Baramycin may be available in the countries listed below.
Bacitracin is reported as an ingredient of Baramycin in the following countries:
Neomycin sulfate (a derivative of Neomycin) is reported as an ingredient of Baramycin in the following countries:
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Bacqure may be available in the countries listed below.
Cilastatin sodium salt (a derivative of Cilastatin) is reported as an ingredient of Bacqure in the following countries:
Imipenem is reported as an ingredient of Bacqure in the following countries:
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Enatral may be available in the countries listed below.
Enalapril maleate (a derivative of Enalapril) is reported as an ingredient of Enatral in the following countries:
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Tensanil may be available in the countries listed below.
Benazepril hydrochloride (a derivative of Benazepril) is reported as an ingredient of Tensanil in the following countries:
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Benaderma may be available in the countries listed below.
Diphenhydramine hydrochloride (a derivative of Diphenhydramine) is reported as an ingredient of Benaderma in the following countries:
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Beclometason-ratiopharm may be available in the countries listed below.
Beclometasone 17α,21-dipropionate (a derivative of Beclometasone) is reported as an ingredient of Beclometason-ratiopharm in the following countries:
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Benemicin may be available in the countries listed below.
Rifampicin is reported as an ingredient of Benemicin in the following countries:
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Budésonide Arrow may be available in the countries listed below.
Budesonide is reported as an ingredient of Budésonide Arrow in the following countries:
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Taltirelin Hydrate may be available in the countries listed below.
Taltirelin Hydrate (JAN) is also known as Taltirelin (Rec.INN)
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Glossary
| JAN | Japanese Accepted Name |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
In the US, Myfortic (mycophenolic acid systemic) is a member of the drug class selective immunosuppressants and is used to treat Dermatomyositis and Rejection Prophylaxis.
US matches:
UK matches:
Mycophenolic Acid is reported as an ingredient of Myfortic in the following countries:
Mycophenolic Acid sodium (a derivative of Mycophenolic Acid) is reported as an ingredient of Myfortic in the following countries:
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Glossary
| SPC | Summary of Product Characteristics (UK) |
Beclometasondipropionaat may be available in the countries listed below.
Beclometasone 17α,21-dipropionate (a derivative of Beclometasone) is reported as an ingredient of Beclometasondipropionaat in the following countries:
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Definition of Schistosoma haematobium: A species of trematode worm that parasitises humans and causes urinary tract disease. See schistosomiasis.
The following drugs and medications are in some way related to, or used in the treatment of Schistosoma haematobium. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.
Rec.INN
S01ED06
0039552-01-7
C16-H21-N-O4
291
ß-Adrenergic blocking agent
Glaucoma treatment
Ethanone, 1-[7-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]-2-benzofuranyl]-
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Glossary
| DCF | Dénomination Commune Française |
| DCIT | Denominazione Comune Italiana |
| IS | Inofficial Synonym |
| JAN | Japanese Accepted Name |
| OS | Official Synonym |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
Venlafaxina Kern Pharma may be available in the countries listed below.
Venlafaxine hydrochloride (a derivative of Venlafaxine) is reported as an ingredient of Venlafaxina Kern Pharma in the following countries:
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TORISEL 25 mg/ml concentrate and diluent for solution for infusion
Temsirolimus
1. What TORISEL is and what it is used for
2. Before you receive TORISEL
3. How TORISEL is given
4. Possible side effects
5. How to store TORISEL
6. Further information
Your doctor has prescribed TORISEL because you have one of the following types of cancer:
TORISEL is a selective inhibitor of mTOR (mammalian target of rapamycin) that blocks tumour cell growth and division.
TORISEL may also
Some medicines can interfere with the breakdown or metabolism of TORISEL. In particular, you should inform your doctor if you are taking any of the following:
Please tell your doctor if you are taking, or have recently taken, any other medicines, including medicines obtained without a prescription.
TORISEL has not been studied in pregnant women, and it must not be used during pregnancy. It is important that you tell your doctor if you are pregnant or are planning to become pregnant before receiving TORISEL.
Women of childbearing potential must avoid pregnancy by using an effective method of birth control during treatment with TORISEL. Men with partners of childbearing potential should use medically acceptable contraception while receiving TORISEL.
Women should not breast-feed during treatment with TORISEL, as this medicine may interfere with the growth and development of the baby. Ask your doctor for advice before breast-feeding your baby, as it is not known if TORISEL passes into breast milk.
No studies on the ability to drive and use machines have been performed. However, the very common side effects include feeling or being sick (nausea and vomiting) and difficulty falling or staying asleep. It is recommended you do not drive immediately after treatment.
For patients receiving the higher dose of TORISEL for the treatment of mantle cell lymphoma, the amount of alcohol in this medicinal product may impair your ability to drive or use machines.
This medicine contains ethanol (alcohol), equivalent to 17.6 ml beer, 7.3 ml wine per 25 mg dose. Patients receiving the higher dose of 175 mg of TORISEL for the initial treatment of mantle cell lymphoma may receive a dose of ethanol equivalent to up to 123 ml beer or 51 ml wine per dose. Harmful for those suffering from alcoholism. To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease or epilepsy. The amount of alcohol in this medicinal product may alter the effects of other medicines.
TORISEL will always be prepared and given to you by a doctor or another healthcare professional as an intravenous infusion (into your vein).
TORISEL 25 mg/ml concentrate must be diluted with 1.8 ml of withdrawn diluent before administration in sodium chloride 9 mg/ml (0.9%) solution for injection (see dilution instructions at the end of the package leaflet).
For renal cancer, the recommended dose is 25 mg infused (as a drip) over a 30- to 60-minute period once weekly.
For mantle cell lymphoma, the recommended dosing is 175 mg infused (as a drip) over a 30- to 60-minute period once weekly for 3 weeks followed by single weekly doses of 75 mg infused (as a drip) over a 30- to 60-minute period.
You should receive an injection of antihistamine (to try to prevent allergic reaction to TORISEL) directly into your vein approximately 30 minutes before your dose of TORISEL.
Treatment with TORISEL should continue until you are no longer benefiting from therapy or until unacceptable side effects occur.
As this medicine is prepared and given by a healthcare professional, it is unlikely you will be given too much.
If you are concerned about this, or think you may have missed a dose, tell your doctor immediately.
Like all medicines, TORISEL can cause side effects, although not everybody gets them. Side effects may be more pronounced during the higher dose of 175 mg / week during initial treatment for mantle cell lymphoma.
Very common serious side effects observed in more than 1 in 10 patients treated with TORISEL are:
Common serious side effects observed in more than 1 in 100 patients treated with TORISEL are:
Very Common side effects occurring in more than 1 in 10 patients are:
General feeling of weakness, chills**, swelling due to fluid retention, pain (including abdominal, back, chest and joint pain), feeling or being sick (nausea and vomiting), diarrhoea, fever, sore throat, sores and inflammation in the mouth and/or the digestive tract, cough, upper respiratory infections**, pneumonia**, nose bleed, runny nose, rash, itching, nail disorder, acne, dry skin, anorexia, shortness of breath, low levels of potassium in the blood (which may cause muscle weakness), low red blood cell count, decreased number of white blood cells**, decreased number of lymphocytes**, high blood sugar, high cholesterol and other blood fats, abscess, infections, urinary tract infections, abnormal kidney function (including kidney failure), change in the sense of taste, difficulty falling or staying asleep, anxiety**, muscle pain**.
Common side effects occurring in less than 1 out of 10 patients, but more than 1 per 100 patients, are:
Gum redness and swelling, mouth pain (including sores inside the mouth), stomach bloating, high blood pressure, redness and swelling of the tissues around the eye, including watery eye disorder, taste loss, redness and swelling of the follicles in the skin, allergic (hypersensitivity) reactions, severe scaling of the skin, and problems with healing after surgery, increased blood clotting (including thrombosis of the veins, embolism in the lung), inflammation of the lung, infection in the blood, dehydration, depression, sleepiness, numbness and tingling of the skin, dizziness, perforation of the gut*, bleeding from the stomach or intestines, inflammation of the lining of the stomach, trouble with swallowing, eye or skin bleeding (bruising), yeast infection, fungal infection of the skin, and blood tests that show changes in the way the liver or kidney are working, low levels of phosphate in the blood, low levels of calcium in the blood.
*occurred as uncommon for renal cell carcinoma
**occurred as common for renal cell carcinoma
Uncommon side effects occurring in less than 1 out of 100 patients, but more than 1 per 1,000 patients are:
Pericardial effusion (fluid around the heart that may require drainage and can affect the pumping of blood).
Bleeding into the brain in patients with brain tumours or who are on blood thinners.
Side effects for which frequency has not been determined are:
Swelling of the face, lips, tongue, and throat, possibly causing difficulty breathing.
Serious reactions of the skin and/or mucous membranes which may include painful blisters and fever (Stevens-Johnson syndrome).
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Keep out of the reach and sight of children.
Do not use TORISEL after the expiry date, which is stated on the vial label and carton. The first two numbers indicate the month; the next four numbers indicate the year.
Store in a refrigerator (2°C-8°C).
Do not freeze.
Keep the vials in the outer carton in order to protect from light.
After first dilution of TORISEL 25 mg/ml concentrate with 1.8 ml of withdrawn diluent, the mixture may be stored for up to 24 hours below 25°C and protected from light prior to further dilution.
After further dilution of the concentrate-diluent mixture with sodium chloride 9 mg/ml (0.9%) solution for injection, the solution may be stored for up to 6 hours below 25°C and protected from light.
The active substance is temsirolimus.
Each vial of 1.2 ml of TORISEL 25 mg/ml concentrate contains 30 mg of temsirolimus.
The other ingredients in TORISEL are anhydrous ethanol, all-rac-alpha-tocopherol (E 307), propylene glycol and anhydrous citric acid (E 330). The diluent contains polysorbate 80 (E 433), macrogol 400 and anhydrous ethanol.
TORISEL is a concentrate for infusion supplied with a diluent.
The concentrate is a clear, colourless to light-yellow solution. The diluent is a clear to slightly turbid, light-yellow to yellow solution. The solutions are essentially free from visable particulates.
Each pack of TORISEL contains one vial of 1.2 ml concentrate and one vial of 2.2 ml diluent.
For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:
This leaflet was last approved in 07/2010
Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu There are also links to other websites about rare diseases and treatments.
Doc ID: 61147 (Clean version of Doc ID: 61146)
Bucktrygama may be available in the countries listed below.
Sulfamethoxazole is reported as an ingredient of Bucktrygama in the following countries:
International Drug Name Search
Generic Name: brompheniramine, hydrocodone, and pseudoephedrine (brom fen EER a meen, hye droe KOE dohn, soo doe e FED rin)
Brand Names: Anaplex HD, Bromcomp HC, Bromph HD, Bromplex HD, BroveX HC, Drocon-CS, Endacof HC, J-Tan D HC, M-END, SymTan A, Visvex
Brompheniramine is an antihistamine that reduces the natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.
Hydrocodone is in a group of drugs called narcotics and is similar to codeine. Hydrocodone is a cough suppressant that affects the signals in the brain that trigger cough reflex.
Pseudoephedrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).
The combination of brompheniramine, hydrocodone, and pseudoephedrine is used to treat cough, sneezing, itching, watery eyes, runny nose, stuffy nose, and sinus congestion caused by allergies, the common cold, or the flu.
Brompheniramine, hydrocodone, and pseudoephedrine may also be used for other purposes not listed in this medication guide.
Before taking brompheniramine, hydrocodone, and pseudoephedrine, tell your doctor if you are allergic to any drugs, or if you have:
kidney or liver disease;
heart disease or high blood pressure;
enlarged prostate or urination problems;
diabetes;
glaucoma;
a thyroid disorder;
asthma, COPD, sleep apnea, or other breathing disorders;
a history of head injury or brain tumor;
epilepsy or other seizure disorder;
low blood pressure;
gallbladder disease;
Addison's disease or other adrenal gland disorders;
mental illness; or
a history of drug or alcohol addiction.
If you have any of these conditions, you may need a dose adjustment or special tests to safely take this medication.
Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label. Cough or cold medicine is usually taken for only a short time until your symptoms clear up.
Measure the liquid form of this medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.
If you need to have any type of surgery, tell the surgeon ahead of time if you have taken a cold medicine within the past few days.
This medication can cause you to have unusual results with allergy skin tests. Tell any doctor who treats you that you are taking an antihistamine.
Since cough or cold medicine is usually taken only as needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.
Avoid becoming overheated or dehydrated during exercise and in hot weather.
Avoid taking diet pills, caffeine pills, or other stimulants (such as ADHD medications) without your doctor's advice. Taking a stimulant together with a decongestant can increase your risk of unpleasant side effects.
fast, pounding, or uneven heartbeats;
shallow breathing, slow heartbeat;
severe dizziness, fainting, anxiety, restless feeling, nervousness, or tremor;
confusion, hallucinations, unusual thoughts or behavior;
easy bruising or bleeding, unusual weakness, fever, chills, body aches, flu symptoms;
urinating less than usual or not at all; or
increased blood pressure (severe headache, blurred vision, trouble concentrating, chest pain, numbness, seizure).
Less serious side effects may include:
blurred vision;
dry mouth;
nausea, vomiting, stomach pain, constipation, mild loss of appetite;
mild dizziness, drowsiness;
problems with memory or concentration;
ringing in your ears;
warmth, tingling, or redness under your skin;
restless or excitability (especially in children);
sleep problems (insomnia); or
skin rash or itching.
This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.
Before taking this medication, tell your doctor if you are using any of the following drugs:
cimetidine (Tagamet);
rifampin (Rifadin, Rifater, Rifamate, Rimactane);
zidovudine (Retrovir, AZT);
antidepressants such as amitriptyline (Elavil), clomipramine (Anafranil), imipramine (Janimine, Tofranil), and others;
aspirin or salicylates (such as Disalcid, Doan's Pills, Dolobid, Salflex, Tricosal, and others);
a beta-blocker such as atenolol (Tenormin), carteolol (Cartrol), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), timolol (Blocadren), and others;
bladder or urinary medications such as oxybutynin (Ditropan, Oxytrol) or tolterodine (Detrol);
a diuretic (water pill), or blood pressure medication;
medication to treat irritable bowel syndrome;
medicines to treat psychiatric disorders, such as chlorpromazine (Thorazine), haloperidol (Haldol), mesoridazine (Serentil), pimozide (Orap), or thioridazine (Mellaril); or
seizure medication such as phenytoin (Dilantin) or phenobarbital (Luminal, Solfoton).
This list is not complete and there may be other drugs that can interact with brompheniramine, hydrocodone, and pseudoephedrine. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.
Hytis may be available in the countries listed below.
Hydroxyzine is reported as an ingredient of Hytis in the following countries:
International Drug Name Search
Rx only
11001623
Revised February 2010
Jolessa™ (levonorgestrel / ethinyl estradiol tablets) 0.15 mg / 0.03 mg
Patients should be counseled that this product does not protect against HIV-infection (AIDS) and other sexually transmitted diseases.
Jolessa™ (levonorgestrel/ethinyl estradiol tablets) is an extended-cycle oral contraceptive consisting of 84 pink active tablets each containing 0.15 mg of levonorgestrel, a synthetic progestogen and 0.03 mg of ethinyl estradiol, and 7 white inert tablets (without hormones).
The chemical formula of levonorgestrel USP is 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-, (17α)-, (-)-, and the chemical formula of ethinyl estradiol USP is 19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-. The structural formulas are as follows:
Levonorgestrel C21H28O2 MW: 312.4
Ethinyl Estradiol C20H24O2 MW: 296.4
Each pink active tablet contains the following inactive ingredients: anhydrous lactose NF, FD&C blue no. 1, FD&C red no. 40, hydroxypropyl methylcellulose USP, microcrystalline cellulose NF, polyethylene glycol NF, magnesium stearate NF, polysorbate 80 NF, and titanium dioxide USP. Each white inert tablet contains the following inactive ingredients: anhydrous lactose NF, hydroxypropyl methylcellulose USP, microcrystalline cellulose NF, and magnesium stearate NF.
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 changes in the endometrium (which reduce the likelihood of implantation).
No specific investigation of the absolute bioavailability of Jolessa™ in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability nearly 100%) and is not subject to first-pass metabolism. Ethinyl estradiol is rapidly and almost completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the bioavailability of ethinyl estradiol is approximately 43%.
| Analyte | AUCt (mean ± SD) | Cmax (mean ± SD) | Tmax (mean ± SD) | T1/2 (mean ± SD) |
| Levonorgestrel | 60.8 ± 25.6 ng*hr/mL | 5.6 ± 1.5 ng/mL | 1.4 ± 0.3 hours | 29.8 ± 8.3 hours |
| Ethinyl estradiol | 1307 ± 361 pg*hr/mL | 145 ± 45 pg/mL | 1.6 ± 0.5 hours | 15.4 ± 3.2 hours |
The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of Jolessa™ has not been evaluated.
The apparent volume of distribution of levonorgestrel and ethinyl estradiol are reported to be approximately 1.8 L/kg and 4.3 L/kg, respectively. Levonorgestrel is about 97.5 - 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. Ethinyl estradiol is about 95 - 97% bound to serum albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis, which leads to decreased levonorgestrel clearance. Following repeated daily dosing of combination levonorgestrel/ethinyl estradiol oral contraceptives, levonorgestrel plasma concentrations accumulate more than predicted based on single-dose kinetics, due in part, to increased SHBG levels that are induced by ethinyl estradiol, and a possible reduction in hepatic metabolic capacity.
Following absorption, levonorgestrel is conjugated at the 17β-OH position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3α,5β-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3α,5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users.
First-pass metabolism of ethinyl estradiol involves formation of ethinyl estradiol-3-sulfate in the gut wall, followed by 2-hydroxylation of a portion of the remaining untransformed ethinyl estradiol by hepatic cytochrome P-450 3A4 (CYP3A4). Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of ethinyl estradiol hydroxylation. Hydroxylation at the 4-, 6-, and 16- positions may also occur, although to a much lesser extent than 2-hydroxylation. The various hydroxylated metabolites are subject to further methylation and/or conjugation.
About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The terminal elimination half-life for levonorgestrel after a single dose of Jolessa™ was about 30 hours.
Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. The terminal elimination half-life of ethinyl estradiol after a single dose of Jolessa™ was found to be about 15 hours.
No formal studies on the effect of race on the pharmacokinetics of Jolessa™ were conducted.
No formal studies have been conducted to evaluate the effect of hepatic disease on the pharmacokinetics of Jolessa™. However, steroid hormones may be poorly metabolized in patients with impaired liver function.
No formal studies have been conducted to evaluate the effect of renal disease on the pharmacokinetics of Jolessa™.
See PRECAUTIONS section – Drug Interactions.
Jolessa™ tablets are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.
In a 1-year controlled clinical trial, 4 pregnancies occurred in women 18-35 years of age during 809 completed 91-day cycles of Jolessa™ during which no backup contraception was utilized. This represents an overall use-efficacy (typical user efficacy) pregnancy rate of 1.98 per 100 women-years of use.
Oral contraceptives are highly effective for pregnancy prevention. Table 2 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 Norplant® Implant System, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.
| Source: Trussell J, 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. | |||
| |||
| % 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 | ||
| Withdrawal | 19 | 4 | |
| Cap Þ | |||
| Parous women | 40 | 26 | 42 |
| Nulliparous women | 20 | 9 | 56 |
| Sponge | |||
| Parous women | 40 | 20 | 42 |
| Nulliparous women | 20 | 9 | 56 |
| Diaphragm Þ | 20 | 6 | 56 |
| Condom ß | |||
| 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 the risk of pregnancy by at least 75%. à | |||
| Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception. è | |||
Oral contraceptives should not be used in women who currently have the following conditions:
Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases 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 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. 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 longterm use of the oral contraceptives with lower doses 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.
Use of Jolessa™ provides women with more hormonal exposure on a yearly basis than conventional monthly oral contraceptives containing similar strength synthetic estrogens and progestins (an additional 9 weeks per year). While this added exposure may pose an additional risk of thrombotic and thromboembolic disease, studies to date with Jolessa™ have not suggested an increased risk of these disorders.
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 infarction 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 1) among women who use oral contraceptives.
Figure 1 Adapted from P.M. Layde and B Beral, Lancet, 1 :541-546,1981
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). The severity and number of risk factors increase heart disease risk. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.
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 nonusers 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 approximate incidence of deep vein thrombosis and pulmonary embolism in users of low dose (<50 μg ethinyl estradiol) combination oral contraceptives is up to 4 per 10,000 woman-years compared to 0.5-3 per 10,000 woman-years for non-users. However, the incidence is less than that associated with pregnancy (6 per 10,000 woman-years). 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 weeks after delivery in women who elect not to breast-feed.
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 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.
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 progestogen 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.
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 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.
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). 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 less than 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. 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 risks 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.
| Adapted from H.W. Ory, Family Planning Perspectives, 15:57-63, 1983. | ||||||
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| Method of control and outcome | 15-19 | 20-24 | AGE 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 |
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 having breast cancer diagnosed may be slightly increased among current and recent users of combined oral contraceptives (RR=1.24), this excess risk decreases over time after combination oral contraceptive discontinuation and by 10 years after cessation the increased risk disappears. The risk does not increase with duration of use and no consistent 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 clinically advanced 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.
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.
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.
Because women using Jolessa™ will likely have withdrawal bleeding only 4 times per year, pregnancy should be ruled out at the time of any missed menstrual period (see DOSAGE AND ADMINISTRATION section). Oral contraceptive use should be discontinued if pregnancy is confirmed.
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.
Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal. The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.
Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users. Oral contraceptives containing greater than 75 micrograms of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1a. and 1d.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.
Women with significant hypertension should not be started on hormonal contraceptive. An increase in blood pressure has been reported in women taking oral contraceptives and this increase is more likely in older oral contraceptive users and with continued use. Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens.
Women with a history of hypertension or hypertension-related diseases, or renal disease should be encouraged to use another method of contraception. If women with hypertension elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued (see CONTRAINDICATIONS section). For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever- and never-users.
The onset or exacerbation of migraine or development of headache with a new pattern that is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause. (See WARNINGS, 1c.)
When prescribing Jolessa™, the convenience of fewer planned menses (4 per year instead of 13 per year) should be weighed against the inconvenience of increased intermenstrual bleeding and/or spotting.
The clinical trial (SEA 301) that compared the efficacy of Jolessa™ (91-day cycles) to an equivalent dosage 28-day cycle regimen also assessed intermenstrual bleeding. The participants in the study were composed primarily of women who had used oral contraceptives previously as opposed to new users. Women with a history of breakthrough bleeding/spotting ≥10 consecutive days on oral contraceptives were excluded from the study. More Jolessa™ subjects, compared to subjects on the 28-day cycle regimen, discontinued prematurely for unacceptable bleeding (7.7% [Jolessa™] vs. 1.8% [28-day cycle regimen]).
Table 4 shows the percentages of women with ≥ 7 days and ≥ 20 days of intermenstrual spotting and/or bleeding in the Jolessa™ and the 28-day cycle treatment groups.
