Veletri

Generic Name: epoprostenol (EE poe PROST en ol)

Brand Names: Flolan, Veletri

What is Veletri (epoprostenol)?

Epoprostenol is a prostaglandin (a hormone-like substance that occurs naturally in the body). Prostaglandins help to control functions in the body such as blood pressure and muscle contractions.

Epoprostenol is used to treat pulmonary arterial hypertension (PAH). It improves your ability to exercise.

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

What is the most important information I should know about Veletri (epoprostenol)?

You should not use this medication if you are allergic to epoprostenol, if you have breathing problems when you first start using epoprostenol, or if you have congestive heart failure caused by a decrease in your heart's ability to pump blood back into the body.

Before using epoprostenol, tell your doctor if you have a bleeding or blood clotting disorder, heart disease, liver or kidney disease, or high blood pressure.

Epoprostenol is injected into a vein using an infusion pump, usually through a permanent central intravenous (IV) catheter placed into a large vein (such as in your chest). You may need to use this medication for many years.

You may be shown how to use an infusion pump at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.

You will receive your first dose of this medicine in a hospital or clinic setting to quickly treat any serious side effects that occur. Your blood pressure and heart rate may also need to be monitored whenever your dose is changed.

Tell your doctor about all other drugs you use, especially medicines to prevent blood clots.

Do not stop using epoprostenol without first talking to your doctor, even if you feel fine or have no symptoms. Even short breaks in the flow of your medication through the IV can cause the treatment to stop working. Missing doses or stopping suddenly may make your condition worse and you may have symptoms such as dizziness, weakness, or trouble breathing. Call your doctor if your symptoms do not improve, or if they get worse while using epoprostenol.

What should I discuss with my healthcare provider before using Veletri (epoprostenol)?

You should not use this medication if you are allergic to epoprostenol, if you have breathing problems when you first start using epoprostenol, or if you have congestive heart failure caused by a decrease in your heart's ability to pump blood back into the body.

To make sure you can safely use epoprostenol, tell your doctor if you have any of these other conditions:

• 
  

  a bleeding or blood clotting disorder;

  
  


• 
  

  heart disease;

  
  


• 
  

  high blood pressure;

  
  


• 
  

  kidney disease; or

  
  


• 
  

  liver disease.

  
  

FDA pregnancy category B. Epoprostenol is not expected to harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether epoprostenol passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I use Veletri (epoprostenol)?

Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label. You may need to use this medication for many years.

Epoprostenol is injected into a vein using a computerized, portable infusion pump to control the rate of medication you receive. Because epoprostenol must be used long-term, it is usually given through a permanent central intravenous (IV) catheter placed into a large vein (such as in your chest).

You may be shown how to use an infusion pump at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.

You will receive your first dose of this medicine in a hospital or clinic setting to quickly treat any serious side effects that occur. Your blood pressure and heart rate may also need to be monitored whenever your dose is changed.

You may be given other medications to prevent blood clots while you are receiving epoprostenol.

Epoprostenol is a powder medicine that must be mixed with a liquid (diluent) before using it. Use only the diluent provided with your medication and do not mix epoprostenol with any other medications or diluents not approved by your doctor.

If you are using the injections at home, be sure you understand how to properly mix and store the medicine. These directions are different for the Flolan and Veletri brands of this medication. Be sure you understand all mixing and storage directions for the specific brand of epoprostenol you are using.

After mixing Flolan with the diluent, store in the refrigerator and use within 48 hours. After mixing Veletri with the diluent, store in the refrigerator ans use within 5 days. The Veletri and diluent mixture may also be stored at room temperature but you must use it within 48 hours after it was mixed. Protect the mixed medicine from light and do not freeze. Throw away any epoprostenol and diluent mixture that has become frozen, has changed colors, or has any particles in it. Call your doctor for a new prescription. The epoprostenol and diluent mixture must be protected from light at all times, whether it is in storage or in use. Do not stop using epoprostenol without first talking to your doctor, even if you feel fine or have no symptoms. Missing doses or stopping suddenly may make your condition worse and you may have symptoms such as dizziness, weakness, or trouble breathing.

Even short breaks in the flow of your medication through the IV can cause the treatment to stop working. To make sure there is no interruption in your treatment, you may need to have a back-up infusion pump in case your first pump fails to work properly. Also keep replacement batteries and extra IV infusion sets on hand at all times. Get your prescription refilled before you run out of medicine completely.

Call your doctor if your symptoms do not improve, or if they get worse while using epoprostenol. Store unopened vials of epoprostenol and its diluent at cool room temperature (below 77 degrees F), away from moisture, heat, and light. Keep in the original carton.

What happens if I miss a dose?

Because this medication is given around the clock, you should not miss a dose if you use the medication properly. Call your doctor right away if your epoprostenol therapy is interrupted for any reason.

What happens if I overdose?

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

Overdose symptoms may include severe forms of some of the side effects listed in this medication guide.

What should I avoid while using Veletri (epoprostenol)?

Avoid using any infusion pump that has not been approved for use by your doctor.

Veletri (epoprostenol) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

• 
  

  fever, flu symptoms, mouth and throat ulcers, rapid heart rate, rapid and shallow breathing, fainting;

  
  


• 
  

  chest pain, trouble breathing;

  
  


• 
  

  fast, slow, or uneven heart rate;

  
  


• 
  

  pale skin, easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

  
  


• 
  

  blood in your urine or stools;

  
  


• 
  

  coughing up blood;

  
  


• 
  

  feeling like you might pass out; or

  
  


• 
  

  numbness or increased sensitivity anywhere in your body.

  
  

Less serious side effects may include:

• 
  

  flushing (warmth, redness, or tingly feeling);

  
  


• 
  

  nausea, vomiting, diarrhea, stomach pain;

  
  


• 
  

  headache or jaw pain;

  
  


• 
  

  joint or muscle pain;

  
  


• 
  

  dizziness, sweating; or

  
  


• 
  

  feeling anxious, nervous, or agitated.

  
  

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

What other drugs will affect Veletri (epoprostenol)?

Epoprostenol can increase your risk of bleeding. This effect is increased when you also use medicines to prevent blood clots, such as:

• 
  

  heparin or warfarin (Coumadin, Jantoven);

  
  


• 
  

  alteplase (Activase), tenecteplase (TNKase), urokinase (Abbokinase);

  
  


• 
  

  dalteparin (Fragmin), enoxaparin (Lovenox), fondaparinux (Arixtra), tinzaparin (Innohep); or

  
  


• 
  

  abciximab (ReoPro), anagrelide (Agrylin), cilostazol (Pletal), clopidogrel (Plavix), dipyridamole (Persantine, Aggrenox), eptifibatide (Integrelin), prasugrel (Effient), ticlopidine (Ticlid), tirofiban (Aggrastat).

  
  

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

• 
  

  digoxin (digitalis, Lanoxin);

  
  


• 
  

  a diuretic (water pill);

  
  


• 
  

  heart or blood pressure medications;

  
  


• 
  

  aspirin or an NSAID (non-steroidal anti-inflammatory drugs) such as ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Cambia, Cataflam, Voltaren, Flector Patch, Pennsaid, Solareze), indomethacin (Indocin), meloxicam (Mobic), and others.

  
  

This list is not complete and other drugs may interact with epoprostenol. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Veletri resources

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

• Veletri MedFacts Consumer Leaflet (Wolters Kluwer)


• Veletri Advanced Consumer (Micromedex) - Includes Dosage Information


• Veletri Prescribing Information (FDA)


• Epoprostenol Prescribing Information (FDA)


• Epoprostenol Sodium Monograph (AHFS DI)


• Flolan Prescribing Information (FDA)

Compare Veletri with other medications

• Pulmonary Arterial Hypertension

Where can I get more information?

• Your doctor or pharmacist can provide more information about epoprostenol.

See also: Veletri side effects (in more detail)

Semprex

Semprex may be available in the countries listed below.

Ingredient matches for Semprex

Acrivastine

Acrivastine is reported as an ingredient of Semprex in the following countries:

• Bahrain


• Bangladesh


• Estonia


• Georgia


• Hong Kong


• Iran


• Italy


• Kuwait


• Latvia


• Malaysia


• Netherlands


• Oman


• Philippines


• Qatar


• Russian Federation


• Singapore


• South Africa


• Turkey


• United Arab Emirates

International Drug Name Search

Velcade

Generic Name: bortezomib (Intravenous route)

bor-TEZ-oh-mib

Commonly used brand name(s)

In the U.S.

• Velcade

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Proteasome Inhibitor

Uses For Velcade

Bortezomib injection is given together with melphalan and prednisone to treat multiple myeloma (blood plasma cell cancer) in patients with or without a prior history of treatment, and mantle cell lymphoma in patients who have received at least one treatment and did not worked well.

Bortezomib interferes with the growth of cancer cells, which are then eventually destroyed by the body. Since the growth of normal body cells may also be affected by bortezomib, other effects will also occur. Some of these may be serious and must be reported to your doctor. Other effects, such as a skin rash, may not be serious but may cause concern. Some effects may not occur until months or years after the medicine is used.

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

Before Using Velcade

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 bortezomib injection 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 bortezomib injection in the elderly.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	D	Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk.

Breast Feeding

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

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

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

• Phenobarbital


• Phenytoin


• Rifabutin


• Rifapentine


• St John's Wort

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.

• Itraconazole


• Ketoconazole

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

• Allergy to boron or


• Allergy to mannitol—Should not be used in patients with these conditions.

• Congestive heart failure or


• Dehydration or


• Heart disease or


• Lung disease (e.g., acute respiratory distress syndrome, lung infiltration, pneumonitis, pulmonary hypertension) or


• Peripheral neuropathy (nerve problem) or


• Syncope (fainting), history of—Use with caution. May make these conditions worse.

• Herpes zoster (shingles)—May reactivate this condition.

• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Proper Use of Velcade

Before receiving this medicine, make sure you understand all the risks and benefits. It is important for you to work closely with your doctor during your treatment.

You will receive this medicine while you are in a hospital or cancer treatment center. A nurse or other trained health professional will give you this medicine. This medicine is given through a needle placed in one of your veins.

You may also receive medicines to help prevent nausea, vomiting, or diarrhea. Ask your doctor or other health caregiver if you should drink extra water while you are using this medicine. This could help you avoid feeling dizzy or lightheaded.

Precautions While Using Velcade

It is very important that your doctor check you at regular visits to make sure that this medicine is working properly. Blood tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control while you are using this medicine to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

Tell your doctor right away if you are having burning, numbness, tingling, or painful sensations in the arms, hands, legs, or feet. These could be symptoms of a condition called peripheral neuropathy.

Dizziness, lightheadedness, or even fainting may occur when you get up suddenly from a lying or sitting position. Getting up slowly may help lessen this problem. Also, lying down for a while may relieve dizziness or lightheadedness.

This medicine may cause some people to become dizzy, drowsy, tired, or less alert than they are normally. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert. You may rise up slowly from sitting or lying position to help prevent lightheadedness or dizziness.

Some people who have used this medicine developed serious heart problems. Tell your doctor right away if you have chest pain or discomfort, shortness of breath, irregular heartbeat, or swelling of the feet, ankles, or legs while you are using this medicine.

This medicine may increase your chance of having a brain condition called reversible posterior leukoencephalopathy syndrome (RPLS). Stop using this medicine and check with your doctor right away if you start having headaches, seizures, extreme drowsiness, confusion, or problems with vision while you are using this medicine.

This medicine may cause nausea, vomiting, constipation, and diarrhea, so it is important to drink plenty of fluids. If you experience dizziness or lightheadedness, contact your doctor. These could be symptoms of dehydration (not enough water in your body).

Bortezomib can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

• If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.


• Check with your doctor immediately if you notice any unusual bleeding or bruising; black, tarry stools; blood in the urine or stools; or pinpoint red spots on your skin.


• Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.


• Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.


• Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.


• Avoid contact sports or other situations where bruising or injury could occur.

This medicine may cause a serious type of reaction called tumor lysis syndrome (TLS). Your doctor may give you a medicine to help prevent this. Call your doctor right away if you have a decrease or change in urine amount; joint pain, stiffness, or swelling; lower back, side, or stomach pain; a rapid weight gain; swelling of the feet or lower legs; or unusual tiredness or weakness.

If you are diabetic and you are taking an oral antidiabetic medicine, you should check your blood sugar level often and report any unusual changes to your doctor.

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 (e.g., St. John's wort) or vitamin supplements.

Velcade Side Effects

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

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

More common

• Black, tarry stools


• bleeding gums


• blood in the urine or stools


• blurred vision


• body aches or pain


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


• chest pain


• chills


• confusion


• cough


• cough producing mucus


• decreased urination


• difficult or labored breathing


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


• dry mouth


• ear congestion


• fainting


• fever


• headache


• increase in heart rate


• loss of voice


• lower back or side pain


• nasal congestion


• nerve pain


• painful blisters on the trunk of the body


• painful or difficult urination


• pale skin


• pinpoint red spots on the skin


• rapid breathing


• runny nose


• shortness of breath


• sneezing


• sore throat


• stuffy nose


• sunken eyes


• sweating


• swollen glands


• thirst


• tightness in the chest


• troubled breathing with exertion


• ulcers, sores, or white spots in the mouth


• unsteadiness or awkwardness


• unusual bleeding or bruising


• unusual tiredness or weakness


• weakness in the arms, hands, legs, or feet


• wheezing


• wrinkled skin

Less common

• Decreased urine output


• dilated neck veins


• general feeling of discomfort or illness


• increased sensitivity to pain


• increased sensitivity to touch


• irregular breathing


• irregular heartbeat


• swelling of the face, fingers, feet, or lower legs


• thickening of bronchial secretions


• tingling in the hands and feet


• troubled breathing


• unsteadiness or awkwardness


• weight gain

Incidence not known

• Abdominal or stomach pain and tenderness


• agitation


• back pain


• blistering, peeling, or loosening of the skin


• bloating


• bruising


• change in consciousness


• coma


• coughing or vomiting blood


• dark urine


• deafness


• deep or fast breathing with dizziness, numbness to feet, hands, and around the mouth


• diarrhea


• drowsiness


• fast heartbeat


• fear or nervousness


• general tiredness and weakness


• hallucinations


• irritability


• itching


• light-colored stools


• loss of consciousness


• mood or mental changes


• pains in the stomach, side, or abdomen, possibly radiating to the back


• persistent bleeding or oozing from puncture sites, mouth, or nose


• pounding, slow heartbeat


• rectal bleeding


• red skin lesions, often with a purple center


• red, irritated eyes


• restlessness


• seeing, hearing, or feeling things that are not there


• seizures


• shaking


• stiff neck


• trouble sleeping


• upper right abdominal or stomach pain


• yellow eyes or skin

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

• Acid or sour stomach


• belching


• bone pain


• constipation


• difficulty having a bowel movement


• difficulty with moving


• feeling unusually cold or shivering


• general feeling of discomfort or illness


• heartburn


• indigestion


• itching skin


• loss of appetite


• loss of taste


• mental depression


• muscle cramps


• muscle pain or stiffness


• nausea


• pain in the joints


• pain in the limb


• rash


• sleeplessness


• stomach discomfort or upset, or pain


• swelling


• swollen joints


• unable to sleep


• vomiting


• weight loss

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: Velcade side effects (in more detail)

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

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

More Velcade resources

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

• Velcade Prescribing Information (FDA)


• Velcade Consumer Overview


• Velcade Monograph (AHFS DI)


• Velcade MedFacts Consumer Leaflet (Wolters Kluwer)


• Bortezomib Professional Patient Advice (Wolters Kluwer)

Compare Velcade with other medications

• Lymphoma
• Multiple Myeloma

Sulpirid Stada

Sulpirid Stada may be available in the countries listed below.

Ingredient matches for Sulpirid Stada

Sulpiride

Sulpiride is reported as an ingredient of Sulpirid Stada in the following countries:

• Germany

International Drug Name Search

Vinorayne

Vinorayne may be available in the countries listed below.

Ingredient matches for Vinorayne

Vinorelbine

Vinorelbine is reported as an ingredient of Vinorayne in the following countries:

• Poland

International Drug Name Search

metronidazole Vaginal

met-roe-NYE-da-zole

Commonly used brand name(s)

In the U.S.

• Metrogel-Vaginal


• Vandazole

In Canada

• Flagyl


• Neo-Metric


• Nidagel

Available Dosage Forms:

• Suppository


• Gel/Jelly


• Cream

Therapeutic Class: Antibacterial

Chemical Class: Nitroimidazole

Uses For metronidazole

Metronidazole vaginal is used to treat women with vaginal infections (e.g., bacterial vaginosis).

Metronidazole belongs to the class of medicines known as antibiotics. It works by killing the bacteria or preventing their growth. However, metronidazole will not work for vaginal fungus or yeast infections.

metronidazole is available only with your doctor's prescription.

Before Using metronidazole

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 metronidazole, the following should be considered:

In deciding whether to use a medicine, the risks of using the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For vaginal metronidazole, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to metronidazole 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 on the relationship of age to the effects of metronidazole vaginal gel have not been performed in the pediatric population. However, pediatric-specific problems that would limit the usefulness of this medication in teenagers are not expected. metronidazole may be used for bacterial vaginosis in teenage females but should not be used before the start of menstruation.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of metronidazole vaginal gel in the elderly.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

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 metronidazole, 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 metronidazole 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.

• Amprenavir


• Disulfiram

Using metronidazole 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.

• Amiodarone


• Busulfan


• Fluorouracil


• Mycophenolate Mofetil


• Warfarin

Using metronidazole 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.

• Carbamazepine


• Cholestyramine


• Cyclosporine


• Lithium


• Milk Thistle


• Tacrolimus

Interactions with Food/Tobacco/Alcohol

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

Using metronidazole with any of the following is not recommended. Your doctor may decide not to treat you with this medication, change some of the other medicines you take, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

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

• Aseptic meningitis, history of or


• Encephalopathy (brain disorder), history of or


• Leukopenia (low white blood cells), history of or


• Optic neuropathy (eye disease with vision changes), history of or


• Peripheral neuropathy (nerve disease with pain, numbness, or tingling), history of or


• Seizures or epilepsy, history of—Use with caution. May make these conditions worse.

• Liver disease, severe—Patients with severe liver disease may have an increase in side effects.

Proper Use of metronidazole

Use metronidazole 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.

metronidazole is to be used only in the vagina. Use it at bedtime, unless your doctor tells you otherwise.

Do not get it in your eyes, nose, mouth, or skin. If metronidazole does get into your eyes, wash them out right away with large amounts of cool tap water. If your eyes still burn or are painful, check with your doctor.

metronidazole usually come with patient directions. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Wash your hands with soap and water before and after using metronidazole.

Metronidazole vaginal gel is in a tube. You will use an applicator to put the gel into your vagina. The applicator has a plastic tube called a barrel that is open at one end and has a plunger (another piece of plastic that can move inside the barrel) at the other end.

• To fill the applicator:
  
  • For cream or gel dosage forms:
    
    • Break the metal seal at the opening of the tube by using the point on the top of the cap.
    
    
    • Screw the applicator onto the tube.
    
    
    • Squeeze the medicine into the applicator slowly until it is full.
    
    
    • Remove the applicator from the tube. Replace the cap on the tube.
    
    
  
  
  • For vaginal tablet dosage form:
    
    • Place the vaginal tablet into the applicator. Wet the vaginal tablet with water for a few seconds.
    
    
  
  


• To insert vaginal metronidazole using the applicator
  
  • For all dosage forms:
    
    • Relax while lying on your back with your knees bent (or in any position that you feel comfortable).
    
    
    • Hold the full applicator in one hand. Insert it slowly into the vagina. Stop before it becomes uncomfortable.
    
    
    • Slowly press the plunger until it stops.
    
    
    • Withdraw the applicator. The medicine will be left behind in the vagina.
    
    
    • Remove the applicator from your vagina. Use each applicator only once, and then throw it away.
    
    
  
  

To help clear up your infection completely, it is very important that you keep using metronidazole for the full time of treatment, even if your symptoms begin to clear up after a few days. If you stop using metronidazole too soon, your symptoms may return. Do not miss any doses. Also, continue using metronidazole even if your menstrual period starts during the time of treatment.

Dosing

The dose of metronidazole 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 metronidazole. 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 bacterial vaginal infections:
  
  • For vaginal dosage form (cream):
    
    • Adults and teenagers—One applicatorful (500 milligrams [mg]), inserted into the vagina. Use the medicine one or two times a day for 10 or 20 days.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For vaginal dosage form (gel):
    
    • Adults and teenagers—One applicatorful (5000 milligrams [mg]) inserted into the vagina once a day (at bedtime) for 5 days. Each applicatorful contains 37.5 mg of metronidazole.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For vaginal dosage form (tablets):
    
    • Adults and teenagers—One 500 milligram (mg) tablet, inserted high into the vagina. Use the medicine once a day in the evening for 10 or 20 days.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of metronidazole, 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 metronidazole

It is important that your doctor check your progress after you finish using metronidazole. This is to make sure that the infection is cleared up.

If your symptoms do not improve within a few days after you start metronidazole or if they become worse, check with your doctor.

You should not use metronidazole if you have taken disulfiram (Antabuse®) within the last 2 weeks. Disulfiram is used to help people who have a drinking problem. If these 2 medicines are taken close together, serious unwanted effects may occur.

Drinking alcoholic beverages while using metronidazole may cause stomach pain, nausea, vomiting, headache, or flushing or redness of the face. Alcohol-containing medicines (e.g., elixirs, cough syrups, tonics) may also cause problems. The chance of these problems occurring may continue for at least a day after you stop using metronidazole. You should not drink alcoholic beverages or take other alcohol-containing medicines while you are using metronidazole and for at least 3 days after stopping it.

Stop using metronidazole and check with your doctor right away if you have dizziness, problems with muscle control or coordination, shakiness or an unsteady walk, slurred speech, or trouble with speaking. These may be symptoms of a serious brain condition called encephalopathy.

Stop using metronidazole and call your doctor right away if you have confusion, drowsiness, fever, a general feeling of illness, a headache, loss of appetite, nausea, a stiff neck or back, or vomiting. These could be symptoms of a serious condition called aseptic meningitis.

Stop using metronidazole and check with your doctor right away if you are having burning, numbness, tingling, or painful sensations in the arms, hands, legs, or feet. These could be symptoms of a condition called peripheral neuropathy.

metronidazole may cause some people to become dizzy or lightheaded. Make sure you know how you react to metronidazole before you drive, use machines, or do anything else that could be dangerous if you are dizzy or are not alert. If these reactions are especially bothersome, check with your doctor.

Vaginal medicines usually leak out of the vagina during treatment. To keep the medicine from getting on your clothing, wear a mini-pad or sanitary napkin. Do not use tampons (like those used for menstrual periods) since they may soak up the medicine.

To help clear up your infection completely and to help make sure it does not return, good health habits are also required.

• Wear cotton panties (or panties or pantyhose with cotton crotches) instead of synthetic (e.g., nylon or rayon) panties.


• Wear only freshly washed panties daily.

Do not have sexual intercourse while you are using metronidazole. Having sexual intercourse may reduce the strength of the medicine. This may keep the medicine from working properly. Also, oils in the cream and vaginal tablets (but not the vaginal gel) may damage latex (rubber) contraceptive devices (e.g., cervical caps, condoms, or diaphragms), causing them to leak, wear out sooner, or not work properly.

Avoid using douches or other vaginal products unless your doctor tells you to.

Many vaginal infections (e.g., trichomoniasis) are spread by having sexual intercourse. You can give the infection to your sexual partner, and the infection could be given back to you. Your partner may also need to be treated for some infections. Until you are sure that the infection is completely cleared up after your treatment with metronidazole, your partner should wear a condom during sexual intercourse . If you have any questions about this, check with your doctor.

Before you have any medical tests, tell the medical doctor in charge that you are using metronidazole. The results of some tests may be affected by metronidazole.

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.

metronidazole 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

• Itching in the vagina


• pain during sexual intercourse


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

Less common

• Abdominal or stomach cramping or pain


• burning on urination or need to urinate more often


• burning or irritation of penis of sexual partner


• itching, stinging, or redness of the genital area

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

Less common

• Diarrhea


• dizziness or lightheadedness


• dryness of the mouth


• feeling of a furry tongue


• headache


• loss of appetite


• metallic taste or other change in taste sensation


• nausea


• vomiting

Metronidazole may cause your urine to become dark. This is harmless and will go away when you stop using metronidazole.

After you stop using metronidazole, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:

• Any vaginal or genital irritation or itching


• pain during sexual intercourse


• thick, white vaginal discharge not present before treatment, with no odor or with a mild odor

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

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

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

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

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Velivet

desogestrel and ethinyl estradiol

Dosage Form: tablets
Velivet™ (desogestrel and ethinyl estradiol tablets, USP - triphasic regimen) Rx only PATIENTS SHOULD BE COUNSELED THAT THIS PRODUCT DOES NOT PROTECT AGAINST HIV INFECTION (AIDS) AND OTHER SEXUALLY TRANSMITTED DISEASES.

Velivet Description

Velivet™ (desogestrel and ethinyl estradiol, USP) Tablets are a triphasic oral contraceptive containing two active components, desogestrel and ethinyl estradiol. Each 28-day treatment cycle pack consists of three active dosing phases: 7 beige tablets containing 0.1 mg desogestrel (13-ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-17-ol) and 0.025 mg ethinyl estradiol (19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3, 17-diol); 7 orange tablets containing 0.125 mg desogestrel and 0.025 mg ethinyl estradiol, and 7 pink tablets containing 0.15 mg desogestrel and 0.025 mg ethinyl estradiol. Inactive ingredients include colloidal silicon dioxide, hypromellose, lactose monohydrate, polyethylene glycol, polysorbate 80, povidone, pregelatinized starch, stearic acid, titanium dioxide and vitamin E. Beige tablets also contain iron oxide red and iron oxide yellow. Pink and orange tablets also contain FD&C Red No. 40 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake. Velivet™ also contains 7 white tablets with the following inert ingredients: lactose anhydrous, magnesium stearate, microcrystalline cellulose and pregelatinized starch. The structural formulas are as follows:

The 7 beige, 7 pink and 7 orange tablets meets dissolution test 2.

Velivet - 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).

Receptor binding studies, as well as studies in animals, have shown that etonogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity (91,92). The relevance of this latter finding in humans is unknown.

Pharmacokinetics

Absorption: Desogestrel is rapidly and almost completely absorbed and converted into etonogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel, based on the lowest and highest tablet strengths, 0.1 mg desogestrel/0.025 mg ethinyl estradiol and 0.15 mg desogestrel/0.025 mg ethinyl estradiol, compared to solution, as measured by serum levels of etonogestrel, is approximately 100%. Ethinyl estradiol is rapidly and almost completely absorbed. When the lowest and highest tablet strengths, 0.1 mg desogestrel/0.025 ethinyl estradiol and 0.15 mg desogestrel/0.025 mg ethinyl estradiol, were compared to solution, the relative bioavailability of ethinyl estradiol was 92% and 98%, respectively. The effect of food on the bioavailability of desogestrel and ethinyl estradiol tablets following oral administration has not been evaluated.

The pharmacokinetics of etonogestrel and ethinyl estradiol following multiple dose administration of desogestrel and ethinyl estradiol tablets were determined during the third cycle in 21 subjects. After multiple dosing with desogestrel and ethinyl estradiol tablets, plasma concentrations of etonogestrel reached steady-state after four days of treatment during dosing Phases 1 and 3. During dosing Phase 2, steady-state was reached after five days of treatment. The dose-normalized AUC0-24 for etonogestrel was increased approximately 20% from Phase 1 to Phase 2 and approximately 10% from Phase 2 to Phase 3. SHBG concentrations were shown to be induced by the daily administration of ethinyl estradiol. Steady state for ethinyl estradiol was reached after four days of dosing in all dosing phases. The pharmacokinetic parameters of etonogestrel and ethinyl estradiol during the third cycle following multiple dose administration of desogestrel and ethinyl estradiol tablets are summarized in Table I.

TABLE I: MEAN (SD) PHARMACOKINETIC PARAMETERS OF DESOGESTREL AND ETHINYL ESTRADIOL TABLETS OVER A 28-DAY DOSING PERIOD IN THE THIRD CYCLE (n=21).

* n=20
Etonogestrel
Phase	Dose†	Cmax	tmax	n-AUC0-24	CL/F
(days)	mg	pg/mL	hr	pg•hr/mL/μg	L/hr
1 (1-7)	0.100	2163.3 (856.4)	1.6 (0.7)	196.0 (75.4)	6.1 (2.3)
2 (8-14)	0.125	3241.5 (1296.5)*	1.1 (0.3)*	234.4 (85.0)*	5.1 (1.9)*
3 (15-21)	0.150	3855.7 (1273.1)	1.5 (0.8)	256.6 (104.0)	4.6 (1.6)
† Desogestrel
Ethinyl Estradiol
Phase	Dose	Cmax	tmax	n-AUC0-24	CL/F
(days)	mg	pg/mL	hr	pg•hr/mL/μg	L/hr
1 (1-7)	0.025	85.4 (51.7)	1.5 (0.8)	26.4 (11.5)	43.5 (15.0)
2 (8-14)	0.025	91.3 (52.2)*	1.2 (1.2)*	29.0 (15.5)*	41.7 (15.5)*
3 (15-21)	0.025	90.1 (48.2)	1.2 (0.7)	28.3 (13.2)	42.5 (18.7)

Cmax – maximum serum drug concentration

tmax – time at which maximum serum drug concentration occurs

n-AUC0-24 – area under the concentration- vs. time curve -0 to 24 hours normalized to 1 μg administered

CL/F – apparent clearance

Note: for information on t1/2 for Day 21, see the Excretion section.

Distribution: Etonogestrel, the active metabolite of desogestrel, was found to be 98% protein bound, primarily to sex hormone-binding globulin (SHBG). Ethinyl estradiol is primarily bound to plasma albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis. Desogestrel, in combination with ethinyl estradiol, does not counteract the estrogen-induced increase in SHBG, resulting in lower serum levels of free testosterone (96–99).

Metabolism: Desogestrel: Desogestrel is rapidly and completely metabolized by hydroxylation in the intestinal mucosa and on first pass through the liver to etonogestrel. In vitro data suggest an important role for the cytochrome P450 CYP2C9 in the bioactivation of desogestrel. Further metabolism of etonogestrel into 6ß-hydroxy, etonogestrel and 6ß-13ethyl-dihydroxylated metabolites as major metabolites is catalyzed by CYP3A4. Other metabolites (i.e., 3α-OH-desogestrel, 3ß-OH-desogestrel, and 3α-OH-5α-H-desogestrel) also have been identified and these metabolites may undergo glucuronide and sulfate conjugation.

Ethinyl Estradiol: Ethinyl estradiol is subject to a significant degree of presystemic conjugation (phase II metabolism). Ethinyl estradiol, escaping gut wall conjugation, undergoes phase I metabolism and hepatic conjugation (phase II metabolism). Major phase I metabolites are 2-OH-ethinyl estradiol and 2-methoxy-ethinyl estradiol. Sulfate and glucuronide conjugates of both ethinyl estradiol and phase I metabolites, which are excreted in bile, can undergo enterohepatic circulation.

Excretion: Etonogestrel and ethinyl estradiol are primarily eliminated in urine, bile and feces. At steady state, on Day 21, the elimination half-lives of etonogestrel and ethinyl estradiol are 37.1±14.8 hours and 28.2±10.5 hours, respectively.

Special Populations

Race: There is no information to determine the effect of race on the pharmacokinetics of desogestrel and ethinyl estradiol tablets.

Hepatic Insufficiency: No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of desogestrel and ethinyl estradiol tablets. However, steroid hormones may be poorly metabolized in patients with impaired liver function (see PRECAUTIONS).

Renal Insufficiency: No formal studies were conducted to evaluate the effect of renal disease on the disposition of desogestrel and ethinyl estradiol tablets.

Drug-Drug Interactions: Interactions between desogestrel and ethinyl estradiol and other drugs have been reported in the literature. No formal drug-drug interaction studies were conducted with desogestrel and ethinyl estradiol tablets (see PRECAUTIONS).

Indications and Usage for Velivet

Velivet™ (desogestrel and ethinyl estradiol, USP) Tablets are indicated for the prevention of pregnancy in women who elect to use this product as a method of contraception.

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

TABLE II: 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.

* 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	Typical Use†	Perfect Use‡
(1)	(2)	(3)	(4)
Chance§	85	85
Spermicides¶	26	6	40
Periodic abstinence	25		63
Calendar		9
Ovulation Method		3
Sympto-Thermal#		2
Post-Ovulation		1
Withdrawal	19	4
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
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 contraception.è 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.

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


• Cerebral vascular 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 hormonal contraceptive use


• Hepatic tumors (benign or malignant) or active liver disease


• Known or suspected pregnancy


• Heavy smoking (≥15 cigarettes per day) and over age 35


• Hypersensitivity to any of the components of Velivet™

Warnings

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This riskincreases with age and with heavy smoking (15 or more cigarettes per day) 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 risks 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 formulations of higher doses of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with formulations of lower doses of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiologic 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 non-users. 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 non-users. The attributable risk does provide information about the actual occurrence of a disease in the population (Adapted from refs. 2 and 3 with the authors’ permission). For further information, the reader is referred to a text on epidemiological methods.

1. Thromboembolic Disorders and Other Vascular Problems

a. 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 (2,3,19–24). 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 (25). The risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped (2).

Several epidemiologic studies indicate that third generation oral contraceptives, including those containing desogestrel, are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives (102–104). In general, these studies indicate an approximate two-fold increased risk, which corresponds to an additional 1–2 cases of venous thromboembolism per 10,000 women-years of use. However, data from additional studies have not shown this two-fold increase in risk.

A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of oral contraceptives (9,26). The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions (9,26). 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 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 breast feed.

b. 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 (4–10). The risk is very low in women under the age of 30.

Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarction in women in their mid-thirties or older with smoking accounting for the majority of excess cases (11). Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non-smokers over the age of 40 (Table III) among women who use oral contraceptives.

TABLE III: CIRCULATORY DISEASE MORTALITY RATES PER 100,000 WOMAN-YEARS BY AGE, SMOKING STATUS, AND ORAL CONTRACEPTIVE USE.

Age	EVER-USERS NON-SMOKERS	EVER-USERS SMOKERS	CONTROLS NON-SMOKERS	CONTROLS SMOKERS
15–24	0.0	10.5	0.0	0.0
25–34	4.4	14.2	2.7	4.2
35–44	21.5	63.4	6.4	15.2
45+	52.4	206.7	11.4	27.9
Adapted from P.M. Layde and V. Beral, ref. #12.

Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity (13). In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism (14–18). Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

c. Cerebrovascular diseases: Oral contraceptives have been shown to increase both the relative and attributable risks 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 non-users, for both -types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes (27–29).

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 (30). The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers 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 (30). The attributable risk is also greater in older women (3). 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 (31–33). A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents (14–16). 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 contraceptives. 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 a product containing the lowest hormone content that provides satisfactory results in the individual.

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 persists for at least 9 years for women 40–49 years old who had used oral contraceptives for five or more years, but this increased risk was not demonstrated in other age groups (8). 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 (34). However, both studies were performed with oral contraceptive formulations containing 50 micrograms or more of estrogen.

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 IV). 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 risks. 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 1970’s - but not reported until 1983 (35). However, current clinical practice involves the use of lower estrogen 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 (100,101), the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the newer low-dose formulations), there are also 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 low-dose oral contraceptive use by healthy non-smoking 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.

TABLE IV: ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 NON-STERILE WOMEN, BY FERTILITY CONTROL METHOD ACCORDING TO AGE

* Deaths are birth-related † Deaths are method-related
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 non-smoker†	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
Adapted from H.W. Ory, ref. #35.

 

3. Carcinoma of the Reproductive Organs and Breasts

Numerous epidemiologic 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 combination oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women (45–48). 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 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 the incidence of benign tumors 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 especially with oral contraceptives of higher dose (49). Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage (50,51).

Studies from Britain have shown an increased risk of developing hepatocellular carcinoma (52–54) 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. 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.