menstrual periods


• longer or heavier menstrual periods


• mild bloating


• stopping of menstrual bleeding


• unusually heavy or unexpected menstrual bleeding


• uterine bleeding between menstrual periods


• vaginal bleeding or spotting

Less common

• Blurred vision


• cramps


• dizziness


• headache


• heavy bleeding


• itching of the vagina or genital area


• itching of the vagina or genitals


• nervousness


• pain


• pain during sexual intercourse


• painful sexual intercourse


• pale skin


• pounding in the ears


• slow or fast heartbeat


• swelling


• thick, white vaginal discharge with mild or no odor


• troubled breathing with exertion


• unusual bleeding or bruising


• unusual tiredness or weakness


• white or brownish vaginal discharge

Rare

• Chills


• confusion


• dizziness, lightheadedness, or fainting


• fast heartbeat


• fast, weak pulse


• fever


• pale, cold, clammy skin


• rapid, shallow breathing


• sudden increase in stomach or shoulder pain


• sweating


• unusual or large amount of vaginal bleeding

Incidence not known

• Clear or bloody discharge from nipple


• dimpling of breast skin


• dull or aching abdominal or stomach pain


• foul-smelling vaginal discharge


• increased urge to urinate


• inverted nipple


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


• lump in the breast or under the arm


• pain on urination


• persistent crusting or scaling of the nipple


• redness or swelling of the breast


• severe abdominal or stomach pain or cramping


• sharp pain on insertion


• shivering fever


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


• unexpected, heavy vaginal bleeding

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

More common

• Blemishes on the skin


• depression


• pimples

Less common

• Back pain


• breast tenderness or pain


• decreased interest in sexual intercourse


• full or bloated feeling


• hair loss


• hives or welts


• increased hair growth, especially on the face


• increased weight


• itching


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


• nausea


• nervousness


• pressure in the stomach


• rash


• redness of the skin


• skin rash, encrusted, scaly, and oozing


• swelling of the abdominal or stomach area


• thinning of the hair

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: Mirena 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 Mirena resources

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

• Mirena Prescribing Information (FDA)


• Mirena Consumer Overview


• Mirena IUD MedFacts Consumer Leaflet (Wolters Kluwer)


• Levonorgestrel MedFacts Consumer Leaflet (Wolters Kluwer)


• Levonorgestrel Professional Patient Advice (Wolters Kluwer)


• Next Choice Prescribing Information (FDA)


• Plan B Prescribing Information (FDA)


• Plan B Consumer Overview


• Plan B One-Step Consumer Overview


• Plan B One-Step MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Mirena with other medications

• Abnormal Uterine Bleeding
• Birth Control

Vincristine-Mayne

Vincristine-Mayne may be available in the countries listed below.

Ingredient matches for Vincristine-Mayne

Vincristine

Vincristine sulfate (a derivative of Vincristine) is reported as an ingredient of Vincristine-Mayne in the following countries:

• Denmark


• France


• Iceland


• Luxembourg


• Norway

International Drug Name Search

Nurofen 200mg Liquicaps

1. Name Of The Medicinal Product

Nurofen 200mg Liquicaps

2. Qualitative And Quantitative Composition

Each capsule, soft contains Ibuprofen 200mg

Excipients:

Potassium hydroxide

Sorbitol

For a full list of excipients see 6.1.

3. Pharmaceutical Form

Capsule, soft

A clear red oval soft gelatin capsule printed with an identifying logo in white.

4. Clinical Particulars

4.1 Therapeutic Indications

Adults and children over 12 years:

Nurofen 200mg Liquicaps are indicated for the symptomatic relief of rheumatic or muscular pain, backache, neuralgia, migraine, headache, dental pain, dysmenorrhoea, feverishness, colds and influenza symptoms

4.2 Posology And Method Of Administration

For oral administration and short-term use only.

Adults, the elderly and children over 12 years:

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms.

The patient should consult a doctor if symptoms persist or worsen, or if the product is required for more than 10 days.

Take one or two capsules, up to three times a day as required.

Leave at least 4 hours between doses.

Do not take more than 6 capsules in any 24 hour period.

4.3 Contraindications

Patients with a known hypersensitivity to ibuprofen or any other constituent of the medicinal product.

Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema, or urticaria) in response to aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs).

Patients with a history of, or existing gastrointestinal ulceration/perforation or bleeding, including that associated with NSAIDs. (See Section 4.4)

Patients with severe hepatic failure, severe renal failure or severe heart failure. See also Section 4.4

Use with concomitant NSAIDs, including cyclo-oxygenase-2 specific inhibitors – increased risk of adverse reactions (see section 4.5)”

During the last trimester of pregnancy as there is a risk of premature closure of the fetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child (see Section 4.6).

4.4 Special Warnings And Precautions For Use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see GI and cardiovascular risks below).

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

Respiratory:

Bronchospasm may be precipitated in patients suffering from, or with a history of, bronchial asthma or allergic disease.

Other NSAIDs:

The use of ibuprofen with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5)

SLE and mixed connective tissue disease:

Systemic lupus erythematosus and mixed connective tissue disease – increased risk of aseptic meningitis (see section 4.8).

Renal:

Renal impairment as renal function may further deteriorate (see sections 4.3 and 4.8)

Hepatic:

Hepatic dysfunction (see Sections 4.3 and 4.8)

Cardiovascular and cerebrovascular effects:

Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that the use of ibuprofen, particularly at high doses (2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g.

Impaired female fertility:

There is some evidence that drugs which inhibit cyclo-oxygenase/ prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment.

Gastrointestinal:

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8).

GI bleeding, ulceration or perforation, which can be fatal has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complaicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available.

Patients with a history of GI toxicity, particularly the elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).

When GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn.

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Ibuprofen should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

The label will include:

Read the enclosed leaflet before taking this product

Do not take if you:

• have (or have had two or more episodes of ) a stomach ulcer, perforation or bleeding

• are allergic to ibuprofen, to any of the ingredients, or to aspirin or other painkillers

• are taking other NSAID pain killers or aspirin with a daily dose above 75mg

Speak to a pharmacist or your doctor before taking if you:

• have or have had asthma, diabetes, high cholesterol, high blood pressure, a stroke, heart, liver, kidney or bowel problems

• Are a smoker

• Are pregnant

This medicine contains 14mg of potassium per dose. To be taken into consideration by patients on a controlled potassium diet.

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Contains 50.5mg of sorbitol per dose, a source of 12.6mg of fructose per dose.

If symptoms persist or worsen, or if new symptoms occur, consult your doctor or pharmacist.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Ibuprofen (like other NSAIDs) should be avoided in combination with:

• Aspirin: unless low-dose aspirin (not above 75mg daily) has been advised by a doctor as this may increase the risk of adverse reactions (see Section 4.4).

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

• Other NSAIDs including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse effects (see section 4.4)

Ibuprofen should be used with caution in combination with:

• Corticosteroids: as these may increase the risk of gastrointestinal ulceration or bleeding (see Section 4.4)

• Antihypertensives and diuretics: since NSAIDs may diminish the effects of these drugs. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

• Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (See section 4.4).

• Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).

• Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

• Lithium: There is evidence for potential increase in plasma levels of lithium.

• Methotrexate: There is evidence for the potential increase in plasma levels of methotrexate.

• Ciclosporin: Increased risk of nephrotoxicity.

• Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

• Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

• Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

• Quinolone antibiotics:Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

4.6 Pregnancy And Lactation

Whilst no teratogenic effects have been demonstrated in animal experiments, the use of Nurofen 200mg Liquicaps should, if possible, be avoided during the first 6 months of pregnancy.

During the 3^rd trimester, ibuprofen is contraindicated as there is a risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child. (See section 4.3 Contraindications).

In limited studies, ibuprofen appears in the breast milk in very low concentration and is unlikely to affect the breast-fed infant adversely.

See section 4.4 regarding female fertility.

4.7 Effects On Ability To Drive And Use Machines

None expected at recommended dose and duration of therapy.

4.8 Undesirable Effects

Hypersensitivity reactions have been reported and these may consist of

a. non-specific allergic reactions and anaphylaxis

b. respiratory tract reactivity e.g. asthma, aggravated asthma, bronchospasm, dyspnoea

c. various skin reactions e.g. pruritus, urticaria, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme)

The list of the following adverse effects relates to those experienced with ibuprofen at OTC doses, for short-term use. In the treatment of chronic conditions, under long-term treatment, additional adverse effects may occur.

Gastrointestinal Disorders	Uncommon: Rare: Very rare:	Abdominal pain, dyspepsia and nausea. Diarrhoea, flatulence, constipation and vomiting Peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly. Ulcerative stomatitis gastritis. Exacerbation of ulcerative colitis and Crohn's disease (See section 4.4) (see section 4.4)
Nervous System	Uncommon: Very rare	Headache Aseptic meningitis – single cases have been reported very rarely
Kidney	Very rare:	Decrease of urea excretion and oedema can occur. Also, acute renal failure. Papillary necrosis, especially in long-term use, and increased serum urea concentrations have been reported.
Liver	Very rare:	Liver disorders, especially in long-term treatment.
Blood	Very rare:	Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.
Skin	Uncommon: Very rare:	Various skin rashes Severe forms of skin reactions such as bullous reactions, including Stevens-Johnson Syndrome, erythema multiforme and toxic epidermal necrolysis can occur.
Immune System	Very rare:	In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed (see section 4.4)
Hypersensitivity Reactions	Uncommon: Very rare:	Hypersensitivity reactions with urticaria and pruritus. Severe hypersensitivity reactions. Symptoms could be: facial, tongue and larynx swelling, dyspnoea, tachycardia, hypotension, (anaphylaxis, angioedema or severe shock). Exacerbation of asthma and bronchospasm.

Cardiovascular and Cerebrovascular:

Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of ibuprofen (particularly at high doses 2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

4.9 Overdose

In children ingestion of more than 400mg/kg may cause symptoms. In adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours.

Symptoms – Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and the prothrombin time/ INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.

Management –

Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code: M01A E01 Propionic acid derivative.

Ibuprofen is a propionic acid derivative NSAID that has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans, ibuprofen reduces inflammatory pain, swellings and fever. Furthermore, ibuprofen reversibly inhibits platelet aggregation.

Clinical evidence demonstrates that when 400mg of ibuprofen is taken the pain relieving effects can last for up to 8 hours.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken within 8 h before or within 30 min after immediate release aspirin dosing (81mg), a decreased effect of ASA on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no relevant effect is considered to be likely for occasional ibuprofen use.

5.2 Pharmacokinetic Properties

Ibuprofen is well absorbed from the gastrointestinal tract. Ibuprofen is extensively bound to plasma proteins.

Nurofen 200mg Liquicaps consist of ibuprofen 200mg dissolved in a hydrophilic solvent inside a gelatin shell. On ingestion, the gelatin shell disintegrates in the gastric juice releasing the solubilised ibuprofen immediately for absorption. The median peak plasma concentration is achieved approximately 30 minutes after administration.

The median peak plasma concentration for Nurofen tablets is achieved approximately 1-2 hours after administration.

Ibuprofen is metabolised in the liver to two major metabolites with primary excretion via the kidneys, either as such or as major conjugates, together with a negligible amount of unchanged ibuprofen. Excretion by the kidney is both rapid and complete.

Elimination half-life is approximately 2 hours.

No significant differences in pharmacokinetic profile are observed in the elderly.

5.3 Preclinical Safety Data

No relevant information, additional to that contained elsewhere in the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Macrogol 600

Potassium hydroxide 50% solution (E525)

Gelatin

Sorbitol Liquid, Partially Dehydrated (E420)

Purified Water

Ponceau 4R (E124)

Lecithin (E322)

Triglycerides , medium chain

Ethanol

White ink*

The ink contains the following residual materials after application: Titanium Dioxide (E171), Polyvinyl Acetate Phthalate, Macrogol 400, ammonium hydroxide (E527), propylene glycol.

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

Store below 25°C

6.5 Nature And Contents Of Container

Blisters formed from Opaque Duplex PVC/PVdC 250µm/60gsm heat sealed to 20µm aluminium foil

or

opaque Tristar (Triplex) PVC/PE/PVdC 250µm/25µm/90gsm heat sealed to 20µm aluminium foil packed into cartons

Each carton may contain 10, 12, 16 in blister strips

Not all packs will be marketed.

6.6 Special Precautions For Disposal And Other Handling

Not applicable

7. Marketing Authorisation Holder

Crookes Healthcare Limited

1 Thane Road West

Nottingham

NG2 3AA

8. Marketing Authorisation Number(S)

PL 00327/0197

9. Date Of First Authorisation/Renewal Of The Authorisation

25/01/2008

10. Date Of Revision Of The Text

03/09/2010

Sulbactam Pivoxil

Sulbactam Pivoxil may be available in the countries listed below.

Ingredient matches for Sulbactam Pivoxil

Sulbactam

Sulbactam Pivoxil (USAN) is known as Sulbactam in the US.

International Drug Name Search

Glossary

USAN	United States Adopted Name

Click for further information on drug naming conventions and International Nonproprietary Names.

Levogen

Levogen may be available in the countries listed below.

Ingredient matches for Levogen

Levofloxacin

Levofloxacin is reported as an ingredient of Levogen in the following countries:

• Bangladesh

International Drug Name Search

Feospan

Feospan may be available in the countries listed below.

Ingredient matches for Feospan

Ferrous Sulfate

Ferrous Sulfate is reported as an ingredient of Feospan in the following countries:

• Ethiopia


• Ireland

International Drug Name Search

Naropin 7.5 mg / ml solution for injection

1. Name Of The Medicinal Product

Naropin^® 7.5 mg/ml solution for injection

2. Qualitative And Quantitative Composition

Naropin^® 7.5 mg/ml:

1 ml solution for injection contains ropivacaine hydrochloride monohydrate equivalent to 7.5 mg ropivacaine hydrochloride.

1 ampoule of 10 ml or 20 ml solution for injection contains ropivacaine hydrochloride monohydrate equivalent to 75 mg and 150 mg ropivacaine hydrochloride respectively.

For excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection for perineural and epidural administration (10–20 ml).

Clear, colourless solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Naropin is indicated for:

1. Surgical anaesthesia

2. Acute pain management

4.2 Posology And Method Of Administration

Naropin should only be used by, or under the supervision of, clinicians experienced in regional anaesthesia.

Posology

Adults and children above 12 years of age:

The following table is a guide to dosage for the more commonly used blocks. The smallest dose required to produce an effective block should be used. The clinician's experience and knowledge of the patient's physical status are of importance when deciding the dose.

	Conc.	Volume	Dose	Onset	Duration
	mg/ml	ml	mg	minutes	hours
Surgical anaesthesia
Lumbar Epidural Administration
Surgery	7.5	15–25	113–188	10–20	3–5
	10	15–20	150–200	10–20	4–6
Caesarean section	7.5	15–20	113–150(1)	10–20	3–5
Thoracic Epidural Administration
To establish block for postoperative pain relief	7.5	5–15 (depending on the level of injection)	38–113	10–20	n/a(2)
Major Nerve Block*
Brachial plexus block	7.5	30–40	225–300(3)	10–25	6–10
Field Block	7.5	1–30	7.5–225	1–15	2–6
(e.g. minor nerve blocks and infiltration)
Acute pain management
Lumbar Epidural Administration
Bolus	2	10–20	20–40	10–15	0.5–1.5
Intermittent injections (top up) (e.g. labour pain management)	2	10–15 (minimum interval 30 minutes)	20–30
Continuous infusion e.g. labour pain	2	6–10 ml/h	12–20 mg/h	n/a(2)	n/a(2)
Postoperative pain management	2	6–14 ml/h	12–28 mg/h	n/a(2)	n/a(2)
Thoracic Epidural Administration
Continuous infusion (postoperative pain management)	2	6–14 ml/h	12–28 mg/h	n/a(2)	n/a(2)
Field Block
(e.g. minor nerve blocks and infiltration)	2	1–100	2–200	1–5	2–6
Peripheral nerve block (Femoral or interscalene block)
Continuous infusion or intermittent injections (e.g. postoperative pain management)	2	5–10 ml/h	10–20 mg/h	n/a	n/a
The doses in the table are those considered to be necessary to produce a successful block and should be regarded as guidelines for use in adults. Individual variations in onset and duration occur. The figures in the column 'Dose' reflect the expected average dose range needed. Standard textbooks should be consulted for both factors affecting specific block techniques and individual patient requirements.
* With regard to major nerve block, only for brachial plexus block a dose recommendation can be given. For other major nerve blocks lower doses may be required. However, there is presently no experience of specific dose recommendations for other blocks.
(1) Incremental dosing should be applied, the starting dose of about 100 mg (97.5 mg = 13 ml; 105 mg = 14 ml) to be given over 3–5 minutes. Two extra doses, in total an additional 50mg, may be administered as needed. (2) n/a = not applicable (3) The dose for a major nerve block must be adjusted according to site of administration and patient status. Interscalene and supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anaesthetic used, (see section 4.4. Special warnings and special precautions for use).

In general, surgical anaesthesia (e.g. epidural administration) requires the use of the higher concentrations and doses. The Naropin 10 mg/ml formulation is recommended for epidural anaesthesia in which a complete motor block is essential for surgery. For analgesia (e.g. epidural administration for acute pain management) the lower concentrations and doses are recommended.

Method of administration

Careful aspiration before and during injection is recommended to prevent intravascular injection. When a large dose is to be injected, a test dose of 3–5 ml lidocaine (lignocaine) with adrenaline (epinephrine) (Xylocaine^® 2% with Adrenaline (epinephrine) 1:200,000) is recommended. An inadvertent intravascular injection may be recognised by a temporary increase in heart rate and an accidental intrathecal injection by signs of a spinal block.

Aspiration should be performed prior to and during administration of the main dose, which should be injected slowly or in incremental doses, at a rate of 25–50 mg/min, while closely observing the patient's vital functions and maintaining verbal contact. If toxic symptoms occur, the injection should be stopped immediately.

In epidural block for surgery, single doses of up to 250 mg ropivacaine have been used and well tolerated.

In brachial plexus block a single dose of 300 mg has been used in a limited number of patients and was well tolerated.

When prolonged blocks are used, either through continuous infusion or through repeated bolus administration, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered. Cumulative doses up to 675 mg ropivacaine for surgery and postoperative analgesia administered over 24 hours were well tolerated in adults, as were postoperative continuous epidural infusions at rates up to 28 mg/hour for 72 hours. In a limited number of patients, higher doses of up to 800 mg/day have been administered with relatively few adverse reactions.

For treatment of postoperative pain, the following technique can be recommended: Unless preoperatively instituted, an epidural block with Naropin 7.5 mg/ml is induced via an epidural catheter. Analgesia is maintained with Naropin 2 mg/ml infusion. Infusion rates of 6–14 ml (12–28 mg) per hour provide adequate analgesia with only slight and non-progressive motor block in most cases of moderate to severe postoperative pain. The maximum duration of epidural block is 3 days. However, close monitoring of analgesic effect should be performed in order to remove the catheter as soon as the pain condition allows it. With this technique a significant reduction in the need for opioids has been observed.

In clinical studies an epidural infusion of Naropin 2 mg/ml alone or mixed with fentanyl 1-4 μg/ml has been given for postoperative pain management for up to 72 hours. The combination of Naropin and fentanyl provided improved pain relief but caused opioid side effects. The combination of Naropin and fentanyl has been investigated only for Naropin 2 mg/ml.

When prolonged peripheral nerve blocks are applied, either through continuous infusion or through repeated injections, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered. In clinical studies, femoral nerve block was established with 300 mg Naropin 7.5 mg/ml and interscalene block with 225 mg Naropin 7.5 mg/ml, respectively, before surgery. Analgesia was then maintained with Naropin 2 mg/ml. Infusion rates or intermittent injections of 10–20 mg per hour for 48 hours provided adequate analgesia and were well tolerated.

Concentrations above 7.5 mg/ml Naropin have not been documented for Caesarean section.

4.3 Contraindications

Hypersensitivity to ropivacaine or to other local anaesthetics of the amide type.

General contraindications related to epidural anaesthesia, regardless of the local anaesthetic used, should be taken into account.

Intravenous regional anaesthesia.

Obstetric paracervical anaesthesia.

Hypovolaemia.

4.4 Special Warnings And Precautions For Use

Regional anaesthetic procedures should always be performed in a properly equipped and staffed area. Equipment and drugs necessary for monitoring and emergency resuscitation should be immediately available. Patients receiving major blocks should be in an optimal condition and have an intravenous line inserted before the blocking procedure. The clinician responsible should take the necessary precautions to avoid intravascular injection (see section 4.2 Posology and method of administration) and be appropriately trained and familiar with diagnosis and treatment of side effects, systemic toxicity and other complications (see section 4.8 Undesirable effects and 4.9 Overdose) such as inadvertent subarachnoid injection, which may produce a high spinal block with apnoea and hypotension. Convulsions have occurred most often after brachial plexus block and epidural block. This is likely to be the result of either accidental intravascular injection or rapid absorption from the injection site.

Caution is required to prevent injections in inflamed areas.

Cardiovascular

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

There have been rare reports of cardiac arrest during the use of Naropin for epidural anaesthesia or peripheral nerve blockade, especially after unintentional accidental intravascular administration in elderly patients and in patients with concomitant heart disease. In some instances, resuscitation has been difficult. Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the possibility of a successful outcome.

Head and neck blocks

Certain local anaesthetic procedures, such as injections in the head and neck regions, may be associated with a higher frequency of serious adverse reactions, regardless of the local anaesthetic used.

Major peripheral nerve blocks

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

Hypersensitivity

A possible cross–hypersensitivity with other amide–type local anaesthetics should be taken into account.

Hypovolaemia

Patients with hypovolaemia due to any cause can develop sudden and severe hypotension during epidural anaesthesia, regardless of the local anaesthetic used.

Patients in poor general health

Patients in poor general condition due to ageing or other compromising factors such as partial or complete heart conduction block, advanced liver disease or severe renal dysfunction require special attention, although regional anaesthesia is frequently indicated in these patients.

Patients with hepatic and renal impairment

Ropivacaine is metabolised in the liver and should therefore be used with caution in patients with severe liver disease; repeated doses may need to be reduced due to delayed elimination. Normally there is no need to modify the dose in patients with impaired renal function when used for single dose or short-term treatment. Acidosis and reduced plasma protein concentration, frequently seen in patients with chronic renal failure, may increase the risk of systemic toxicity.

Acute porphyria

Naropin^® solution for injection and infusion is possibly porphyrinogenic and should only be prescribed to patients with acute porphyria when no safer alternative is available. Appropriate precautions should be taken in the case of vulnerable patients, according to standard textbooks and/or in consultation with disease area experts.

Excipients with recognised action/effect

This medicinal product contains maximum 3.7 mg sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

Prolonged administration

Prolonged administration of ropivacaine should be avoided in patients concomitantly treated with strong CYP1A2 inhibitors, such as fluvoxamine and enoxacin, see section 4.5.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Naropin should be used with caution in patients receiving other local anaesthetics or agents structurally related to amide-type local anaesthetics, e.g. certain antiarrhythmics, such as lidocaine and mexiletine, since the systemic toxic effects are additive. Simultaneous use of Naropin with general anaesthetics or opioids may potentiate each others (adverse) effects. Specific interaction studies with ropivacaine and anti-arrhythmic drugs class III (e.g. amiodarone) have not been performed, but caution is advised (see also section 4.4 Special warnings and precautions for use).

Cytochrome P450 (CYP) 1A2 is involved in the formation of 3-hydroxy-ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by up to 77% during co

In vivo, the plasma clearance of ropivacaine was reduced by 15% during co

In vitro, ropivacaine is a competitive inhibitor of CYP2D6 but does not seem to inhibit this isozyme at clinically attained plasma concentrations.

4.6 Pregnancy And Lactation

Pregnancy

Apart from epidural administration for obstetrical use, there are no adequate data on the use of ropivacaine in human pregnancy. Experimental animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fœtal development, parturition or postnatal development (see section 5.3 Preclinical safety data).

Lactation

There are no data available concerning the excretion of ropivacaine into human milk.

4.7 Effects On Ability To Drive And Use Machines

No data are available. Depending on the dose, local anaesthetics may have a minor influence on mental function and co-ordination even in the absence of overt CNS toxicity and may temporarily impair locomotion and alertness.

4.8 Undesirable Effects

General

The adverse reaction profile for Naropin is similar to those for other long acting local anaesthetics of the amide type. Adverse drug reactions should be distinguished from the physiological effects of the nerve block itself e.g. a decrease in blood pressure and bradycardia during spinal/epidural block.

Table of adverse drug reactions

Within each system organ class, the ADRs have been ranked under the headings of frequency, most frequent reactions first.

Very common (>1/10)	Vascular Disorders	Hypotension
	Gastrointestinal Disorders	Nausea
Common (>1/100)	Nervous System Disorders	Headache, paraesthesia, dizziness
	Cardiac Disorders	Bradycardia, tachycardia
	Vascular Disorders	Hypertension
	Gastrointestinal Disorders	Vomiting
	Renal and Urinary Disorders	Urinary retention
	General Disorder and Administration Site Conditions	Temperature elevation, rigor, back pain
Uncommon (>1/1,000)	Psychiatric Disorders	Anxiety
	Nervous System Disorders	Symptoms of CNS toxicity (convulsions, grand mal convulsions, seizures, light headedness, circumoral paraesthesia, numbness of the tongue, hyperacusis, tinnitus, visual disturbances, dysarthria, muscular twitching, tremor)* , Hypoaesthesia.
	Vascular Disorders	Syncope
	Respiratory, Thoracic and Mediastinal Disorders	Dyspnoea
	General Disorders and Administration Site Conditions	Hypothermia
Rare (>1/10,000)	Cardiac Disorders	Cardiac arrest, cardiac arrhythmias
	General Disorder and Administration Site Conditions	Allergic reactions (anaphylactic reactions, angioneurotic oedema and urticaria)

^* These symptoms usually occur because of inadvertent intravascular injection, overdose or rapid absorption, see section 4.9

Class-related adverse drug reactions:

Neurological complications

Neuropathy and spinal cord dysfunction (e.g. anterior spinal artery syndrome, arachnoiditis, cauda equina), which may result in rare cases of permanent sequelae, have been associated with regional anaesthesia, regardless of the local anaesthetic used.

Total spinal block

Total spinal block may occur if an epidural dose is inadvertently administered intrathecally.

Acute systemic toxicity

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

Central nervous system toxicity

Central nervous system toxicity is a graded response with symptoms and signs of escalating severity. Initially symptoms such as visual or hearing disturbances, perioral numbness, dizziness, light-headedness, tingling and paraesthesia are seen. Dysarthria, muscular rigidity and muscular twitching are more serious and may precede the onset of generalised convulsions. These signs must not be mistaken for neurotic behaviour. Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercarbia occur rapidly during convulsions due to the increased muscular activity, together with the interference with respiration. In severe cases even apnoea may occur. The respiratory and metabolic acidosis increases and extends the toxic effects of local anaesthetics.

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

Cardiovascular system toxicity

Cardiovascular toxicity indicates a more severe situation. Hypotension, bradycardia, arrhythmia and even cardiac arrest may occur as a result of high systemic concentrations of local anaesthetics. In volunteers the intravenous infusion of ropivacaine resulted in signs of depression of conductivity and contractility.

Cardiovascular toxic effects are generally preceded by signs of toxicity in the central nervous system, unless the patient is receiving a general anaesthetic or is heavily sedated with drugs such as benzodiazepines or barbiturates.

In children, early signs of local anaesthetic toxicity may be difficult to detect since they may not be able to verbally express them. See also section 4.4.

Treatment of acute systemic toxicity

See section 4.9 Overdose.

4.9 Overdose

Symptoms:

Accidental intravascular injections of local anaesthetics may cause immediate (within seconds to a few minutes) systemic toxic reactions. In the event of overdose, peak plasma concentrations may not be reached for one to two hours, depending on the site of the injection, and signs of toxicity may thus be delayed. (See section 4.8 Acute systemic toxicity, Central nervous system toxicity and Cardiovascular system toxicity).

Treatment

If signs of acute systemic toxicity appear, injection of the local anaesthetic should be stopped immediately and CNS symptoms (convulsions, CNS depression) must promptly be treated with appropriate airway/respiratory support and the administration of anticonvulsant drugs.

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

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

Should cardiac arrest occur, a successful outcome may require prolonged resuscitative efforts.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Anaesthetics, local, Amides

ATC code: N01B B09

Ropivacaine is a long-acting, amide-type local anaesthetic with both anaesthetic and analgesic effects. At high doses Naropin produces surgical anaesthesia, while at lower doses it produces sensory block with limited and non-progressive motor block.

The mechanism is a reversible reduction of the membrane permeability of the nerve fibre to sodium ions. Consequently the depolarisation velocity is decreased and the excitable threshold increased, resulting in a local blockade of nerve impulses.

The most characteristic property of ropivacaine is the long duration of action. Onset and duration of the local anaesthetic efficacy are dependent upon the administration site and dose, but are not influenced by the presence of a vasoconstrictor (e.g. adrenaline (epinephrine)). For details concerning the onset and duration of action of Naropin, see table under posology and method of administration.

Healthy volunteers exposed to intravenous infusions tolerated ropivacaine well at low doses and with expected CNS symptoms at the maximum tolerated dose. The clinical experience with this drug indicates a good margin of safety when adequately used in recommended doses.

5.2 Pharmacokinetic Properties

Ropivacaine has a chiral center and is available as the pure S-(-)-enantiomer. It is highly lipid-soluble. All metabolites have a local anaesthetic effect but of considerably lower potency and shorter duration than that of ropivacaine.

The plasma concentration of ropivacaine depends upon the dose , the route of administration and the vascularity of the injection site. Ropivacaine follows linear pharmacokinetics and the C_max is proportional to the dose.

Ropivacaine shows complete and biphasic absorption from the epidural space with half-lives of the two phases of the order of 14 min and 4 h in adults. The slow absorption is the rate-limiting factor in the elimination of ropivacaine, which explains why the apparent elimination half-life is longer after epidural than after intravenous administration.

Ropivacaine has a mean total plasma clearance in the order of 440 ml/min, a renal clearance of 1 ml/min, a volume of distribution at steady state of 47 litres and a terminal half-life of 1.8 h after iv administration. Ropivacaine has an intermediate hepatic extraction ratio of about 0.4. It is mainly bound to α₁- acid glycoprotein in plasma with an unbound fraction of about 6%.

An increase in total plasma concentrations during continuous epidural infusion has been observed, related to a postoperative increase of α₁- acid glycoprotein.

Variations in unbound, i.e. pharmacologically active, concentration have been much less than in total plasma concentration.

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

Ropivacaine is extensively metabolised, predominantly by aromatic hydroxylation. In total, 86% of the dose is excreted in the urine after intravenous administration, of which only about 1% relates to unchanged drug. The major metabolite is 3-hydroxy-ropivacaine, about 37% of which is excreted in the urine, mainly conjugated. Urinary excretion of 4-hydroxy-ropivacaine, the N-dealkylated metabolite and the 4-hydroxy-dealkylated accounts for 1–3%. Conjugated and unconjugated 3-hydroxy-ropivacaine shows only detectable concentrations in plasma.

There is no evidence of in vivo racemisation of ropivacaine.

5.3 Preclinical Safety Data

Based on conventional studies of safety pharmacology, single and repeated dose toxicity, reproduction toxicity, mutagenic potential and local toxicity, no hazards for humans were identified other than those which can be expected on the basis of the pharmacodynamic action of high doses of ropivacaine (e.g. CNS signs, including convulsions, and cardiotoxicity).

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium chloride

Hydrochloric acid

Sodium hydroxide

Water for injection

6.2 Incompatibilities

In alkaline solutions precipitation may occur as ropivacaine shows poor solubility at pH > 6

6.3 Shelf Life

3 years.

Shelf life after first opening:

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2–8°C.

6.4 Special Precautions For Storage

Do not store above 30°C. Do not freeze.

For storage after opening, see section 6.3.

6.5 Nature And Contents Of Container

10 ml polypropylene ampoules (Polyamp) in packs of 5 and 10.

10 ml polypropylene ampoules (Polyamp) in sterile blister packs of 5 and 10.

20 ml polypropylene ampoules (Polyamp) in packs of 5 and 10.

20 ml polypropylene ampoules (Polyamp) in sterile blister packs of 5 and 10.

The polypropylene ampoules (Polyamp) are specially designed to fit Luer lock and Luer fit syringes.

6.6 Special Precautions For Disposal And Other Handling

Naropin products are preservative-free and are intended for single use only. Discard any unused solution.

The intact container must not be re-autoclaved. A blistered container should be chosen when a sterile outside is required.

7. Marketing Authorisation Holder

AstraZeneca UK Ltd.,

600 Capability Green,

Luton, LU1 3LU, UK.

8. Marketing Authorisation Number(S)

PL 17901/0152

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 3^rd October 1995

Date of last renewal: 15^th September 2005

10. Date Of Revision Of The Text

15^th August 2008