Generic Name: diphenhydramine (DYE fen HYE dra meen)



Pronunciation: nye-MOE-di-peen



na-PROX-en

Oral route(Tablet;Tablet, Enteric Coated;Suspension)

NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may be increased in patients with cardiovascular disease or risk factors for cardiovascular disease. Naproxen is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery. NSAIDs can also cause an increased risk of serious gastrointestinal adverse events especially in the elderly, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal .

Commonly used brand name(s)

In the U.S.

Aflaxen Aleve Aleve Arthritis Anaprox Anaprox DS EC Naprosyn Naprelan Naprelan 500 Naprelan Dose Card Naprosyn

In Canada

Naxen

Available Dosage Forms:

Tablet Suspension Tablet, Enteric Coated Tablet, Extended Release

Therapeutic Class: Analgesic

Pharmacologic Class: NSAID

Chemical Class: Propionic Acid (class)

Uses For naproxen

Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) used to relieve symptoms of arthritis (osteoarthritis, rheumatoid arthritis, or juvenile arthritis) such as inflammation, swelling, stiffness, and joint pain. Naproxen also helps relieve symptoms of ankylosing spondylitis, which is a type of arthritis that affects the joints in the spine. However, naproxen does not cure arthritis and will help you only as long as you continue to take it.

naproxen may also be used to treat mild to moderate pain, including acute gout and other painful conditions such as bursitis, tendonitis, or menstrual cramps.

naproxen is available only with your doctor's prescription.

Before Using naproxen

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 naproxen, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to naproxen 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 naproxen controlled-release tablets in the pediatric population. Safety and efficacy have not been established.

Appropriate studies have not been performed on the relationship of age to the effects of naproxen delayed release tablets, suspension, and tablets in children younger than 2 years of age. 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 naproxen in the elderly. However, elderly patients may be more sensitive to the effects of naproxen than younger adults, and are more likely to have age-related kidney or stomach problems, which may require caution and an adjustment in the dose for patients receiving naproxen.

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

Studies in women suggest that this medication poses minimal risk to the infant when used during 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 naproxen, 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 naproxen 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.

Ketorolac Pentoxifylline

Using naproxen 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.

Abciximab Ardeparin Argatroban Aspirin Beclamide Beta Glucan Bivalirudin Caramiphen Carbamazepine Certoparin Chlormethiazole Cilostazol Citalopram Clopidogrel Clovoxamine Dabigatran Etexilate Dalteparin Danaparoid Desirudin Diazepam Dipyridamole Enoxaparin Escitalopram Ethotoin Felbamate Femoxetine Flesinoxan Fluoxetine Fluvoxamine Fondaparinux Fosphenytoin Gabapentin Ginkgo Heparin Lacosamide Lepirudin Mephenytoin Mephobarbital Methotrexate Nadroparin Nefazodone Oxcarbazepine Paraldehyde Paramethadione Parnaparin Paroxetine Pemetrexed Phenacemide Phenobarbital Phenytoin Piracetam Pregabalin Protein C Reviparin Rivaroxaban Rufinamide Sertraline Sibutramine Stiripentol Tacrolimus Tiagabine Ticlopidine Tinzaparin Tirofiban Topiramate Trimethadione Valproic Acid Vigabatrin Vilazodone Warfarin Zimeldine Zonisamide

Using naproxen 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.

Acebutolol Acetohexamide Alacepril Alprenolol Amiloride Arotinolol Atenolol Azilsartan Medoxomil Azosemide Befunolol Bemetizide Benazepril Bendroflumethiazide Benzthiazide Betaxolol Bevantolol Bisoprolol Bopindolol Bucindolol Bumetanide Bupranolol Buthiazide Candesartan Cilexetil Canrenoate Captopril Carteolol Carvedilol Celiprolol Chlorothiazide Chlorpropamide Chlorthalidone Cilazapril Clopamide Cyclopenthiazide Cyclosporine Delapril Desvenlafaxine Dilevalol Duloxetine Enalaprilat Enalapril Maleate Eprosartan Esmolol Ethacrynic Acid Fosinopril Furosemide Gliclazide Glimepiride Glipizide Gliquidone Glyburide Hydrochlorothiazide Hydroflumethiazide Imidapril Indapamide Irbesartan Labetalol Landiolol Levobetaxolol Levobunolol Lisinopril Lithium Losartan Mepindolol Methyclothiazide Metipranolol Metolazone Metoprolol Milnacipran Moexipril Nadolol Nebivolol Nipradilol Olmesartan Medoxomil Oxprenolol Penbutolol Pentopril Perindopril Pindolol Piretanide Polythiazide Propranolol Quinapril Ramipril Sotalol Spirapril Spironolactone Talinolol Tasosartan Telmisartan Temocapril Tertatolol Timolol Tolazamide Tolbutamide Torsemide Trandolapril Triamterene Trichlormethiazide Valsartan Venlafaxine Xipamide Zofenopril Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

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

Anemia or Bleeding problems or Blood clots or Edema (fluid retention or body swelling) or Heart attack, history of or Heart disease (e.g., congestive heart failure) or Hypertension (high blood pressure) or Kidney disease or Liver disease (e.g., hepatitis) or Stomach or intestinal ulcers or bleeding, history of or Stroke, history of—Use with caution. May make these conditions worse. Aspirin-sensitive asthma or Aspirin sensitivity, history of—Should not be used in patients with these conditions. Heart surgery (e.g., coronary artery bypass graft [CABG])—Should not be used to relieve pain right before or after the surgery. Proper Use of naproxen

For safe and effective use of naproxen, do not take more of it, do not take it more often, and do not take it for a longer time than ordered by your doctor. Taking too much of naproxen may increase the chance of unwanted effects, especially in elderly patients.

naproxen should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

When used for severe or continuing arthritis, naproxen must be taken regularly as ordered by your doctor in order for it to help you. naproxen usually begins to work within one week, but in severe cases up to two weeks or even longer may pass before you begin to feel better. Also, several weeks may pass before you feel the full effects of naproxen.

Check with your doctor first before changing dosage forms (e.g., tablets, suspension). These forms are very different from each other.

Swallow the delayed-release tablet whole. Do not crush, break, or chew it.

If you are using the suspension, shake it gently before using it. Use the marked measuring cup included in the package to measure the dose.

Dosing

The dose of naproxen 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 naproxen. 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 naproxen (e.g., Naprosyn®) tablet and oral suspension dosage forms: For rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis: Adults—At first, 250 milligrams (mg) (10 milliliters (mL)/2 teaspoonfuls), 375 mg (15 mL/3 teaspoonfuls), or 500 mg (20 mL/4 teaspoonfuls) two times a day, in the morning and evening. Your doctor may increase your dose, as needed, up to a total of 1500 mg per day. Children 2 years of age and older—Dose is based on body weight and must be determined by your doctor. The dose is usually 5 milligrams (mg) per kilogram (kg) of body weight two times a day. Children younger than 2 years of age—Use and dose must be determined by your doctor. For bursitis, tendonitis, menstrual cramps, and other kinds of pain: Adults—500 milligrams (mg) for the first dose, then 250 mg every 6 to 8 hours as needed. Children—Use and dose must be determined by your doctor. For acute gout: Adults—750 milligrams (mg) for the first dose, then 250 mg every 8 hours until the attack is relieved. Children—Use and dose must be determined by your doctor. For naproxen controlled-release tablet (e.g., Naprelan®) dosage form: For rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis: Adults—At first, 750 milligrams (mg) (taken as one 750 mg or two 375 mg tablets) or 1000 mg (taken as two 500 mg tablets) once a day. Your doctor may adjust your dose as needed, up to a total of 1500 mg (taken as two 750 mg or three 500 mg tablets) per day. Children—Use and dose must be determined by your doctor. For bursitis, tendonitis, menstrual cramps, and other kinds of pain: Adults—At first, 1000 milligrams (mg) (taken as two 500 mg tablets) once a day. Some patients may need 1500 mg (taken as two 750 mg or three 500 mg tablets) per day, for a limited period. However, the dose is usually not more than 1000 mg per day. Children—Use and dose must be determined by your doctor. For acute gout: Adults—1000 to 1500 milligrams (mg) (taken as two to three 500 mg tablets) once a day for the first dose, then 1000 mg (taken as two 500 mg tablets) once a day until the attack is relieved. Children—Use and dose must be determined by your doctor. For naproxen delayed-release tablet (e.g., EC-Naprosyn®) dosage form: For rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis: Adults—At first, 375 or 500 milligrams (mg) two times a day, in the morning and evening. Your doctor may increase the dose, if necessary, up to a total of 1500 mg per day. Children—Use and dose must be determined by your doctor. For naproxen sodium (e.g., Anaprox®, Anaprox® DS) tablet dosage form: For rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis: Adults—At first, 275 or 550 milligrams (mg) two times a day, in the morning and evening. Your doctor may increase the dose, if necessary, up to a total of 1500 mg per day. Children—Use and dose must be determined by your doctor. For bursitis, tendonitis, menstrual cramps, and other kinds of pain: Adults—550 milligrams (mg) for the first dose, then 550 mg every 12 hours or 275 mg every 6 to 8 hours as needed. Your doctor may increase the dose, if necessary, up to a total of 1375 mg per day. Children—Use and dose must be determined by your doctor. For acute gout: Adults—825 milligrams (mg) for the first dose, then 275 mg every 8 hours until the attack is relieved. Children—Use and dose must be determined by your doctor. Missed Dose

If you miss a dose of naproxen, 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 naproxen

It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it. Blood and urine tests may be needed to check for unwanted effects.

naproxen may raise your risk of having a heart attack or stroke. This is more likely in people who already have heart disease. People who use naproxen for a long time might also have a higher risk.

naproxen may cause bleeding in your stomach or intestines. This problem can happen without warning signs. This is more likely if you have had a stomach ulcer in the past, if you smoke or drink alcohol regularly, if you are over 60 years of age, are in poor health, or are using certain other medicines (such as a steroid or a blood thinner).

Serious skin reactions can occur during treatment with naproxen. Check with your doctor right away if you have any of the following symptoms while taking naproxen: blistering, peeling, or loosening of the skin; chills; cough; diarrhea; fever; itching; joint or muscle pain; red skin lesions; sore throat; sores, ulcers, or white spots in the mouth or on the lips; or unusual tiredness or weakness.

Possible warning signs of some serious side effects that can occur during treatment with naproxen may include swelling of the face, fingers, feet, or lower legs; severe stomach pain, black, tarry stools, or vomiting of blood or material that looks like coffee grounds; unusual weight gain; yellow skin or eyes; decreased urination; unusual bleeding or bruising; or skin rash. Also, signs of serious heart problems could occur such as chest pain, tightness in the chest, fast or irregular heartbeat, unusual flushing or warmth of the skin, weakness, or slurring of speech. Stop taking naproxen and check with your doctor immediately if you notice any of these warning signs.

naproxen may also cause a serious type of allergic reaction called anaphylaxis. Although this is rare, it may occur more often in patients who are allergic to aspirin or to any of the nonsteroidal anti-inflammatory drugs. Anaphylaxis can be life-threatening and requires immediate medical attention. The most serious signs of this reaction are very fast or irregular breathing, gasping for breath, wheezing, or fainting. Other signs may include changes in color of the skin of the face; very fast but irregular heartbeat or pulse; hive-like swellings on the skin; and puffiness or swellings of the eyelids or around the eyes. If these effects occur, get emergency help at once.

Using naproxen during late pregnancy can harm your unborn baby. If you think you have become pregnant while using the medicine, tell your doctor right away.

Check with your doctor immediately if blurred vision, difficulty with reading, or any other change in vision occurs during or after your treatment. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

Before having any kind of surgery or medical tests, tell your doctor that you are taking naproxen. It may be necessary for you to stop treatment for a while, or to change to a different nonsteroidal anti-inflammatory drug before your procedure.

naproxen may cause some people to become dizzy, lightheaded, drowsy, or less alert than they are normally. Even if taken at bedtime, it may cause some people to feel drowsy or less alert on arising. Make sure you know how you react to naproxen before you drive, use machines, or do anything else that could be dangerous if you are not alert. .

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.

naproxen 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:

More common Belching bruising difficult or labored breathing feeling of indigestion headache itching skin large, flat, blue, or purplish patches in the skin pain in the chest below the breastbone shortness of breath skin eruptions stomach pain swelling tightness in the chest wheezing Less common Bloating bloody or black, tarry stools blurred or loss of vision burning upper abdominal or stomach pain cloudy urine constipation decrease in urine output or decrease in urine-concentrating ability disturbed color perception double vision fast, irregular, pounding, or racing heartbeat or pulse halos around lights indigestion loss of appetite nausea or vomiting night blindness overbright appearance of lights pale skin pinpoint red or purple spots on the skin severe and continuing nausea severe stomach burning, cramping, or pain skin rash swelling or inflammation of the mouth troubled breathing with exertion tunnel vision unusual bleeding or bruising unusual tiredness or weakness vomiting of material that looks like coffee grounds weight loss Rare Anxiety back or leg pains bleeding gums blindness blistering, peeling, or loosening of the skin blood in the urine or stools blue lips and fingernails canker sores change in the ability to see colors, especially blue or yellow chest pain or discomfort clay-colored stools cold sweats coma confusion cool, pale skin cough or hoarseness coughing that sometimes produces a pink frothy sputum cracks in the skin darkened urine decreased vision depression diarrhea difficult, burning, or painful urination difficult, fast, or noisy breathing difficulty with swallowing dilated neck veins dizziness dry cough dry mouth early appearance of redness, or swelling of the skin excess air or gas in the stomach extreme fatigue eye pain fainting fever with or without chills fluid-filled skin blisters flushed, dry skin frequent urination fruit-like breath odor greatly decreased frequency of urination or amount of urine hair loss high fever hives increased hunger increased sensitivity of the skin to sunlight increased sweating increased thirst increased urination increased volume of pale, dilute urine irregular breathing joint or muscle pain large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs late appearance of rash with or without weeping blisters that become crusted, especially in sun-exposed areas of skin, may extend to unexposed areas light-colored stools lightheadedness loss of heat from the body lower back or side pain nervousness nightmares no blood pressure no breathing no pulse nosebleeds numbness or tingling in the hands, feet, or lips pain in the ankles or knees pain or burning in the throat pain or discomfort in the arms, jaw, back, or neck painful, red lumps under the skin, mostly on the legs pains in the stomach, side, or abdomen, possibly radiating to the back pale or blue lips, fingernails, or skin pounding in the ears puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue rapid, shallow breathing red, irritated eyes red skin lesions, often with a purple center red-green color blindness redness or other discoloration of the skin redness, swelling, or soreness of the tongue scaly skin seizures severe sunburn shakiness skin thinness slurred speech sneezing sore throat sores, ulcers, or white spots on the lips or tongue or inside the mouth sores, welting, or blisters spots on your skin resembling a blister or pimple stiff neck or back stomach cramps or tenderness stomach upset swelling in the legs and ankles swelling of the face, fingers, feet, or lower legs swollen, painful, or tender lymph glands in the neck, armpit, or groin tiny bumps on the inner lining of the eyelid unexplained weight loss unpleasant breath odor watery or bloody diarrhea weakness or heaviness of the legs weight gain yellow eyes or skin

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

Symptoms of overdose Bleeding under the skin confusion about identity, place, and time muscle tremors restlessness sleepiness

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 Continuing ringing or buzzing or other unexplained noise in the ears hearing loss Less common Acid or sour stomach change in hearing feeling of constant movement of self or surroundings passing gas sensation of spinning stomach soreness or discomfort Rare Appetite changes burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings burning, dry, or itching eyes difficulty with moving discharge, excessive tearing general feeling of discomfort or illness lack or loss of strength menstrual changes muscle aching, cramping, stiffness, or weakness not able to concentrate redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid seeing, hearing, or feeling things that are not there shakiness in the legs, arms, hands, or feet sleeplessness swollen joints trembling or shaking of the hands or feet trouble getting pregnant trouble performing routine tasks trouble sleeping unable to sleep unusual drowsiness, dullness, or feeling of sluggishness

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: naproxen side effects (in more detail)

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More naproxen resources Naproxen Side Effects (in more detail) Naproxen Use in Pregnancy & Breastfeeding Drug Images Naproxen Drug Interactions Naproxen Support Group 131 Reviews for Naproxen - Add your own review/rating Naproxen Professional Patient Advice (Wolters Kluwer) Naproxen Prescribing Information (FDA) Naproxen Monograph (AHFS DI) Naproxen MedFacts Consumer Leaflet (Wolters Kluwer) Aleve Consumer Overview Anaprox MedFacts Consumer Leaflet (Wolters Kluwer) EC-Naprosyn Enteric-Coated Tablets MedFacts Consumer Leaflet (Wolters Kluwer) Naprosyn Consumer Overview Naprosyn Prescribing Information (FDA) Compare naproxen with other medications Ankylosing Spondylitis Aseptic Necrosis Back Pain Bursitis Costochondritis Diffuse Idiopathic Skeletal Hyperostosis Dysautonomia Fever Frozen Shoulder Gout, Acute Headache Juvenile Rheumatoid Arthritis Muscle Pain Osteoarthritis Pain Period Pain Rheumatoid Arthritis Sciatica Spondylolisthesis Tendonitis



1. Name Of The Medicinal Product

Nivemycin Tablets 500mg

2. Qualitative And Quantitative Composition

Neomycin sulphate Ph Eur.

an amount equivalent to 550mg of material having a potency of 700 units per mg

3. Pharmaceutical Form

Tablets

4. Clinical Particulars 4.1 Therapeutic Indications

Nivemycin (Neomycin sulphate BP) is indicated for pre-operative sterilisation of the bowel and may be useful in the treatment of impending hepatic coma, including portal systemic encephalopathy.

For oral administration.

4.2 Posology And Method Of Administration

Pre-operative sterilisation of the bowel.

Adults: 2 tablets every hour for 4 hours; then 2 tablets every 4 hours for two or three days before the operation.

Children over 12 years: 2 tablets every 4 hours for 2 or 3 days before the operation.

Children from 6 to 12 years: ? to 1 tablet every 4 hours for 2 or 3 days before the operation.

For practical reasons, use of the tablets in children under 6 years is not recommended.

In hepatic coma, the adult dose is 4-12 gm/day in divided doses for a period of 5-7 days, whilst for children, 50-100mg/kg/day in divided doses appears appropriate. Chronic hepatic insufficiency may require up to 4 gm/day over an indefinite period.

The elderly dose is the same as for adults.

4.3 Contraindications

Nivemycin should not be given when intestinal obstruction is present.

Hypersensitivity to aminoglycosides.

Infants under 1 year.

Myasthenia gravis

4.4 Special Warnings And Precautions For Use

The absorption of neomycin is poor from the alimentary tract, with about 97% of an orally administered dose being excreted unchanged in the faeces. Impaired G.I. motility however may increase absorption of the drug and it is therefore possible, as with other broad spectrum antibiotics, that prolonged therapy could result in ototoxicity and nephrotoxicity, particularly in patients with a degree of renal failure. In such patients, and in infants and the elderly, it is generally desirable to determine dosage requirements of aminoglycosides by individual monitoring. Some authorities consider that monitoring is also important in obese patients and those with cystic fibrosis.

Impaired hepatic function or auditory function, bacteraemia, fever, and possibly exposure to loud noises have been reported to increase the risk of ototoxicity, while volume depletion or hypotension, liver disease, or female sex have been reported as additional risk factors for nephrotoxicity. Regular assessment of auditory, vestibular and renal function is particularly necessary in patients with additional risk factors.

When used as an adjunct in the management of hepatic coma, care should be taken that administration is of the minimal period necessary, since prolonged exposure to the drug may result in malabsorption.

Neomycin should be used with caution in patients with neuromuscular disorders and parkinsonism.

There is almost complete cross-resistance between neomycin, kanamycin, paromomycin and framycetin. Cross-resistance with gentamicin has also been reported.

Since prolonged therapy may result in the overgrowth of non-sensitive organisms, treatment should not be continued longer than necessary to prevent superinfection due to the overgrowth of non-sensitive organisms.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Neomycin may impair absorption of other drugs including phenoxymethylpenicillin,digoxin, methotrexate and some vitamins. Aminoglycosides exhibit synergistic activity with a number of beta lactams, but aminoglycoside activity was reported to be diminished in a few patients with severe renal impairment.

Care should be taken when considering the use of neomycin concurrently with drugs with a potential to cause nephrotoxicity (including other aminoglycosides, some of the cephalosporins, amphotericin, ciclosporin, capreomycin, polymyxins, platinum compounds, teicoplanin and vancomycin) or ototoxicity (including, loop diuretics, capreomycin, teicoplanin, vancomycin and possibly platinum coumpounds).

The effect of non-depolarising muscle relaxants may be enhanced by aminoglycosides.

Care is required if other drugs with a neuromuscular blocking action, including botulinum toxin, are given concomitantly. Care is required when patients being treated with aminoglycosides are to receive a general anaesthetic or opioids in order to avoid the possible neuromuscular side-effects provoking severe respiratory depression.

The effect of the parasympathomimetic drugs neostigmine and pyridostigmine, may be antagonised by aminoglycosides.

The hypoglycaemic effect of acarbose may be enhanced by neomycin and the severity of gastrointestinal side effects increased.

Aminoglycosides may increase the risk of hypocalcaemia in patients receiving bisphosphonates.

Experience in anticoagulant clinics suggests that INR (International Normalised Ratio) may be altered by antibacterials such as neomycin given for local action on the gut, although studies have failed to demonstrate an interaction with phenindione.

The efficacy of oral contraceptives may be reduced with broad spectrum antibiotics.

Oral typhoid vaccine is inactivated by concomitant antibiotic administration.

4.6 Pregnancy And Lactation

The use of neomycin in pregnancy is not recommended unless the benefits outweigh the potential risks.

There are no reports linking the use of neomycin to congenital defects. However, small amounts of the drug are absorbed when given orally and neomycin and other aminoglycosides may have harmful effects on the foetus following oral absorption during pregnancy.

In some circumstances neomycin may enter the breast milk of lactating mothers. There is little risk of ototoxicity in the infant, but abnormal development of the gut flora may occur. The use of neomycin in lactating mothers is not recommended unless the benefits outweigh the potential risks.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Nausea, vomiting, diarrhoea, increased salivation, stomatitis, nephrotoxicity, ototoxicity, rise in serum levels of hepatic enzymes and bilirubin, blood dyscrasias, haemolytic anaemia, confusion, paraesthesia, disorientation, nystagmus, hypersensitivity reactionsincluding dermatitis, pruritus, drug fever and anaphylaxis.

Cross-sensitivity with other aminoglycosides may occur.

Malabsorption syndrome with steatorrhoea and diarrhoea, which can be severe, may be caused by prolonged oral therapy.

Superinfection may occur, especially with prolonged oral treatment.

Electrolyte disturbances (notably hypomagnesaemia but also hypocalcaemia and hypokalaemia) have occurred with other aminoglycosides.

4.9 Overdose

In overdose, exacerbation of the adverse events reported for neomycin (nausea, diarrhoea, nephrotoxicity, ototoxicity etc.) is expected.

Monitor renal and auditory function. If these are impaired, haemodialysis is indicated. Prolonged assisted ventilation may also be required.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Neomycin is an aminoglycoside antibiotic.

Neomycin acts by binding to polysomes, inhibiting protein synthesis and generating errors in the transcription of the genetic code.

5.2 Pharmacokinetic Properties

The absorption of neomycin from the alimentary tract is poor: Only ~ 3% of an oral dose is absorbed, neomycin is rapidly excreted by the kidneys in the unchanged form. The plasma half-life in healthy adults is approximately 2-3 hours. Oral doses of 3 g produce peak plasma concentrations of up to 4 ?g/ml.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Plasdone K29-32

Isopropyl alcohol

Calcium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Store below 30°C in a dry place – protect from light.

6.5 Nature And Contents Of Container

An amber glass bottle having a tin-plate screw cap with a waxed aluminium-faced pulpboard liner. The ullage is filled with cotton wool.

Pack size: 100 tablets.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

Administrative Data 7. Marketing Authorisation Holder

Waymade Plc.

Trading as Sovereign Medical

Sovereign House

Miles Gray Road

Basildon

Essex SS14 3FR

8. Marketing Authorisation Number(S)

PL 06464/0710

9. Date Of First Authorisation/Renewal Of The Authorisation

11 January 1999

10. Date Of Revision Of The Text

July 2003





Pronunciation: NAR-a-TRIP-tan



1. Name Of The Medicinal Product

NORMACOL.

2. Qualitative And Quantitative Composition

The active ingredient is Sterculia 62% w/w.

3. Pharmaceutical Form

Oral granules.

4. Clinical Particulars 4.1 Therapeutic Indications

The treatment of constipation, particularly simple or idiopathic constipation and constipation during pregnancy.

Management of colostomies and ileostomies.

The 'High Residue Diet' management of diverticular disease of the colon and other conditions requiring a high fibre regimen.

The initiation and maintenance of bowel action after rectal and anal surgery.

Administration after ingestion of sharp foreign bodies to provide a coating and reduce the possibility of intestinal damage during transit.

4.2 Posology And Method Of Administration

Adults: 1 or 2 sachets or 1-2 heaped 5ml spoonfuls, once or twice daily after meals.

Elderly: As adult dose.

Children: (6-12 years): one half the above amount.

The granules should be placed dry on the tongue and without chewing or crushing, swallowed immediately with plenty of water or a cool drink. Prior to drinking they may also be sprinkled onto and taken with soft food such as yoghurt.

4.3 Contraindications

Intestinal obstruction, faecal impaction, and total atony of the colon.

Known hypersensitivity to any of the ingredients

4.4 Special Warnings And Precautions For Use

Caution should be exercised in cases of ulcerative colitis.

Patients with rare hereditary problems of fructose intolerance, glucose –galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Not to be taken immediately before going to bed or in a recumbent position especially in the elderly. Adequate fluid should be maintained.

Not to be taken for more than 4 days if there has been no movement of the bowels.

It is not unusual for stool to appear paler in colour than normal as a result of local contact with sterculia. This does not indicate anything untoward.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

NORMACOL may be recommended during pregnancy or lactation.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Immune system disorders:

Allergic reactions

Gastrointestinal disorders:

Intestinal/colonic obstruction or impaction, flatulence

Occasionally mild abdominal distension may occur.

Oesophageal obstruction is possible if the product is taken in overdosage or if it is not adequately washed down with fluid.

4.9 Overdose

Intestinal obstruction is possible in overdosage particularly in combination with inadequate fluid intake. Management is as for intestinal obstruction from other causes.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Sterculia acts in the colon by forming a soft bulky stool and inducing a laxative effect.

5.2 Pharmacokinetic Properties

Sterculia is not absorbed or digested in the gastrointestinal tract and its laxative action is normally effective within 12 hours of oral administration.

5.3 Preclinical Safety Data

There is no evidence that Sterculia has a significant systemic toxicity potential.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium bicarbonate

Sucrose

Talc

Paraffin wax

Titanium dioxide

Vanillin

6.2 Incompatibilities

None known.

6.3 Shelf Life

Sachet and lined carton: 2 years

6.4 Special Precautions For Storage

Store in a dry place below 25°C.

6.5 Nature And Contents Of Container

Sachet containing 7 g of white granules in boxes of 2, 7, 30 or 60 sachets.

Lined box of 100 g or 500 g of white granules.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Norgine Limited

Norgine House

Widewater Place

Moorhall Road

Harefield

UXBRIDGE

Middlesex UB9 6NS

United Kingdom

8. Marketing Authorisation Number(S)

PL 0322/5010R

9. Date Of First Authorisation/Renewal Of The Authorisation

January 1991

10. Date Of Revision Of The Text

July 2010



1. Name Of The Medicinal Product

NiQuitin 4 mg Mint Lozenges.

NiQuitin Pre-Quit 4 mg Mint Lozenges.

2. Qualitative And Quantitative Composition

Each lozenge contains 4 mg nicotine (as nicotine resinate). For excipients see Section 6.1.

3. Pharmaceutical Form

Lozenge.

White, round lozenge with convex surfaces, debossed NL4S on one side.

4. Clinical Particulars 4.1 Therapeutic Indications

NiQuitin Mint Lozenges relieve and/or prevent craving and nicotine withdrawal symptoms associated with tobacco dependence. They are indicated to aid smokers wishing to quit or reduce prior to quitting, to assist smokers who are unwilling or unable to smoke, and as a safer alternative to smoking for smokers and those around them.

NiQuitin Mint Lozenges are indicated in pregnant and lactating women making a quit attempt.

NiQuitin Mint Lozenges should preferably be used in conjunction with a behavioural support programme.

4.2 Posology And Method Of Administration

Directions for use:

NiQuitin 4 mg Mint Lozenges are suitable for smokers who have their first cigarette of the day within 30 minutes of waking up.

One lozenge should be placed in the mouth and allowed to dissolve. Periodically, the lozenge should be moved from one side of the mouth to the other, and repeated, until the lozenge is completely dissolved (approximately 20 – 30 minutes). The lozenge should not be chewed or swallowed whole.

Users should not eat or drink while a lozenge is in the mouth.

Behavioural therapy, advice & support will normally improve the success rate.

Adults (18 years and over):

Abrupt cessation of smoking:

Users should make every effort to stop smoking completely during treatment with NiQuitin Mint Lozenges.

Recommended treatment schedule:

Step 1

Weeks 1 to 6

Step 2

Weeks 7 to 9

Step 3

Weeks 10 to 12

Initial treatment period

Step down treatment period

Step down treatment period

1 lozenge every 1 to 2 hours

1 lozenge every 2 to 4 hours

1 lozenge every 4 to 8 hours

During weeks 1 to 6 it is recommended that users take a minimum of 9 lozenges per day. Users should not exceed 15 lozenges per day.

To help stay smoke free beyond 12 weeks, users may take 1-2 lozenges per day only on occasions when they are strongly tempted to smoke.

Those who have quit smoking but are having difficulty discontinuing using the lozenges are recommended to seek additional help and advice from a healthcare professional.

Gradual cessation of smoking:

For smokers who are unwilling or unable to quit abruptly.

Use a lozenge whenever there is a strong urge to smoke in order to reduce the number of cigarettes smoked as far as possible and to refrain from smoking as long as possible.

The number of lozenges a day is variable and depends on the patients needs. Nonetheless it should not exceed 15 lozenges per day.

If a reduction in cigarette consumption has not been achieved after 6 weeks of treatment, a healthcare professional should be consulted.

Reduced tobacco consumption should lead to complete cessation of smoking. This should be attempted as soon as possible. When the number of cigarettes has been reduced to a level from which the user feels able to quit completely, then start on the schedule for “abrupt cessation” as given above.

If an attempt to stop smoking completely has not been started within 6 months after the beginning of treatment, it is recommended to consult a healthcare professional.

Reduction in smoking:

For smokers who wish to cut down with no immediate plans to quit.

Use a lozenge whenever there is a strong urge to smoke in order to reduce the number of cigarettes smoked as far as possible and to refrain from smoking as long as possible. Users should be encouraged to stop smoking completely as soon as possible.

The number of lozenges a day is variable and depends on the patients needs. Nonetheless it should not exceed 15 lozenges per day.

If users are still feeling the need to use the lozenges on a regular basis 6 months after the start of treatment and have still been unable to undertake a permanent quit attempt, then it is recommended to seek additional help and advice from a healthcare professional.

Temporary abstinence:

Use a lozenge every 1-2 hours to control troublesome withdrawal symptoms including cravings. Users should not take more than 15 lozenges per day.

Users should be encouraged to stop smoking completely as soon as possible.

If users are still feeling the need to use lozenges on a regular basis 6 months after the start of treatment and have still been unable to undertake a permanent quit attempt, then it is recommended to seek additional help and advice from a healthcare professional.

Adolescents and children:

Adolescents (12-17 years) should follow the schedule of treatment for abrupt cessation of smoking as given above. Where adolescents are unwilling or unable to quit smoking abruptly, advice from a healthcare professional should be sought.

Safety and effectiveness in children who smoke has not been evaluated. NiQuitin Mint Lozenges are not recommended for use in children under 12 years of age.

4.3 Contraindications

NiQuitin Mint Lozenges are contraindicated in:

• those with hypersensitivity to nicotine or any of the excipients;

• children under the age of 12 years and non-smokers.

4.4 Special Warnings And Precautions For Use

The risks associated with the use of NRT are substantially outweighed in virtually all circumstances by the well established dangers of continued smoking.

Patients hospitalised for MI, severe dysrhythmia or CVA who are considered to be haemodynamically unstable should be encouraged to stop smoking with non-pharmacological interventions. If this fails, NiQuitin Mint Lozenges may be considered, but as data on safety in this patient group are limited, initiation should only be under medical supervision. Once patients are discharged from hospital they can use NRT as normal.

Diabetes Mellitus: Patients with diabetes mellitus should be advised to monitor their blood sugar levels more closely than usual when NRT is initiated as catecholamines released by nicotine can affect carbohydrate metabolism.

Allergic reactions: Susceptibility to angioedema and urticaria

A risk-benefit assessment should be made by an appropriate healthcare professional for patients with the following conditions:

Renal and hepatic impairment: Use with caution in patients with moderate to severe hepatic impairment and/or severe renal impairment as the clearance of nicotine or its metabolites may be decreased with the potential for increased adverse effects.

Phaeochromocytoma and uncontrolled hyperthyroidism: Use with caution in patients with uncontrolled hyperthyroidism or phaeochromocytoma as nicotine causes release of catecholamines.

GI disease: Swallowed nicotine may exacerbate symptoms in patients suffering from oesophagitis, gastric or peptic ulcers and oral NRT preparations should be used with caution in these conditions. Ulcerative stomatitis has been reported.

Danger in small children: Doses of nicotine tolerated by adult and adolescent smokers can produce severe toxicity in small children that may be fatal. Products containing nicotine should not be left where they may be misused, handled or ingested by children.

Stopping smoking: Polycyclic aromatic hydrocarbons in tobacco smoke induce the metabolism of drugs catalysed by CYP 1A2 (and possibly by CYP 1A1). When a smoker stops this may result in a slower metabolism and a consequent rise in blood levels of such drugs.

Transferred dependence: Transferred dependence is rare and is both less harmful and easier to break than smoking dependence.

Phenylketonuria: NiQuitin Mint Lozenges contain a source of phenylalanine equivalent to 3mg/dose. May be harmful for people with phenylketonuria.

Sodium content: Each NiQuitin Mint Lozenge contains 15 mg of sodium. People on a low sodium diet should take this into account.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No clinically relevant interactions between nicotine replacement therapy and other drugs have definitely been established, however nicotine may possibly enhance the haemodynamic effects of adenosine.

4.6 Pregnancy And Lactation

Pregnancy

Stopping smoking is the single most effective intervention for improving the health of both the pregnant smoker and her baby, and the earlier abstinence is achieved the better. However, if the mother cannot (or is considered unlikely to) quit without pharmacological support, NRT may be used as the risk to the foetus is lower than that expected with smoking tobacco. Stopping completely is by far the best option but NRT may be used in pregnancy as a safer alternative to smoking. Because of the potential for nicotine-free periods, intermittent dose forms are preferable, but patches may be necessary if there is significant nausea and/or vomiting. If patches are used they should, if possible, be removed at night when the foetus would not normally be exposed to nicotine.

Lactation

The relatively small amounts of nicotine found in breast milk during NRT use are less hazardous to the infant than second-hand smoke. Intermittent dose forms would minimize the amount of nicotine in breast milk and permit feeding when levels were at their lowest.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

NRT can cause adverse reactions similar to those associated with nicotine administered in other ways, including smoking. These may be attributed to the pharmacological effects of nicotine, some of which are dose dependent. At recommended doses NiQuitin Mint Lozenges have not been found to cause any serious adverse effects. Excessive consumption of NiQuitin Mint Lozenges by those who have not been in the habit of inhaling tobacco smoke could possibly lead to nausea, faintness or headaches.

Certain symptoms which have been reported such as depression, irritability, anxiety and insomnia may be related to withdrawal symptoms associated with smoking cessation. Subjects quitting smoking by any means could expect to suffer from headache, dizziness, sleep disturbance, increased coughing or a cold.

Related adverse events with excess in active compared to placebo group in a controlled study.

Immune system disorder

   

Very rare <1/10000: anaphylactic reactions

   

Platelet, bleeding and clotting disorders

   

Uncommon >1/1000; <1/100: gingival bleeding

   

Metabolic and nutritional disorders

   

Uncommon >1/1000; <1/100: thirst; excessive thirst

   

Psychiatric disorders

   

Common >1/100; >1/10: insomnia

 

Uncommon >1/1000; <1/100: anxiety; anxiety attack; anxiety reaction; nightmares; marked restlessness; decreased appetite; lost appetite; lethargy

   

Central and peripheral nervous system disorders

   

Common >1/100; <1/10: dizziness; headache

 

Uncommon >1/1000; <1/100; migraine; mucosal burning; burning sensation; paraesthesia mouth; sensory disturbance; hyperalertness

   

Respiratory system disorders

   

Common >1/100; <1/10: coughing; pharyngitis; sore throat

 

Uncommon >1/1000; <1/100: dyspnoea; shortness of breath; aggravated cough; lower respiratory tract infection; respiratory disorder; excessive sneezing

   

Gastrointestinal system disorders

   

Very common >1/10: nausea; hiccup, flatulence

 

Common >1/100; <1/10: vomiting; constipation, diarrheoa; dysphagia; dyspepsia; heartburn; indigestion; belching; mouth irritation, mouth ulceration; tongue ulceration; dry mouth; bloating

 

Uncommon >1/1000; <1/100: gastroesophageal reflux; oesophageal reflux aggravated; retching; eructation; gagging; catarrh; increased saliva; lip ulceration; GI disorder; abdominal griping; sore lips; dry throat

   

Special senses other, disorders:

   

Uncommon >1/1000; <1/100: taste perversion

   

Skin and appendages disorders:

   

Uncommon >1/1000; <1/100: itching; rash

   

Body as a whole: general disorders:

   

Uncommon >1/1000; <1/100: throat swelling; chest pain; tightness of chest; overdose effect; withdrawal syndrome; malaise; hot flushes; halitosis

4.9 Overdose Symptoms: The minimum lethal dose of nicotine in a non-tolerant man has been estimated to be 40 to 60mg. Symptoms of acute nicotine poisoning include nausea, salivation, abdominal pain, diarrhoea, sweating, headache, dizziness, disturbed hearing and marked weakness. In extreme cases, these symptoms may be followed by hypotension, rapid or weak or irregular pulse, breathing difficulties, prostration, circulatory collapse and terminal convulsions.

Management of an overdose: All nicotine intake should stop immediately and the patient should be treated symptomatically. Artificial respiration with oxygen should be instituted if necessary. Activated charcoal reduces the gastro-intestinal absorption of nicotine.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

ATC Code: N07B A01

Nicotine is an agonist at nicotine receptors in the peripheral and central nervous system and has pronounced CNS and cardiovascular effects. When consumed in tobacco products, it has been shown to be addictive and abstinence is linked to craving and withdrawal symptoms. These craving and withdrawal symptoms include urge to smoke, depressed mood, insomnia, irritability, frustration or anger, anxiety, difficulty in concentrating, restlessness and increased appetite or weight gain. The lozenges replace some of the nicotine provided by tobacco and help reduce the severity of these nicotine craving and withdrawal symptoms.

5.2 Pharmacokinetic Properties

NiQuitin Mint Lozenges dissolve completely in the oral cavity, and the entire amount of nicotine contained in the lozenge becomes available for buccal absorption or ingestion (swallowing). The complete dissolution of NiQuitin Mint Lozenges is typically achieved in 20-30 minutes. The peak plasma concentrations of nicotine achieved after single dose are approximately 10.8 ng/ml. When dosed every 1.5 hours, the steady state peak and trough concentrations are 26.0 and 19.7 ng/ml respectively. Ingestion of NiQuitin Mint Lozenges not following dosing instruction (chewed, retained in the mouth, and swallowed; chewed and immediately swallowed) does not result in faster or higher absorption, but a substantial amount of nicotine (80-93%) is still absorbed.

As the plasma protein binding of nicotine is low (4.9% - 20%), the volume of distribution of nicotine is large (2.5 l/kg). The distribution of nicotine to tissue is pH dependent, with the highest concentrations of nicotine found in the brain, stomach, kidney and liver.

Nicotine is extensively metabolized to a number of metabolites, all of which are less active than the parent compound. The metabolism of nicotine primarily occurs in the liver, but also in the lung and kidney. Nicotine is metabolized primarily to cotinine but is also metabolized to nicotine N?-oxide. Cotinine has a half-life of 15-20 hours and its blood levels are 10 times higher than nicotine. Cotinine is further oxidized to trans-3?-hydroxycotinine, which is the most abundant metabolite of nicotine in the urine. Both nicotine and cotinine undergo glucuronidation.

The elimination half-life of nicotine is approximately 2 hours (range 1 - 4 hours). Total clearance for nicotine ranges from approximately 62 to 89 l/hr. Non-renal clearance for nicotine is estimated to be about 75% of total clearance. Nicotine and its metabolites are excreted almost exclusively in the urine. The renal excretion of unchanged nicotine is highly dependent on urinary pH, with greater excretion occurring at acidic pH.

5.3 Preclinical Safety Data

The general toxicity of nicotine is well known and taken into account in the recommended posology. Nicotine was not mutagenic in appropriate assays. The results of carcinogenicity assays did not provide any clear evidence of a tumorigenic effect of nicotine. In studies in pregnant animals, nicotine showed maternal toxicity, and consequential mild fetal toxicity. Additional effects included pre- and postnatal growth retardation and delays and changes in postnatal CNS development.

Effects were only noted following exposure to nicotine at levels in excess of those which will result from recommended use of NiQuitin Mint Lozenges. Effects on fertility have not been established.

Comparison of the systemic exposure necessary to elicit these adverse responses from preclinical test systems with that associated with the recommended use of NiQuitin Mint Lozenges indicate that the potential risk is low and outweighed by the demonstrable benefit of nicotine therapy in smoking cessation. However, NiQuitin Mint Lozenges should only be used by pregnant women on medical advice if other forms of treatment have failed.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Mannitol

Sodium alginate

Xanthan gum

Potassium bicarbonate

Calcium polycarbophil

Sodium carbonate anhydrous

Aspartame

Magnesium stearate

Mint flavour powder 57581

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Do not store above 25°C. Store in the original package.

6.5 Nature And Contents Of Container

Clear or opaque Polyvinyl Chloride/Polyethylene/Polyvinylidene Chloride blisters in packs of 12, 24, 36, 48, 72, 96, 108 and 144, or a polypropylene tablet container with cap containing 24 lozenges in packs of 24, 48 and 72.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Beecham Group plc

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

T/A GlaxoSmithKline Consumer Healthcare

Brentford, TW8 9GS, UK

8. Marketing Authorisation Number(S)

PL 00079/0370

9. Date Of First Authorisation/Renewal Of The Authorisation

24 September 2001

10. Date Of Revision Of The Text

23/03/2011



Pronunciation: nor-ETH-in-drone/ETH-i-nil ES-tra-DYE-ol/FER-us FUE-ma-rate



Generic Name: vitamin e (Oral route)

VYE-ta-min E

Commonly used brand name(s)

In the U.S.

Alpha-E Aqua Gem-E Aquasol E D-Alpha Gems E-400 E-600 E-Gems Formula E 400 Gamma E-Gems Gamma E Plus Key-E Natural Vitamin Blend E-400IU Nutr-E-Sol

Available Dosage Forms:

Liquid Solution Tablet Capsule, Liquid Filled Tablet, Chewable Powder for Solution Capsule

Therapeutic Class: Nutritive Agent

Pharmacologic Class: Vitamin E (class)

Uses For Nutr-E-Sol

Vitamins are compounds that you must have for growth and health. They are needed in only small amounts and are available in the foods that you eat. Vitamin E prevents a chemical reaction called oxidation, which can sometimes result in harmful effects in your body. It is also important for the proper function of nerves and muscles.

Some conditions may increase your need for vitamin E. These include:

Intestine disease Liver disease Pancreas disease Surgical removal of stomach

Increased need for vitamin E should be determined by your health care professional.

Infants who are receiving a formula that is not fortified with vitamin E may be likely to have a vitamin E deficiency. Also, diets high in polyunsaturated fatty acids may increase your need for vitamin E.

Claims that vitamin E is effective for treatment of cancer and for prevention or treatment of acne, aging, loss of hair, bee stings, liver spots on the hands, bursitis, diaper rash, frostbite, stomach ulcer, heart attacks, labor pains, certain blood diseases, miscarriage, muscular dystrophy, poor posture, sexual impotence, sterility, infertility, menopause, sunburn, and lung damage from air pollution have not been proven. Although vitamin E is being used to prevent certain types of cancer, there is not enough information to show that this is effective.

Lack of vitamin E is extremely rare, except in people who have a disease in which it is not absorbed into the body.

Vitamin E is available without a prescription.

Importance of Diet

For good health, it is important that you eat a balanced and varied diet. Follow carefully any diet program your health care professional may recommend. For your specific dietary vitamin and/or mineral needs, ask your health care professional for a list of appropriate foods. If you think that you are not getting enough vitamins and/or minerals in your diet, you may choose to take a dietary supplement.

Vitamin E is found in various foods including vegetable oils (corn, cottonseed, soybean, safflower), wheat germ, whole-grain cereals, and green leafy vegetables. Cooking and storage may destroy some of the vitamin E in foods.

Vitamin supplements alone will not take the place of a good diet and will not provide energy. Your body also needs other substances found in food such as protein, minerals, carbohydrates, and fat. Vitamins themselves often cannot work without the presence of other foods. For example, small amounts of fat are needed so that vitamin E can be absorbed into the body.

The daily amount of vitamin E needed is defined in several different ways.

For U.S.— Recommended Dietary Allowances (RDAs) are the amount of vitamins and minerals needed to provide for adequate nutrition in most healthy persons. RDAs for a given nutrient may vary depending on a person's age, sex, and physical condition (e.g., pregnancy). Daily Values (DVs) are used on food and dietary supplement labels to indicate the percent of the recommended daily amount of each nutrient that a serving provides. DV replaces the previous designation of United States Recommended Daily Allowances (USRDAs). For Canada— Recommended Nutrient Intakes (RNIs) are used to determine the amounts of vitamins, minerals, and protein needed to provide adequate nutrition and lessen the risk of chronic disease.

Vitamin E is available in various forms, including d- or dl-alpha tocopheryl acetate, d- or dl-alpha tocopherol, and d- or dl-alpha tocopheryl acid succinate. In the past, the RDA for vitamin E have been expressed in Units. This term has been replaced by alpha tocopherol equivalents (alpha-TE) or milligrams (mg) of d-alpha tocopherol. One Unit is equivalent to 1 mg of dl-alpha tocopherol acetate or 0.6 mg d-alpha tocopherol. Most products available in stores continue to be labeled in Units.

Normal daily recommended intakes in milligrams (mg) of alpha tocopherol equivalents (mg alpha-TE) and Units for vitamin E are generally defined as follows:

                                                  Persons U.S. Canada mg



Pronunciation: ar-moe-DAF-i-nil



Address NexMed, Inc,



Generic Name: oxymetazoline nasal (ox ee me TAZ oh leen)



Generic Name: nitroglycerin (Transdermal route)

nye-troe-GLIS-er-in

Commonly used brand name(s)

In the U.S.

Minitran Nitrek Nitro-Bid Nitro-Dur

In Canada

Nitrodur 0.2 Nitro-Dur 0.2 Nitro-Dur 0.3 Nitrodur 0.4 Nitro-Dur 0.4 Nitrodur 0.6 Nitro-Dur 0.6 Nitro-Dur 0.8 Transderm-Nitro Trinipatch 0.2 Trinipatch 0.4 Trinipatch 0.6

Available Dosage Forms:

Ointment Patch, Extended Release

Therapeutic Class: Antianginal

Chemical Class: Nitrate

Uses For Nitrodur 0.6

Nitroglycerin transdermal 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.

Nitroglycerin transdermal 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 Nitrodur 0.6

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 nitroglycerin transdermal 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 nitroglycerin transdermal 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 nitroglycerin transdermal.

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

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.

Alteplase, Recombinant

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.

Acetylcysteine Aspirin Dihydroergotamine Pancuronium 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.

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:

Cardioversion (medical heart procedure) or Defibrillation (medical heart procedure)—Use with caution. The patch should be removed before having these procedures. Congestive heart failure or Heart attack, recent or Hypertrophic cardiomyopathy (a heart disease) or Hypotension (low blood pressure) or Hypovolemia (low amount of blood)—Use with caution. May make these conditions worse. Proper Use of nitroglycerin

This section provides information on the proper use of a number of products that contain nitroglycerin. It may not be specific to Nitrodur 0.6. Please read with care.

Use this medicine exactly as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered. It will only work if applied correctly.

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 ointment and patch forms release medicine gradually to provide an effect for 7 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 use 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 use 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.

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

For patients using the ointment:

Before applying a new dose of ointment, remove any ointment remaining on the skin from a previous dose. This will allow the fresh ointment to release the nitroglycerin properly. This medicine comes with papers to help measure the dose. Use them to measure the length of ointment squeezed from the tube and to apply the ointment to the skin. Do not rub or massage the ointment into the skin. Spread it in a thin, even layer, and cover an area of skin that is the same size each time it is applied. Apply the ointment to skin with little or no hair that is free of scars, cuts, or irritation. Apply each dose of ointment to a different area of skin to prevent irritation. If your doctor has ordered an airtight covering or dressing (such as plastic kitchen wrap) be placed over this medicine, make sure you know how to apply it. Airtight dressings will increase the amount of medicine absorbed through the skin and may cause more side effects. Use them only as directed and check with your doctor if you have any questions about this.

For patients using the patch system:

Wash your hands with soap and water before and after applying a patch. Do not touch your eyes until after you have washed your hands. Do not try to trim or cut the adhesive patch to adjust the dosage. Check with your doctor if you think the medicine is not working as it should. Apply the patch to a clean, dry skin area with little or no hair that is free of scars, cuts, or irritation. Always remove a previous patch before applying a new one. Apply a new patch if the first one becomes loose or falls off. Apply each patch to a different area to prevent skin irritation. 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 transdermal dosage form (ointment): Adults—At first, 7.5 milligrams (mg), one-half inch of ointment, two times a day. Apply the first dose in the morning right after you wake up, and the second dose 6 hours later. Your doctor may increase your dose as needed. Children—Use and dose must be determined by your doctor. For transdermal dosage form (skin patch): Adults—Apply one patch once a day in the morning. Leave the patch in place for a total of 12 to 14 hours. Children—Use and dose must be determined by your doctor. Missed Dose

If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

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

Storage

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

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

After removing a used patch, fold it in half with the sticky sides together. Make sure to dispose of it out of the reach of children and pets.

Precautions While Using Nitrodur 0.6

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 with your doctor first. Your doctor may want you to gradually reduce the amount you are using before stopping it completely.

Tell the doctor in charge that you are using this medicine before having a magnetic resonance imaging (MRI) scan. Skin burns may occur at the site where the patch is worn during this procedure. Ask your doctor if the patch should be removed before having an MRI scan. You might need to put on a new patch after the procedure.

Nitrodur 0.6 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:

More common Lightheadedness Less common 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 nausea shortness of breath sweating unusual tiredness or weakness Rare Bluish-colored lips, fingernails, or palms dark urine difficulty with breathing fever headache pale skin rapid heart rate sore throat unusual bleeding or bruising Incidence not known Blistering, burning, crusting, dryness, or flaking of the skin cough difficulty with swallowing hives itching, scaling, severe redness, soreness, or swelling of the skin puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue skin rash wheezing

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 disturbed color perception double vision feeling of constant movement of self or surroundings halos around lights headache, severe and throbbing loss of consciousness night blindness overbright appearance of lights paralysis sensation of spinning tunnel vision

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:

Rare Burning, itching, redness, skin rash, swelling, or soreness at the application site

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: Nitrodur 0.6 side effects (in more detail)

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Generic Name: topical emollients (TOP i kal ee MOL i ents)



Generic Name: ketoconazole



Pronunciation: DEX-klor-fen-IR-a-meen/SOO-doe-e-FED-rin/pir-IL-a-meen



1. Name Of The Medicinal Product

Nastrosa 1mg film-coated tablets

2. Qualitative And Quantitative Composition

Each tablet contains 1 mg anastrozole as active substance.

Excipients: Each tablet contains 90.3 mg lactose (as lactose monohydrate).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

White, round, biconvex, film-coated tablets. Debossed with '1' on one side and plain on the reverse side.

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment of advanced breast cancer in postmenopausal women.

Efficacy has not been demonstrated in oestrogen receptor-negative patients unless they had a previous positive clinical response to tamoxifen.

4.2 Posology And Method Of Administration

Adults including the elderly:

One 1 mg tablet to be taken orally once a day.

Children:

Not recommended for use in children.

Renal impairment:

No dose change is recommended in patients with mild or moderate renal impairment.

Hepatic impairment:

No dose change is recommended in patients with mild hepatic disease.

 

4.3 Contraindications

Anastrozole is contraindicated in:

- premenopausal women.

- pregnant or lactating women.

- patients with severe renal impairment (creatinine clearance less than 20 ml / min)

- patients with moderate or severe hepatic disease

- patients with hypersensitivity to anastrozole or to any of the excipients as referenced in section 6.1.

Oestrogen-containing therapies should not be co-administered with anastrozole as they would negate its pharmacological action.

Concurrent tamoxifen therapy (see section 4.5)

4.4 Special Warnings And Precautions For Use

Anastrozole is not recommended for use in children as safety and efficacy have not been established in this group of patients.

The menopause should be defined biochemically in any patient where there is doubt about hormonal status.

There are no data to support the safe use of anastrozole in patients with moderate or severe hepatic impairment, or patients with severe impairment of renal function (creatinine clearance less than 20 ml/min).

Women with osteoporosis or at risk of osteoporosis, should have their bone mineral density formally assessed by bone densitometry e.g. DEXA scanning at the commencement of treatment and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored.

There are no data available for the use of anastrozole with LHRH analogues. This combination should not be used outside clinical trials.

As anastrozole lowers circulating oestrogen levels it may cause a reduction in bone mineral density. Adequate data to show the effect of bisphosphonates on bone mineral density loss caused by anastrozole, or their utility when used prophylactically, are not currently available.

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Anastrozole inhibited cytochrome P450 1A2, 2C8/9 and 3A4 in vitro. A clinical interaction study indicated that anastrozole at a 1 mg dose does not significantly alter the pharmacokinetics of warfarin, a CYP2C9 substrate.

No clinically significant interactions between anastrozole and bisphosphonates have been identified.

Antipyrine and cimetidine clinical interaction studies indicate that co-administration of anastrozole with other drugs is unlikely to result in clinically significant drug interactions mediated by cytochrome P450.

A review of the clinical trial safety datatbase did not reveal evidence of clinically significant interaction in patients treated with anastrozole who also received other commonly prescribed drugs.

Tamoxifen should not be co-administered with anastrozole, as this may diminish its pharmacological action (see section 4.3).

4.6 Pregnancy And Lactation

Anastrozole is contraindicated in pregnant or lactating women.

Pregnancy

There are no data on the use of anastrozole in pregnant patients. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Anastrozole 1mg should not be used in pregnancy.

Lactation

It is unknown whether anastrozole is excreted in human milk. Anastrozole 1mg should nor be used during breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

Anastrozole is unlikely to impair the ability of patients to drive and operate machinery. However, asthenia and somnolence have been reported with the use of anastrozole and caution should be observed when driving or operating machinery while such symptoms persist.

4.8 Undesirable Effects

The assessment of the side effects is based on the following frequencies:

Very common (

Common (

Uncommon (

Rare (

Very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Nervous system disorders

Common: Headache, mainly mild or moderate in nature

Carpal Tunnel Syndrome

Uncommon: Somnolence, mainly mild or moderate in nature

Gastrointestinal disorders

Common: Nausea, mainly mild or moderate in nature, diarrhoea, mainly mild or moderate

Uncommon: Vomiting, mainly mild or moderate in nature

Skin and subcutaneous tissue disorders

Common: Hair thinning, mainly mild or moderate in nature, Rash, mainly mild or moderate in nature

Very rare: Erythema multiforme, Stevens-Johnson syndrome, allergic reactions including angiooedema, urticaria and anaphylaxis

Musculoskeletal and connective tissue disorders

Common: Joint pain/stiffness, mainly mild or moderate in nature

Metabolism and nutrition disorders

Uncommon: Anorexia, mainly mild in nature, hypercholesterolaemia, mainly mild or moderate in nature

Vascular disorders

Very common: Hot flushes, mainly mild or moderate in nature

General disorders and administration site conditions

Common: Asthenia, mainly mild or moderate in nature

Hepatobiliary disorders

Common: Increases in alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase

Uncommon: Increases in gamma-GT and bilirubin, hepatitis

Reproductive system and breast disorders

Common: Vaginal dryness, mainly mild or moderate in nature

Uncommon: Vaginal bleeding, mainly mild or moderate in nature*

*Vaginal bleeding has been reported uncommonly, mainly in patients with advanced breast cancer during the first few weeks after changing from existing hormonal therapy to treatment with anastrozole. If bleeding persists, further evaluation should be considered.

As anastrozole lowers circulating oestrogen levels, it may cause a reduction in bone mineral density placing some patients at a higher risk of fracture (see section 4.4).

Elevated gamma-GT has been reported uncommonly (

The table below presents the frequency of pre-specified adverse events in the ATAC study, irrespective of causality, reported in patients receiving trial therapy and up to 14 days after cessation of trial therapy.

Adverse effects

Anastrozole

(N=3092)

Tamoxifen

(N=3094)

Hot flushes

1104 (35.7%)

1264 (40.9%)

Joint pain/stiffness

1100 (35.6%)

911 (29.4%)

Mood disturbances

597 (19.3%)

554 (17.9%)

Fatigue/asthenia

575 (18.6%)

544 (17.6%)

Nausea and vomiting

393 (12.7%)

384 (12.4%)

Fractures

315 (10.2%)

209 (6.8%)

Fractures of the spine, hip, or wrist/Colles

133 (4.3%)

91 (2.9%)

Wrist/Colles fractures

67 (2.2%)

50 (1.6%)

Spine fractures

43 (1.4%)

22 (0.7%)

Hip fractures

28 (0.9%)

26 (0.8%)

Cataracts

182 (5.9%)

213 (6.9%)

Vaginal bleeding

167 (5.4%)

317 (10.2%)

Ischaemic cardiovascular disease

127 (4.1%)

104 (3.4%)

Angina pectoris

71 (2.3%)

51 (1.6%)

Myocardial infarct

37 (1.2%)

34 (1.1%)

Coronary artery disorder

25 (0.8%)

23 (0.7%)

Myocardial ischaemia

22 (0.7%)

14 (0.5%)

Vaginal discharge

109 (3.5%)

408 (13.2%)

Any venous thromboembolic event

87 (2.8%)

140 (4.5%)

Deep venous thromboembolic events including PE

48 (1.6%)

74 (2.4%)

Ischaemic cerebrovascular events

62 (2.0%)

88 (2.8%)

Endometrial cancer

4 (0.2%)

13 (0.6%)

Fracture rates of 22 per 1000 patient-years and 15 per 1000 patient-years were observed for the anastrozole and tamoxifen groups, respectively, after a median follow-up of 68 months. The observed fracture rate for anastrozole is similar to the range reported in age-matched postmenopausal populations. It has not been determined whether the rates of fracture and osteoporosis seen in ATAC in patients on anastrozole treatment reflect a protective effect of tamoxifen, a specific effect of anastrozole, or both. The incidence of osteoporosis was 10.5% in patients treated with anastrozole and 7.3% in patients treated with tamoxifen.

4.9 Overdose

There is limited clinical experience of accidental overdosage. In animal studies, anastrozole demonstrated low acute toxicity. Clinical trials have been conducted with various dosages of anastrozole, up to 60 mg in a single dose given to healthy male volunteers and up to 10 mg daily given to postmenopausal women with advanced breast cancer; these dosages were well tolerated. A single dose of anastrozole that results in life-threatening symptoms has not been established. There is no specific antidote to overdosage and treatment must be symptomatic.

In the management of an overdose, consideration should be given to the possibility that multiple agents may have been taken. Vomiting may be induced if the patient is alert. Dialysis may be helpful because anastrozole is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents – Endocrine therapy – Hormone antagonists and related agents – Enzyme inhibitors.

ATC code: L02B G03

Anastrozole is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, estradiol is produced primarily from the conversion of androstenedione to estrone through the aromatase enzyme complex in peripheral tissues. Estrone is subsequently converted to estradiol. Reducing circulating estradiol levels has been shown to produce a beneficial effect in women with breast cancer. In postmenopausal women, anastrozole at a daily dose of 1 mg produced estradiol suppression of greater than 80% using a highly sensitive assay.

Anastrozole does not possess any progestogenic, androgenic or oestrogenic activity. Daily doses of anastrozole up to 10 mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard ACTH challenge testing. Corticoid supplements are therefore not needed.

An extensive phase III clinical study programme showed that anastrozole is an effective treatment of hormone-receptor positive breast cancer in post menopausal women.

5.2 Pharmacokinetic Properties

Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within two hours of dosing (under fasted conditions). Anastrozole is eliminated slowly with a plasma elimination half-life of 40 to 50 hours. Food slightly decreases the rate but not the extent of absorption. The small change in the rate of absorption is not expected to result in a clinically significant effect on steady-state plasma concentrations during once daily dosing of anastrozole. Approximately 90 to 95% of plasma anastrozole steady-state concentrations are attained after 7 daily doses. There is no evidence of time or dose-dependency of anastrozole pharmacokinetic parameters.

Anastrozole pharmacokinetics are independent of age in postmenopausal women.

Pharmacokinetics have not been studied in children.

Anastrozole is only 40% bound to plasma proteins.

Anastrozole is extensively metabolised by postmenopausal women with less than 10% of the dose excreted in the urine unchanged within 72 hours of dosing. Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. The metabolites are excreted primarily via the urine. Triazole, the major metabolite in plasma, does not inhibit aromatase.

The apparent oral clearance of anastrozole in volunteers with stable hepatic cirrhosis or renal impairment was in the range observed in healthy volunteers.

5.3 Preclinical Safety Data

Acute toxicity

In acute toxicity studies in rodents, the median lethal dose of anastrozole was greater than 100 mg/kg/day by the oral route and greater than 50 mg/kg/day by the intraperitoneal route. In an oral acute toxicity study in the dog, the median lethal dose was greater than 45 mg/kg/day.

Chronic toxicity

Multiple dose toxicity studies utilized rats and dogs. No no-effect levels were established for anastrozole in the toxicity studies, but those effects that were observed at the low doses (1 mg/kg/day) and mid doses (dog 3 mg/kg/day; rat 5 mg/kg/day) were related to either the pharmacological or enzyme-inducing properties of anastrozole and were unaccompanied by significant toxic or degenerative changes.

Mutagenicity

Genetic toxicology studies with anastrozole show that it is not a mutagen or a clastogen.

Reproductive toxicology

Oral administration of anastrozole to female rats produced a high incidence of infertility at 1 mg/kg/day and increased pre-implantation loss at 0.02 mg/kg/day. These effects occurred at clinically relevant doses. An effect in man cannot be excluded. These effects were related to the pharmacology of the compound and were completely reversed after a 5-week compound withdrawal period.

Oral administration of anastrozole to pregnant rats and rabbits caused no teratogenic effects at doses up to 1.0 and 0.2 mg/kg/day respectively. Those effects that were seen (placental enlargement in rats and pregnancy failure in rabbits) were related to the pharmacology of the compound.

The survival of litters born to rats given anastrozole at 0.02 mg/kg/day and above (from day 17 of pregnancy to day 22 post-partum) was compromised. These effects were related to the pharmacological effects of the compound on parturition. There were no adverse effects on behaviour or reproductive performance of the first generation offspring attributable to maternal treatment with anastrozole.

Carcinogenicity

A two year rat oncogenicity study resulted in an increase in incidence of hepatic neoplasms and uterine stromal polyps in females and thyroid adenomas in males at the high dose (25 mg/kg/day) only. These changes occurred at a dose which represents 100-fold greater exposure than occurs at human therapeutic doses, and are considered not to be clinically relevant to the treatment of patients with anastrozole.

A two year mouse oncogenicity study resulted in the induction of benign ovarian tumours and a disturbance in the incidence of lymphoreticular neoplasms (fewer histiocytic sarcomas in females and more deaths as a result of lymphomas). These changes are considered to be mouse-specific effects of aromatase inhibition and not clinically relevant to the treatment of patients with anastrozole.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Tablet core:

Lactose monohydrate

Sodium starch glycolate (Type A)

Magnesium stearate

Film coating:

Opadry II white 85F18422 consisting of

Poly (vinyl alcohol) –partially hydrolysed

Titanium dioxide

Macrogol 3350

Talc

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions

6.5 Nature And Contents Of Container

PVC/PVDC aluminium blisters.

Pack sizes :

20, 28, 30. 84, 98, 100 and 300 film-coated tablets

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Niche Generics Limited,

1 The Cam Centre,

Wilbury Way,

Hitchin,

Hertfordshire,

SG4 0TW,

United Kingdom.

8. Marketing Authorisation Number(S)

PL 19611/0157.

9. Date Of First Authorisation/Renewal Of The Authorisation

3rd December 2009.

10. Date Of Revision Of The Text

January 2011



clonidine



1. Name Of The Medicinal Product

NAPRATEC™ OP

2. Qualitative And Quantitative Composition

Napratec is a combination pack containing 56 Naproxen 500mg tablets and 56 Cytotec (misoprostol) 200mcg tablets.

For excipients, see 6.1

3. Pharmaceutical Form

Tablet

Naproxen 500mg tablets are yellow, oblong and engraved 'NXN500' with a breakline on one side and CP on the reverse.

Cytotec is a white/off-white hexagonal tablet, scored on both sides, engraved SEARLE 1461 on one side.

4. Clinical Particulars 4.1 Therapeutic Indications

Napratec combination pack is indicated for patients who require Naproxen 500mg twice daily and Cytotec 200mcg twice daily.

Naproxen is indicated for the treatment of rheumatoid arthritis, osteoarthritis (degenerative arthritis) and ankylosing spondylitis.

Cytotec is indicated for the prophylaxis of nonsteroidal anti-inflammatory drug (NSAID)-induced gastroduodenal ulceration.

4.2 Posology And Method Of Administration

For oral administration

Adults

1 tablet of Naproxen and 1 tablet of Cytotec to be taken together twice daily with or after food.

Elderly

Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly.

With Cytotec the usual dosage may be used in the elderly.

Napratec should only be used in those patients for whom 500mg naproxen twice daily is appropriate and in whom no reduction of naproxen dosage is necessary (see also sections on renal and hepatic impairment).

The elderly are at an increased risk of the serious consequences of adverse reactions. The patient should be monitored regularly for GI bleeding during NSAID therapy.

Renal Impairment

As the final pathway for the elimination of naproxen metabolites is largely (95%) by urinary excretion via glomerular filtration it should be used with great caution in patients with impaired renal function and the monitoring of serum creatinine and/or creatinine clearance is advised in these patients. Naproxen is not recommended in patients having a baseline creatinine clearance of less than 20ml/minute.

Certain patients, specifically those whose renal blood flow is compromised, such as in extracellular volume depletion, cirrhosis of the liver, sodium restriction, congestive heart failure, and pre-existing renal disease, should have renal function assessed before and during naproxen therapy. Some elderly patients in whom impaired renal function may be expected could also fall within this category. Where there is a possibility of accumulation of naproxen metabolites, such patients may not be suitable to receive naproxen 500mg twice daily.

With Cytotec no dosage alteration is necessary in patients with impaired renal function.

Hepatic Impairment

Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased.

With Cytotec no dosage alteration is necessary in patients with impaired hepatic function.

Children

Napratec is not recommended.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).

4.3 Contraindications

Use in Pregnancy and Lactation

Napratec is contraindicated in pregnancy and lactation (see section 4.6)

This medicine is also contraindicated in patients planning to become pregnant.

Napratec is contraindicated in patients with a known hypersensitivity to naproxen, or to misoprostol or to any of the excipients.

As the potential exists with naproxen for cross-sensitivity to aspirin and other nonsteroidal anti-inflammatory drugs, Napratec should not be administered to patients in whom aspirin, ibuprofen and other NSAIDs induce asthma, rhinitis, urticaria or angioedema.

As Napratec is a "prevention pack" it should not be used for treating arthritis in patients with active gastric or duodenal ulceration / haemorrhage. Such patients may be treated with a healing dose of Cytotec, 800 micrograms daily in divided doses with meals, and the NSAID continued or discontinued at the physician's discretion.

Use in pre-menopausal women

Napratec should not be used in pre-menopausal women unless the patient is at high risk of complications from NSAID-induced ulceration. In such patients it is advised that Napratec should only be used if the patient:

- takes effective contraceptive measures

- has been advised of the risks of taking the product if pregnant

Napratec is contraindicated in patients with severe heart failure, hepatic failure and renal failure (see section 4.4).

4.4 Special Warnings And Precautions For Use

Precautions

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).

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

Naproxen, in common with other NSAIDs, decreases platelet aggregation and prolongs bleeding time. This effect should be considered when bleeding times are determined.

Elderly:

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2)

Respiratory disorders:

Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma or allergic disease since NSAIDs have been reported to precipitate bronchospasm in such patients.

Cardiovascular, Renal and Hepatic Impairment:

The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients (see also section 4.3).

Mild peripheral oedema has been observed in a few patients receiving naproxen. Although sodium retention has not been reported in metabolic studies, it is possible that patients with questionable or compromised cardiac function may be at a greater risk when taking naproxen.

Cardiovascular and cerebrovascular effects:

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Although data suggest that the use of naproxen (1000 mg daily) may be associated with a lower risk, some risk cannot be excluded.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with naproxen after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Gastrointestinal bleeding, ulceration and perforation:

Gastrointestinal bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. When GI bleeding or ulceration occurs in patients receiving Napratec OP, the treatment should be withdrawn. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation and in the elderly.

Patients with a history of GI toxicity, particularly if complicated when 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)

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).

SLE and mixed connective tissue disease:

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8)

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 use of NSAID (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: onset of the reaction occurring in the majority of cases within the first month of treatment. Napratec should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Sporadic abnormalities in laboratory tests (e.g. liver function tests) have occurred in patients on naproxen, but no definite trend was seen in any test indicating toxicity.

Cytotec should be used with caution in disease states where hypotension might precipitate severe complications, e.g. cerebrovascular disease, coronary artery disease or severe peripheral vascular disease including hypertension.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Drug Interactions

Due to the high plasma protein binding of naproxen, patients simultaneously receiving hydantoins, anti-coagulants or a highly protein-bound sulphonamide should be observed for signs of over dosage of these drugs. No interactions have been observed in clinical studies with naproxen and anti-coagulants or sulphonylureas, but caution is nevertheless advised since interaction has been seen with other non-steroidal agents of this class.

Diuretics: NSAIDs may attenuate the natriuretic efficacy of diuretics due to inhibition of intrarenal synthesis of prostaglandins. NSAIDs may also cause a reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Ciclosporin: Because of their effect on renal prostaglandins, cyclo-oxygenase inhibitors such as naproxen can increase the nephrotoxicity of ciclosporin

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

Lithium: NSAIDs including naproxen have been reported to increase steady state plasma lithium levels. It is recommended that these are monitored whenever initiating, adjusting or discontinuing naproxen products.

Cardiac glycosides: Concomitant administration of Naproxen with cardiac glycosides may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Anti-hypertensives: Concomitant administration of naproxen with beta-blockers may reduce their antihypertensive effect.

Corticosteroids: Concomitant administration of naproxen with corticosteroids increases the risk of gastrointestinal ulceration or bleeding (see section 4.4) and may increase the frequency of side effects generally.

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.

Probenecid: Increases naproxen plasma levels and extends its plasma half-life considerably.

Methotrexate: Caution is advised when methotrexate is administered concurrently because of possible enhancement of its toxicity since naproxen, among other NSAIDs, has been reported to induce the tubular secretion of methotrexate in an animal model.

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

Anti-coagulants: NSAIDs may enhance the effects of anti-coagulatnts, 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).

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 of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Naproxen therapy should be temporarily withdrawn before adrenal function tests are performed as it may artificially interfere with some tests for 17-ketogenic steroids. Similarly, naproxen may interfere with some assays of urinary 5-hydroxyindoleacetic acid.

Cytotec is predominantly metabolised via fatty acid oxidising systems and has shown no adverse effect on the hepatic microsomal mixed function oxidase (P450) enzyme system. No drug interactions have been attributed to Cytotec, and in specific studies, no clinically significant pharmacokinetic or pharmacodynamic interaction has been demonstrated with antipyrine, diazepam, propranolol or NSAIDs.

4.6 Pregnancy And Lactation

Napratec is contraindicated in pregnancy and lactation. The product is contraindicated in pregnancy on the basis that Cytotec is contraindicated in pregnancy or women planning a pregnancy as it increases uterine tone and contractions in pregnancy which may cause partial or complete expulsion of the products of conception.

Teratology studies with naproxen in rats and rabbits at dose levels equivalent on a human multiple basis to those which have produced foetal abnormality with certain other NSAIDs, e.g. aspirin, have not produced evidence of foetal damage with naproxen. As with other drugs of this type, naproxen delays parturition in animals (the relevance of this finding to human patients is unknown) and also affects the human foetal cardiovascular system (closure of the ductus arteriosus).

4.7 Effects On Ability To Drive And Use Machines

Dizziness, drowsiness, fatigue, visual disturbances or headaches are possible undesirable effects after taking NSAIDs. If affected, patients should not drive or operate machinery.

4.8 Undesirable Effects

Naproxen:

Gastrointestinal: The most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, particularly in the elderly may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain or discomfort and epigastric distress, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease (see section 4.4) have been reported following administration. The more serious reaction, colitis, may occasionally occur. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Naproxen also causes gastrointestinal bleeding and gastric and duodenal ulceration, the consequences of which may be haemorrhage and perforation. The inclusion of Cytotec in the combination pack is to prevent naproxen-induced gastric and duodenal ulceration.

Hypersensitivity and Dermatological: Non-specific allergic reactions and anaphylaxis, respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, assorted skin disorders including rashes of various types,, pruritus, purpura, urticaria, angio-oedema.. Anaphylactic reactions to naproxen and naproxen sodium formulations; eosinophilic pneumonitis, alopecia, photosensitivity reactions and more rarely epidermolysis bullosa, epidermal necrolysis, erythema multiforme, pseudoporphyria, Stevens Johnson syndrome and toxic epidermal necrolysis (very rare).

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 some NSAIDs (particularly at high doses 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).

Neurological and special senses: Headache, visual disturbances, insomnia, optic neuritis, paraesthesia, inability to concentrate, cognitive dysfunction, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease) with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4), depression, confusion, hallucinations, tinnitus, hearing impairment, vertigo, dizziness, malaise, fatigue and drowsiness.

Renal: As a class NSAIDs have been associated with renal pathology including nephropathy, papillary necrosis, interstitial nephritis, nephrotic syndrome and renal failure.

Hepatic: Abnormal liver function, fatal hepatitis and jaundice.

Haematological: Thrombocytopenia, neutropenia, granulocytopenia, agranulocytosis, aplastic anaemia and haemolytic anaemia may occur rarely.

Other: Mild peripheral oedema, vasculitis, and haematuria.

Cytotec:

Gastrointestinal: Diarrhoea has been reported and is occasionally severe and prolonged, and may require withdrawal of the drug. It can be minimised by taking Cytotec with food and by avoiding the use of predominantly magnesium-containing antacids when an antacid is required. Abdominal pain with or without associated dyspepsia can follow Cytotec therapy. Other gastrointestinal adverse effects reported include dyspepsia, flatulence, nausea and vomiting.

Female Reproductive System: Menorrhagia, vaginal bleeding and intermenstrual bleeding have been reported in both pre- and post-menopausal women.

Other Adverse Effects: Skin rashes have been reported. Dizziness has been infrequently reported.

4.9 Overdose

Naproxen:

Symptoms - Symptoms include drowsiness, heartburn, indigestion, nausea, vomiting, headache, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientataion, excitation, coma, dizziness, tinnitus, fainting, occasionally convulsions. A few patients have experienced seizures, but it is not clear whether these were naproxen-related or not. In cases of significant poisoning acute renal failure and liver damage are possible. It is not known what dose of the drug would be life-threatening.

Therapeutic measures - In the event of overdosage with naproxen, the stomach may be emptied and usual supportive measures employed.

• Patients should be treated symptomatically as required.

• Within one hour of ingestion of a potential toxic amount, activated charcoal should be considered. Animal studies indicate that the prompt administration of activated charcoal in adequate amounts would tend to reduce markedly the absorption of the drug. Alternatively, in adult, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose.

• Good urine output should be insured.

• Renal and liver function should be closely monitored

• Patients should be observed for at least four hours after ingestion of potentially toxic amounts

• Frequent or prolonged convulsions should be treated with intravenous diazepam

• Other measures may be indicated by the patient's clinical condition.

Haemodialysis does not decrease the plasma concentration of naproxen because of the high degree of protein binding. However, haemodialysis may still be appropriate in a patient with renal failure who has taken naproxen.

Cytotec:

Intensification of pharmacological and adverse effects may occur with overdose. In the event of overdosage with Cytotec, symptomatic and supportive therapy should be given as appropriate.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Naproxen is a non-steroidal anti-inflammatory drug with well-documented properties, i.e. analgesic, antipyretic and anti-inflammatory.

Misoprostol is a synthetic prostaglandin E1 analogue which enhances several of the factors that maintain gastroduodenal mucosal integrity.

5.2 Pharmacokinetic Properties

Naproxen is readily absorbed from the GI tract. Peak plasma concentrations are obtained 2-4 hours after ingestion. At therapeutic concentrations, naproxen is more than 98% bound to plasma proteins and has an elimination half-life of between 12-15 hours.

Misoprostol is rapidly absorbed following oral administration with peak plasma levels of the active metabolite (misoprostol acid) occurring after about 30 minutes. The plasma elimination half-life of misoprostol acid is 20-40 minutes.

Increases in Cmax and AUC for misoprostol acid have been observed when co-administered with naproxen in a single dose study. These changes are not thought to be clinically significant since the higher values are still well within the variation seen after 200 micrograms misoprostol in other studies. No accumulation of misoprostol acid in plasma occurs after repeated dosing of 400 micrograms twice daily.

5.3 Preclinical Safety Data

Naproxen causes gastric erosions when given orally or subcutaneously to fasting rats. There is no evidence of mutagenicity or carcinogenicity when administered to rats in studies of two years duration. There is no evidence of teratogenicity in mice, rats or rabbits.

Misoprostol in multiples of the recommended therapeutic dose in animals has produced gastric mucosal hyperplasia. This characteristic response to E-series prostaglandins reverts to normal on discontinuation of the compound.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Naproxen 500mg tablets contain: Lactose, maize starch, povidone, sodium starch glycolate, magnesium stearate, yellow lake CLF 3076 (E104 and E172).

Cytotec 200mcg tablets contain: microcrystalline cellulose, sodium starch glycolate, hydrogenated castor oil and hypromellose.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 30?C. Store in the original package.

6.5 Nature And Contents Of Container

Combination pack containing 8 x 7 day blisters containing 56 Naproxen 500mg tablets and 56 Cytotec 200mcg tablets in cold-formed aluminium blisters.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Pfizer Limited

Ramsgate Road

Sandwich

Kent, CT13 9NJ

United Kingdom

8. Marketing Authorisation Number(S)

PL00057/1018

9. Date Of First Authorisation/Renewal Of The Authorisation

26 June 2002

10. Date Of Revision Of The Text

June 2011

11. LEGAL CATEGORY

POM

Ref: NA 5_0 UK



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