Cuprofen for Children

1. Name Of The Medicinal Product

Cuprofen for Children

2. Qualitative And Quantitative Composition

Ibuprofen 100mg / 5ml

For excipients, see 6.1

3. Pharmaceutical Form

Oral Suspension

White, opaque smooth suspension

4. Clinical Particulars

4.1 Therapeutic Indications

For reduction in fever (including post immunization fever); and relief of mild to moderate pain such as headache, sore throat, earache, teething pain and toothache, cold and flu symptoms, minor aches and sprains.

4.2 Posology And Method Of Administration

For oral administration and short term use only, as required:

• Children over 7 years: 10ml three times daily.

• Children 4 to 7 years: 7.5ml three times daily.

• Children 1 to 4 years: 5ml three times daily.

• Infants 6 months to 1 year: 2.5ml three to four times daily.

If the child's symptoms persist for more than 3 days, consult your doctor.

• Babies 3 to 6 months: 2.5ml three times daily.

Do not give to babies aged 3 to 6 months for more than 24 hours.

Doses should usually be given every 6-8 hours. Leave at least four hours between doses.

Not to be given to children under 3 months of age. Not recommended for children weighing less than 5kg.

For post immunisation fever: 2.5ml followed by one further 2.5ml 6 hours later, if necessary. No more than 2 doses (5ml) in 24 hours. If fever is not reduced, consult your doctor.

4.3 Contraindications

Hypersensitivity to ibuprofen or any of the excipients in the product.

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

Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

History of upper gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

Severe heart failure, renal failure or hepatic failure (see section 4.4 Special Warnings and Precautions for Use).

Last trimester of pregnancy (see section 4.6 Pregnancy and lactation).

4.4 Special Warnings And Precautions For Use

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

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

Respiratory:

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

Other NSAIDs:

The use of Ibuprofen for children 100mg/5ml oral suspension with concomitant NSAIDs including cyclooxengenase-2-selective inhibitors should be avoided.

SLE and mixed connective tissue disease:

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

Renal:

Renal impairment as renal function may further deteriorate (see section 4.3 Contraindications and section 4.8 Undesirable effects).

Hepatic:

Hepatic dysfunction (see section 4.3 Contraindications and section 4.8 Undesirable effects).

Cardiovascular and cerebrovascular effects:

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

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

Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g.

Impaired female fertility:

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

Gastrointestinal:

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

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

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

Patients with a history of GI toxicity, particularly 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 gastrotoxicity or bleeding, such as oral corticosteroids, or anticoagulants such as warfarin, selective serotonin reuptake inhibitors, or anti-platelet agents such as aspirin (see section 4.5 Interactions).

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

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8 Undesirable Effects). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Ibuprofen for children 100mg/5ml oral suspension should be discontinued at the first appearance of skin rash mucosal lesions, or any other sign of hypersensitivity.

Information about some of the ingredients in this medicine:

Contains Liquid Maltitol (E965). Patients with rare hereditary problems of fructose intolerance should not take this medicine.

The label will include:

Please read the enclosed leaflet carefully before using this product.

Do not give this product if your child:

• has or has had a stomach ulcer, perforation or bleeding of the stomach

• is allergic to ibuprofen or any other ingredient of the product, aspirin or other related painkillers

• is taking other NSAID painkillers, or aspirin with a daily dose above 75mg

Talk to a pharmacist or your doctor before giving this product if your child:

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

If you are an adult:

• if you are pregnant do not take this product and ask your doctor for advice

• consult your doctor or pharmacist before taking this product if you are elderly or if you are a smoker

Do not exceed the stated dose. Keep all medicines out of the reach and sight of children.

If your child's symptoms persist for more than 3 days, or if new symptoms occur, talk to your doctor.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Ibuprofen should not be used in combination with:

Aspirin: Unless low-dose aspirin (not above 75mg daily) has been advised by a doctor, as this may increase the risk of adverse reactions (see section 4.3 Contraindications).

Other NSAIDs including cyclooxegenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse effects (see section 4.3 Contraindications).

Ibuprofen should be used with caution in combination with:

Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4 Special Warnings and Precautions for Use).

Antihypertensives and diuretics: NSAIDs may diminish the effect of these drugs. Diuretics can increase the risk of nephrotoxicity to NSAID's.

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see section 4.4 Special Warnings and Precautions for Use).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding.

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

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

Methotrexate: There is a potential for an increase in plasma methotrexate.

Cyclosporin: Increased risk of nephrotoxicity

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone. Administration of NSAID's can reduce the effect of mifepristone.

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

Zidovudine: Increased risk of haematological activity 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.

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

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

4.6 Pregnancy And Lactation

Children under 9 years are unlikely to become pregnant or breast feed. However, whilst no teratogenic effects have been demonstrated in animal experiments, the use of the suspension should, if possible, be avoided during the first 6 months of pregnancy.

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

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

See section 4.4 regarding female fertility.

4.7 Effects On Ability To Drive And Use Machines

None expected at recommended doses and duration of therapy.

4.8 Undesirable Effects

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

Blood and Lymphatic System Disorders:

Very rare: Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.

Immune System Disorders:

Non-specific allergic reactions.

Respiratory tract reactivity (e.g. asthma, aggravated asthma and bronchospasm).

Various skin reactions including exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Uncommon: Hypersensitivity reactions with urticaria and pruritus.

Very rare: Severe hypersensitivity reactions. Symptoms could include: facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension (anaphylaxis, angioedema or severe shock).

In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed (see section 4.4 Special Warnings and Precautions for Use).

Nervous System Disorders:

Uncommon: Headache.

Vary rare: Aseptic Meningitis – single cases have been reported very rarely.

Cardiac Disorders and Vascular Disorders:

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

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

Gastrointestinal Disorders:

The most commonly observed side effects of ibuprofen are gastrointestinal in nature.

Uncommon: Abdominal pain, nausea and dyspepsia.

Rare: Diarrhoea, flatulence, constipation and vomiting.

Very rare: Peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly, ulcerative stomatitis, gastritis.

Exacerbation of ulcerative colitis and Crohn's disease (see section 4.4 Special Warnings and Precautions for Use).

Hepatobiliary Disorders:

Very rare: Liver disorders.

Skin and Subcutaneous Tissue Disorders:

Uncommon: Various skin rashes.

Very rare: Severe forms of skin reactions such as bullous reactions, including Stevens Johnson syndrome, erythema multiforme and toxic epidermal necrolysis can occur.

Renal and Urinary Disorders:

Very rare: Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema.

4.9 Overdose

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

Symptoms

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

Management

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

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antiinflammatory and antirheumatic products, non-steroids, propionic acid derivatives.

ATC code: M01A E01

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

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

5.2 Pharmacokinetic Properties

Ibuprofen is rapidly absorbed following administration and is rapidly distributed throughout the whole body. The excretion is rapid and complete via the kidneys.

Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty stomach. When taken with food, high peak levels are observed after 1 to 2 hours. These times may vary with different dosage forms.

The half life of ibuprofen is about 2 hours.

In limited studies, ibuprofen appears in the breast milk in very low concentrations.

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Methyl Parahydroxybenzoate (E219)

Sodium Propyl Parahydroxybenzoate (E217)

Citric Acid Anhydrous

Saccharin Sodium

Sodium Benzoate (E211)

Dispersible Cellulose

Juicy Orange Flavour

Polysorbate 80

Liquid Maltitol (E965)

Xanthan Gum

Purified Water.

6.2 Incompatibilities

None.

6.3 Shelf Life

Amber glass or PET bottles with PP closures: 2 years.

6.4 Special Precautions For Storage

Do not store above 25^oC. Store in the original container.

6.5 Nature And Contents Of Container

Amber glass or PET bottles with polypropylene child resistant screw closures, containing 100, 150 or 200ml enclosed in an outer carton. A measuring spoon is provided.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Galpharm Healthcare Ltd

Hugh House

Upper Cliffe Road

Dodworth Business Park

Dodworth

South Yorkshire

S75 3SP

8. Marketing Authorisation Number(S)

PL 16028/0075

9. Date Of First Authorisation/Renewal Of The Authorisation

10/02/2006

10. Date Of Revision Of The Text

03/11/2010

Carmol Scalp Treatment Lotion

Pronunciation: sul-fa-SEE-ta-mide/yoor-EE-a
Generic Name: Sulfacetamide/Urea
Brand Name: Carmol Scalp Treatment

Carmol Scalp Treatment Lotion is used for:

Treating certain skin conditions (eg, seborrheic dermatitis), dandruff, and certain bacterial infections of the skin. It may also be used for other conditions as determined by your doctor.

Carmol Scalp Treatment Lotion is a sulfonamide antibiotic. It works by killing bacteria, helping to shed scaly skin, and softening the skin.

Do NOT use Carmol Scalp Treatment Lotion if:

• you are allergic to any ingredient in Carmol Scalp Treatment Lotion


• you have had a severe allergic reaction (eg, severe rash, hives, difficulty breathing, dizziness) to any other sulfonamide medicine, such as acetazolamide, celecoxib, certain diuretics (eg, hydrochlorothiazide), glyburide, probenecid, sulfamethoxazole, valdecoxib, or zonisamide


• you are taking methenamine

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

Before using Carmol Scalp Treatment Lotion:

Some medical conditions may interact with Carmol Scalp Treatment Lotion. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have a history of lupus

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

• Silver-containing products (eg, silver sulfadiazine) because they may decrease Carmol Scalp Treatment Lotion's effectiveness


• Methenamine because it may increase the risk of Carmol Scalp Treatment Lotion's side effects

This may not be a complete list of all interactions that may occur. Ask your health care provider if Carmol Scalp Treatment Lotion may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Carmol Scalp Treatment Lotion:

Use Carmol Scalp Treatment Lotion as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Carmol Scalp Treatment Lotion is for use on the skin only. Wash your hands before and immediately after using Carmol Scalp Treatment Lotion. Clean the affected area before applying Carmol Scalp Treatment Lotion. Apply a thin film of medicine to the affected areas as directed.


• To clear up your infection completely, use Carmol Scalp Treatment Lotion for the full course of treatment. Keep using it even if you feel better in a few days.


• Carmol Scalp Treatment Lotion works best if it is used at the same time each day.


• Continue to use Carmol Scalp Treatment Lotion even if you feel well. Do not miss any doses.


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

Ask your health care provider any questions you may have about how to use Carmol Scalp Treatment Lotion.

Important safety information:

• It may take several days for Carmol Scalp Treatment Lotion to work fully.


• Avoid getting Carmol Scalp Treatment Lotion in your eyes, nose, or mouth.


• Talk with your doctor before you use any other medicines or cleansers on your skin.


• Contact your doctor right away if stomach pain or cramps, severe diarrhea, or bloody stools occur. Do not treat diarrhea without first checking with your doctor.


• Carmol Scalp Treatment Lotion only works against bacteria; it does not treat viral infections.


• Be sure to use Carmol Scalp Treatment Lotion for the full course of treatment. If you do not, the medicine may not clear up your infection completely. The bacteria could also become less sensitive to this or other medicines. This could make the infection harder to treat in the future.


• Long-term or repeated use of Carmol Scalp Treatment Lotion may cause a second infection. Tell your doctor if signs of a second infection occur. Your medicine may need to be changed to treat this.


• Carmol Scalp Treatment Lotion should be used with extreme caution in CHILDREN younger than 12 years old; safety and effectiveness in these children have not been confirmed.


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

Possible side effects of Carmol Scalp Treatment Lotion:

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

Irritation, stinging, or burning of the skin.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bloody diarrhea; fever; joint pain; red, swollen, or blistered skin; severe diarrhea; sores in the mouth; stomach cramps/pain.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Carmol Scalp Treatment side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Carmol Scalp Treatment Lotion may be harmful if swallowed. Symptoms of ingestion may include change in the amount of urine; nausea; vomiting.

Proper storage of Carmol Scalp Treatment Lotion:

Store Carmol Scalp Treatment Lotion at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Do not freeze. Keep Carmol Scalp Treatment Lotion out of the reach of children and away from pets.

General information:

• If you have any questions about Carmol Scalp Treatment Lotion, please talk with your doctor, pharmacist, or other health care provider.


• Carmol Scalp Treatment Lotion is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Carmol Scalp Treatment Lotion. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

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• Carmol Scalp Treatment Side Effects (in more detail)
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• Carmol Scalp Treatment Support Group
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Caverject Impulse

Pronunciation: al-PROS-ta-dil
Generic Name: Alprostadil
Brand Name: Examples include Caverject and Caverject Impulse

Caverject Impulse is used for:

Treating erectile problems in men. It may also be used to help diagnose erectile dysfunction.

Caverject Impulse is a prostaglandin (PGE-1). It works by relaxing certain muscles in the penis and widening blood vessels, which increases blood flow to the penis and helps to cause an erection. When the effect of the alprostadil wears off, blood flow returns to normal and the erection disappears.

Do NOT use Caverject Impulse if:

• you are allergic to any ingredient in Caverject Impulse


• you have blood problems (eg, sickle cell anemia or sickle cell trait, leukemia), bone marrow problems (eg, multiple myeloma), or other conditions that may increase your risk for a prolonged, painful erection (priapism)


• you have a penile implant, deformed penis, or certain other penile problems (eg, Peyronie disease, fibrosis of the penis)


• you have any other physical reason that you should not have sexual intercourse

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

Before using Caverject Impulse:

Tell your health care provider if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have inflammation or infection of the penis, kidney problems, urinary problems (eg, inflammation or narrowing of the urethra), or a history of prolonged or painful erections


• if you use other medicine for erectile problems


• if you have a blood-borne disease (eg, HIV, hepatitis)

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

• Anticoagulants (eg, warfarin) or heparin because the risk of bleeding may be increased

This may not be a complete list of all interactions that may occur. Ask your health care provider if Caverject Impulse may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Caverject Impulse:

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

• An extra patient leaflet is available with Caverject Impulse. Talk to your pharmacist if you have questions about this information.


• Caverject Impulse is injected into the penis to produce an erection. A health care provider will teach you how to prepare and use Caverject Impulse. Be sure you understand how to use Caverject Impulse. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.


• Do not use Caverject Impulse if it contains particles, is cloudy or discolored, or if the cartridge is cracked or damaged.


• Use Caverject Impulse within 24 hours after mixing.


• If the needle breaks during the injection, grasp and remove the broken end if possible and contact your doctor. Contact your doctor right away if the needle breaks and you cannot remove it.


• Use each vial or cartridge one time only. Do not reuse any medicine left in the container.


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


• Caverject Impulse usually starts to work within 5 to 20 minutes after you inject it and lasts about 30 to 60 minutes.


• Do not use more than one dose of Caverject Impulse in a 24-hour period or more than 3 doses per week without first checking with your doctor.


• If you forget to use Caverject Impulse and you still intend to engage in sexual activity, use it as soon as you remember or as directed by your doctor.

Ask your health care provider any questions you may have about how to use Caverject Impulse.

Important safety information:

• Caverject Impulse may cause dizziness. This effect may be worse if you take it with alcohol or certain medicines. Use Caverject Impulse with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do NOT use more than the recommended dose or change your dose without checking with your doctor.


• Seek medical attention if you experience a painful erection or have an erection that lasts for more than 4 hours (priapism). If this is not treated right away, it could lead to permanent sexual problems such as impotence. Contact your doctor right away if this happens.


• Caverject Impulse does not protect against the spread of sexually transmitted diseases (STDs) (eg, HIV) or blood-borne diseases (eg, hepatitis B). Use barrier methods of birth control (eg, condoms) if you have an STD or blood-borne disease.


• If your partner experiences vaginal dryness or painful vaginal sensations, talk with your doctor. It might be necessary to use a water-based lubricant during sexual intercourse.


• You will need to have regular check-ups with your doctor while you are using Caverject Impulse. Be sure to keep all doctor and lab appointments.


• Use Caverject Impulse with caution in the ELDERLY; they may be more sensitive to its effects.


• PREGNANCY AND BREAST-FEEDING: It is not known if Caverject Impulse can cause harm to the fetus. It is not known if Caverject Impulse if found in breast milk. Caverject Impulse is not approved for use in women.

Possible side effects of Caverject Impulse:

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

Mild bleeding at the injection site; mild to moderate genital pain.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abnormal ejaculation; bleeding from the tip of the penis; bloody urine or change in the amount of urine; chest pain; curving of the erect penis; dizziness; fainting; fast or irregular heartbeat; new or worsening genital pain; painful or prolonged erection; redness, lumps, swelling, tenderness, inflammation, numbness, strange sensation, or discoloration of the penis; severe or persistent bleeding or bruising at the injection site; severe or persistent pain, swelling, or redness at the injection site; swelling of the leg veins; white patches or discharge from the penis.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Caverject Impulse side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include fainting; lasting pain in the penis; lightheadedness; painful or prolonged erection (eg, erection lasting more than 4 hours).

Proper storage of Caverject Impulse:

Before mixing, store Caverject Impulse at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. After mixing, you may store Caverject Impulse below 77 degrees (25 degrees C) for up to 24 hours. Do not refrigerate or freeze. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Caverject Impulse out of the reach of children and away from pets.

General information:

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


• Caverject Impulse is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Caverject Impulse. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Caverject Impulse resources

• Caverject Impulse Side Effects (in more detail)
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Menactra

Generic Name: meningococcal vaccine, diphtheria conjugate (Intramuscular route)

me-NINJ-oh-kok-kal VAX-een, dif-THEER-ee-a KON-joo-gate

Available Dosage Forms:

• Powder for Suspension


• Suspension

Therapeutic Class: Vaccine

Uses For Menactra

Meningococcal diphtheria conjugate vaccine is an active immunizing agent used to prevent infection by certain groups of meningococcal bacteria. The vaccine works by causing your body to produce its own protection (antibodies) against the disease.

The following information applies only to the meningococcal vaccine used for meningococcal bacteria Groups A, C, Y, and W-135. These groups cause nearly all of the meningococcal meningitis cases in the U.S. The vaccine will not protect against infection caused by other meningococcal bacteria groups, such as Group B.

Meningococcal infection can cause life-threatening illnesses, such as meningococcal meningitis, which affects the brain, and meningococcemia, which affects the blood. Some persons with meningococcal meningitis and/or meningococcemia also may die. The rate of these diseases peak in adolescence and early adulthood and are more likely to occur in persons with certain diseases or conditions that make them more susceptible to a meningococcal infection or more likely to develop serious problems from a meningococcal infection.

Immunization against meningococcal disease is recommended for persons 9 months to 55 years of age who are at risk of getting the disease because:

• They have certain diseases or conditions that make them more susceptible to a meningococcal infection or more likely to develop serious problems from a meningococcal infection.


• They are living in, working in, or visiting an area where there is a strong possibility of contracting meningococcal disease. .

This vaccine is to be administered only by or under the supervision of your doctor.

Before Using Menactra

In deciding to use a vaccine, the risks of taking the vaccine must be weighed against the good it will do. This is a decision you and your doctor will make. For this vaccine, 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 meningococcal diphtheria conjugate vaccine in infants younger than 9 months of age. Safety and efficacy have not been established.

Geriatric

Appropriate studies have not been performed on the relationship of age to the effects of meningococcal diphtheria conjugate vaccine in adults older than 55 years of age. Safety and efficacy have not been established.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this vaccine, 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.

Receiving this vaccine 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.

• Measles Virus Vaccine, Live

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 this vaccine. Make sure you tell your doctor if you have any other medical problems, especially:

• Guillain-Barré syndrome (nerve disease that causes paralysis), history of—Should not be used in patients with this condition.

• Hemophilia (blood disorder with tendency to bleed uncontrollably) or


• Illness, recent or critical or


• Other bleeding problems—May make these conditions worse.

• Immunodeficiency disorder or


• Weak immune system—This vaccine may not work well in patients with these conditions.

Proper Use of Menactra

A nurse or other trained health professional will give you or your child this vaccine. This vaccine is given as a shot into one of your or your child’s muscles.

This vaccine is usually given only once. You will not need a booster dose, unless your doctor tells you otherwise.

Vaccine information statements are given to the patient, parent, or guardian before receiving this vaccine. Read the information carefully. Ask your doctor if you have any questions.

Precautions While Using Menactra

It is very important that your doctor check you or your child at regular visits to make sure this vaccine is working properly and to check for unwanted effects.

The stopper of the vial contains dry natural latex rubber. Make sure your doctor knows if you or your child have had an allergic reaction to latex rubber.

Check with your doctor right away if you have a cough, difficulty with swallowing, dizziness, fast heartbeat, hives, itching, puffiness or swelling of the eyelids or around the eyes, face, lips or tongue, shortness of breath, skin rash, tightness in the chest, unusual tiredness or weakness, and/or wheezing. These could be symptoms of an allergic reaction to the vaccine.

Contact your doctor immediately if you or your child have sudden weakness or are not able to move your arms or legs. This could be a sign of a serious condition called Guillain-Barré syndrome (GBS).

Make sure your doctor knows if you or your child are receiving medicine or a procedure that may weaken the immune system, such as steroids, cancer medicines, or radiation.

It is important that your doctor should know about all other vaccines you or your child have recently received, including a flu shot.

It is important to tell your doctor if you become pregnant. Your doctor may want you to join a pregnancy registry for patients receiving this vaccine.

This vaccine will not prevent diphtheria, and will not treat symptoms of meningococcal infection if you already have the disease.

Menactra Side Effects

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

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

Rare

• Cough


• difficulty with swallowing


• dizziness


• fast heartbeat


• hives


• itching


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


• shortness of breath


• skin rash


• tightness in the chest


• unusual tiredness or weakness


• wheezing

Incidence not known

• Inability to move the arms and legs


• fainting


• sudden and progressing muscle weakness


• sudden and severe back pain


• sudden numbness and weakness in the arms and legs


• weakness of the muscles in your face

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

• Chills


• diarrhea


• difficulty with moving


• fever


• general feeling of discomfort or illness


• hard lump at the injection site


• headache


• irritability


• loss of appetite


• muscle pain or stiffness


• pain in the joints


• pain, redness, or swelling at the injection site


• sleepiness


• weight loss

Less common

• Vomiting

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

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

See also: Menactra side effects (in more detail)

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

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

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Folbecal

Pronunciation: pree-NATE-al VYE-ta-mins/MIN-er-als/FOE-lik AS-id
Generic Name: Prenatal Multivitamins with Minerals and Folic Acid
Brand Name: Examples include Folbecal and Premesis Rx

Folbecal is used for:

Treating or preventing a lack of vitamins or minerals before, during, and after pregnancy, and while breast-feeding. It may also be used for other conditions as determined by your doctor.

Do NOT use Folbecal if:

• you are allergic to any ingredient in Folbecal


• you have high blood calcium levels

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

Before using Folbecal:

Some medical conditions may interact with Folbecal. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances (including soy products)


• if you have a history of bowel problems (eg, bowel blockage), certain blood disorders (eg, megaloblastic anemia, pernicious anemia), high calcium levels in the urine, kidney problems, kidney stones, peptic ulcer, sarcoidosis, or parathyroid gland problems


• if you have had multiple blood transfusions

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

• Fluorouracil because the risk of its side effects may be increased by Folbecal


• Hydantoins (eg, phenytoin) or mycophenolate because their effectiveness may be decreased by Folbecal

This may not be a complete list of all interactions that may occur. Ask your health care provider if Folbecal may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Folbecal:

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

• Take Folbecal by mouth with or without food. If stomach upset occurs, take with food to reduce stomach irritation.


• Take Folbecal with a full glass of water (8 oz/240 mL).


• If you also take an azole antifungal (eg, ketoconazole), bisphosphonate (eg, etidronate), cation exchange resin (eg, sodium polystyrene sulfonate), cephalosporin (eg, cefdinir), iron, quinolone (eg, ciprofloxacin), tetracycline (eg, doxycycline), or thyroid hormone (eg, levothyroxine), ask your doctor how you should take it with Folbecal.


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

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

Important safety information:

• Do not take more than the recommended dose without checking with your doctor.


• Do not take large doses of vitamins (megadoses or megavitamin therapy) while you use Folbecal unless your doctor tells you to.


• Tell your doctor or dentist that you take Folbecal before you receive any medical or dental care, emergency care, or surgery.


• Folbecal has folic acid in it. Before you start any new medicine, check the label to see if it also has folic acid in it too. If it does or if you are not sure, check with your doctor or pharmacist.


• Folbecal should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.

Possible side effects of Folbecal:

All medicines may cause side effects, but many people have no, or minor, side effects. No COMMON side effects have been reported with Folbecal. Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); severe or persistent constipation.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Folbecal side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include confusion; diarrhea; headache; lack of feeling alert; loss of balance; mental or mood changes; nausea; vomiting.

Proper storage of Folbecal:

Store Folbecal at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Folbecal out of the reach of children and away from pets.

General information:

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


• Folbecal is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Folbecal. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

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Ikotril

Ikotril may be available in the countries listed below.

Ingredient matches for Ikotril

Nicorandil

Nicorandil is reported as an ingredient of Ikotril in the following countries:

• Greece

International Drug Name Search

Loestrin 24 FE

Generic Name: norethindrone acetate. ethinyl estradiol, ferrous fumarate

Dosage Form: tablets
Loestrin® 24 Fe

(norethindrone acetate and ethinyl estradiol tablets, USP and ferrous fumarate tablets)

Ferrous fumarate tablets are not USP for dissolution and assay.

Rx Only

Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Loestrin 24 FE Description

Loestrin® 24 Fe  provides a dosage regimen consisting of 24 white progestogen-estrogen contraceptive tablets and 4 brown ferrous fumarate (placebo) tablets.

Each white tablet contains 1 mg norethindrone acetate and 20 mcg ethinyl estradiol.

Each white tablet also contains the following inactive ingredients: acacia, lactose, magnesium stearate, starch, confectioner’s sugar, and talc.

Each brown tablet contains ferrous fumarate, microcrystalline cellulose, magnesium stearate, povidone, sodium starch glycolate, and compressible sugar. The ferrous fumarate tablets do not serve any therapeutic purpose.

The structural formulas for the active hormones are:

Ethinyl Estradiol [19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-]

Norethindrone Acetate [19-Norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-, (17α)-]

Loestrin 24 FE - Clinical Pharmacology

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

PHARMACOKINETICS

Absorption

Norethindrone acetate appears to be completely and rapidly deacetylated to norethindrone after oral administration, because the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol are rapidly absorbed from Loestrin 24 FE tablets, with maximum plasma concentrations of norethindrone and ethinyl estradiol occurring 1 to 4 hours postdose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 43% for ethinyl estradiol.

The plasma norethindrone and ethinyl estradiol pharmacokinetics following single- and multiple-dose administrations of Loestrin 24 FE tablets in 17 healthy female volunteers are provided in Figures 1 and 2, and Table 1.

Following multiple-dose administration of Loestrin 24 FE tablets, mean maximum concentrations of norethindrone and ethinyl estradiol were increased by 95% and 27%, respectively, as compared to single-dose administration. Mean norethindrone and ethinyl estradiol exposures (AUC values) were increased by 164% and 51% respectively, as compared to single-dose administration of Loestrin 24 FE tablets.

Steady-state with respect to norethindrone was reached by Day 17 and steady-state with respect to ethinyl estradiol was reached by Day 13.

Mean SHBG concentrations were increased by 150% from baseline (57.5 nmol/L) to 144 nmol/L at steady-state.

Figure 1. Mean Plasma Norethindrone Concentration-Time Profiles Following Single- and Multiple-Dose Oral Administration of Loestrin 24 FE Tablets to Healthy Female Volunteers under Fasting Condition (n = 17)

Figure 2. Mean Plasma Ethinyl Estradiol Concentration-Time Profiles Following Single- and Multiple-Dose Oral Administration of Loestrin 24 FE Tablets to Healthy Female Volunteers under Fasting Condition (n = 17)

Table 1. Summary of Norethindrone (NE) and Ethinyl Estradiol (EE) Pharmacokinetics Following Single- and Multiple-Dose Oral Administration of Loestrin 24 FE Tablets to Healthy Female Volunteers under Fasting Condition (n = 17)

* The harmonic mean (0.693/mean apparent elimination rate constant) is reported for t½, and the median (range) is reported for tmax. † The SHBG concentration reported here is the pre-dose concentration.
Regimen	Analyte	Arithmetic Mean *(%CV) by Pharmacokinetic Parameter
		Cmax (pg/mL)	tmax (hr)	AUC(0-24) (pg/mL•h)	Cmin (pg/mL)	t½ (hr)	Cavg (pg/mL)
Day 1 (Single Dose)	NE	8420 (31)	1.0 (0.7-4.0)	33390 (40)	--	--	--
	EE	64.5 (27)	1.3 (0.7-4.0)	465.4 (26)	--	--	--
	SHBG	--	--	--	57.5 (37)†	--	--
Day 24 (Multiple Dose)	NE	16400 (26)	1.3 (0.7–4.0)	88160 (30)	880 (51)	8.4	3670 (30)
	EE	81.9 (24)	1.7 (1.0–2.0)	701.3 (28)	11.4 (43)	14.5	29.2 (28)
	SHBG	--	--	--	144 (24)	--	--
Cmax = Maximum plasma concentration; tmax = Time of Cmax ; Cmin = minimum plasma concentration at steady-state ; AUC(0-24) = Area under plasma concentration versus time curve from 0 to 24 hours ; t½ = Apparent first-order terminal elimination half-life ; Cavg = Average plasma concentration = AUC(0–24)/24 %CV = Coefficient of Variation (%); SHBG = Sex Hormone Binding Globulin (nmol/L)

Effect of Food: Loestrin 24 FE tablets may be administered without regard to meals. A single-dose administration of Loestrin 24 FE tablet with food decreased the maximum concentration of norethindrone by 11% and increased the extent of absorption by 27% and decreased the maximum concentration of ethinyl estradiol by 30% but not the extent of absorption.

Distribution

Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (>95%); norethindrone binds to both albumin and SHBG, whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis.

Metabolism

Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites.

Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation.

Excretion

Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of Loestrin 24 FE tablets are approximately 8 hours and 14 hours, respectively.

Special Populations

Race. The effect of race on the disposition of norethindrone and ethinyl estradiol after Loestrin 24 FE administration has not been evaluated.

Renal Insufficiency. The effect of renal disease on the disposition of norethindrone and ethinyl estradiol after Loestrin 24 FE administration has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function.

Hepatic Insufficiency. The effect of hepatic disease on the disposition of norethindrone and ethinyl estradiol after Loestrin 24 FE administration has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function.

Drug-Drug Interactions

See PRECAUTIONS section—DRUG INTERACTIONS

Indications and Usage for Loestrin 24 FE

Loestrin 24 FE is indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.

Oral contraceptives are highly effective. Table 2 lists the typical unplanned pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and the Norplant® system, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

TABLE 2 Percentage of women experiencing an unintended pregnancy during the first year of typical use and the first year of perfect use of contraception and the percentage continuing use at the end of the first year. United States.

Source: Trussell J, Stewart F, Contraceptive Efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology:Seventeenth Revised Edition. New York, NY: Irvington Publishers, 1998.
* Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year † Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason ‡ Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason § The percentage of women becoming pregnant noted in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% became pregnant in one year. This estimate was lowered slightly (to 85%) to represent the percentage that would become pregnant within one year among women now relying on reversible methods of contraception if they abandon contraception altogether ¶ Foams, creams, gels, vaginal suppositories and vaginal film # Cervical mucous (ovulation) method supplemented by calendar in the preovulatory and basal body temperature in the postovulatory phases Þ With spermicidal cream or jelly ß Without spermicides à The treatment schedule is one dose within 72 hours after unprotected intercourse and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral® (1 dose is 2 white pills), Alesse® (1 dose is 5 pink pills), Nordette® or Levlen® (1 dose is 2 light orange pills), Lo/Ovral® (1 dose is 4 white pills), Triphasil® or Tri-Levlen® (1 dose is 4 yellow pills) è However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced or the baby reaches six months of age
	% of Women Experiencing an Unintended Pregnancy within the First Year of Use		% of Women Continuing Use at One Year*
Method      (1)	Typical Use† (2)	Perfect Use‡ (3)	(4)
Chance§	85	85
Spermicides¶	26	6	40
Periodic abstinence	25		63
Calendar		9
Ovulation Method		3
Sympto-thermal#		2
Post-Ovulation		1
CapÞ
Parous Women	40	26	42
Nulliparous Women	20	9	56
Sponge
Parous Women	40	20	42
Nulliparous Women	20	9	56
DiaphragmÞ	20	6	56
Withdrawal	19	4
Condomß
Female (reality)	21	5	56
Male	14	3	61
Pill	5		71
Progestin only		0.5
Combined		0.1
IUD
Progesterone T	2.0	1.5	81
Copper T 380A	0.8	0.6	78
LNg 20	0.1	0.1	81
Depo-Provera®	0.3	0.3	70
Norplant® and Norplant® 2	0.05	0.05	88
Female Sterilization	0.5	0.5	100
Male Sterilization	0.15	0.10	100
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces risk of pregnancy by at least 75%à
Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraceptionè

Clinical Studies

In a clinical study, 743 women, 18 to 45 years of age, were treated with Loestrin 24 FE for up to six 28-day cycles providing a total of 3,823 treatment-cycles of exposure. A total of 583 women completed 6 cycles of treatment. There were a total of 5 on-treatment pregnancies in 3,565 treatment cycles during which no backup contraception was used. The Pearl Index for Loestrin 24 FE was 1.82.

Contraindications

Oral contraceptives should not be used in women who currently have the following conditions:

• Thrombophlebitis or thromboembolic disorders


• A past history of deep vein thrombophlebitis or thromboembolic disorders


• Cerebrovascular or coronary artery disease (current or history)


• Valvular heart disease with thrombogenic complications


• Severe hypertension


• Diabetes with vascular involvement


• Headaches with focal neurological symptoms


• Major surgery with prolonged immobilization


• Known or suspected carcinoma of the breast or personal history of breast cancer


• Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia


• Undiagnosed abnormal genital bleeding


• Cholestatic jaundice of pregnancy or jaundice with prior pill use


• Hepatic adenomas or carcinomas, or active liver disease


• Known or suspected pregnancy


• Hypersensitivity to any component of this product

Warnings

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with the extent of smoking (in epidemiologic studies, 15 or more cigarettes per day was associated with a significantly increased risk) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

The use of oral contraceptives is associated with increased risk of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, and stroke), hepatic neoplasia, gallbladder disease, and hypertension, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as certain inherited thrombophilias, hypertension, hyperlipidemias, obesity and diabetes.

Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population. For further information, the reader is referred to a text on epidemiological methods.

1. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS

a. Myocardial Infarction

An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six. The risk is very low under the age of 30.

Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older, with smoking accounting for the majority of excess cases. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Figure 3) among women who use oral contraceptives.

FIGURE 3. CIRCULATORY DISEASE MORTALITY RATES FOR 100,000 WOMEN-YEARS BY AGE, SMOKING STATUS AND ORAL CONTRACEPTIVE USE

Layde PM, Beral V. Lancet 1981;1:541-546.

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age, and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS). Such increases in risk factors have been associated with an increased risk of heart disease and the risk increases with the number of risk factors present. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

b. Thromboembolism

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped.

A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four to six weeks after delivery in women who elect not to breastfeed.

c. Cerebrovascular diseases

Oral contraceptives have been shown to increase both the relative and attributable risk of cerebrovascular events (thrombotic and hemorrhagic strokes) although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes.

In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension. The attributable risk is also greater in older women. Oral contraceptives also increase the risk for stroke in women with other underlying risk factors such as certain inherited or acquired thrombophilias, hyperlipidemias, and obesity. Women with migraine (particularly migraine with aura) who take combination oral contraceptives may be at an increased risk of stroke.

d. Dose-related risk of vascular disease from oral contraceptives

A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease. A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents. A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogens used in the contraceptive. The amount of both hormones should be considered in the choice of an oral contraceptive.

Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual patient.

e. Persistence of risk of vascular disease 

There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persisted for at least 9 years for women 40 to 49 years old who had used oral contraceptives for five or more years but this increased risk was not demonstrated in other age groups. In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small. However, both studies were performed with oral contraceptive formulations containing 50 micrograms or higher of estrogens.

2. ESTIMATES OF MORTALITY FROM CONTRACEPTIVE USE

One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 3).

TABLE 3 ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NONSTERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE

* Deaths are birth related † Deaths are method related
	AGE
Method of control and outcome	15-19	20-24	25-29	30-34	35-39	40-44
No fertility control methods*	7.0	7.4	9.1	14.8	25.7	28.2
Oral contraceptives nonsmoker†	0.3	0.5	0.9	1.9	13.8	31.6
Oral contraceptives smoker†	2.2	3.4	6.6	13.5	51.1	117.2
IUD†	0.8	0.8	1.0	1.0	1.4	1.4
Condom*	1.1	1.6	0.7	0.2	0.3	0.4
Diaphragm/spermicide*	1.9	1.2	1.2	1.3	2.2	2.8
Periodic abstinence*	2.5	1.6	1.6	1.7	2.9	3.6
Ory HW. Family Planning Perspectives 1983; 15:57-63.

These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risk. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth.

The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970s but not reported until 1983. However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling.

Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular disease risk may be increased with oral contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.

Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective and meets the individual patient needs.

3. CARCINOMA OF THE REPRODUCTIVE ORGANS AND BREASTS

Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives. Although the risk of breast cancer may be slightly increased among current users of oral contraceptives (RR = 1.24), this excess risk decreases over time after oral contraceptive discontinuation and by 10 years after cessation the increased risk disappears. The risk does not increase with duration of use, and no relationships have been found with dose or type of steroid. The patterns of risk are also similar regardless of a woman's reproductive history or her family breast cancer history. The subgroup for whom risk has been found to be significantly elevated is women who first used oral contraceptives before age 20, but because breast cancer is so rare at these young ages, the number of cases attributable to this early oral contraceptive use is extremely small. Breast cancers diagnosed in current or previous oral contraceptive users tend to be less advanced clinically than in never-users. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormone-sensitive tumor.

Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

In spite of many studies of the relationship between oral contraceptive use and breast cancer and cervical cancers, a cause-and-effect relationship has not been established.

4. HEPATIC NEOPLASIA

Benign hepatic adenomas are associated with oral contraceptive use, although their occurrence is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.

5. OCULAR LESIONS

There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives that may lead to partial or complete loss of vision. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.

6. ORAL CONTRACEPTIVE USE BEFORE OR DURING EARLY PREGNANCY

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when taken inadvertently during early pregnancy (see CONTRAINDICATIONS section).

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion.

It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out. If the patient has not adhered to the prescribed schedule, the possibility