Citalopram Aristo may be available in the countries listed below.
Citalopram hydrobromide (a derivative of Citalopram) is reported as an ingredient of Citalopram Aristo in the following countries:
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Ketricin Tablet may be available in the countries listed below.
Triamcinolone is reported as an ingredient of Ketricin Tablet in the following countries:
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Cefaclor Bexal may be available in the countries listed below.
Cefaclor monohydrate (a derivative of Cefaclor) is reported as an ingredient of Cefaclor Bexal in the following countries:
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Trofentyl may be available in the countries listed below.
Fentanyl citrate (a derivative of Fentanyl) is reported as an ingredient of Trofentyl in the following countries:
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Cardyn may be available in the countries listed below.
Atorvastatin calcium (a derivative of Atorvastatin) is reported as an ingredient of Cardyn in the following countries:
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Cyprohexal may be available in the countries listed below.
Cyproterone 17α-acetate (a derivative of Cyproterone) is reported as an ingredient of Cyprohexal in the following countries:
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Cyproteronacetat beta may be available in the countries listed below.
Cyproterone 17α-acetate (a derivative of Cyproterone) is reported as an ingredient of Cyproteronacetat beta in the following countries:
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Articox may be available in the countries listed below.
Celecoxib is reported as an ingredient of Articox in the following countries:
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Hemabate is a brand name of carboprost, approved by the FDA in the following formulation(s):
No. There is currently no therapeutically equivalent version of Hemabate available.
Note: Fraudulent online pharmacies may attempt to sell an illegal generic version of Hemabate. These medications may be counterfeit and potentially unsafe. If you purchase medications online, be sure you are buying from a reputable and valid online pharmacy. Ask your health care provider for advice if you are unsure about the online purchase of any medication.
See also: About generic drugs.
There are no current U.S. patents associated with Hemabate.
Indometacine Actavis may be available in the countries listed below.
Indometacin is reported as an ingredient of Indometacine Actavis in the following countries:
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Carbocal may be available in the countries listed below.
Calcium Carbonate is reported as an ingredient of Carbocal in the following countries:
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Curacit may be available in the countries listed below.
Suxethonium Chloride is reported as an ingredient of Curacit in the following countries:
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Rec.INN
G03HA01
0002098-66-0
C22-H27-Cl-O3
374
Contraceptive
Antiandrogen
3'H-Cyclopropa[1,2]pregna-1,4,6-triene-3,20-dione, 6-chloro-1,2-dihydro-17-hydroxy-, (1ß,2ß)-
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Glossary
| BAN | British Approved Name |
| BANM | British Approved Name (Modified) |
| DCF | Dénomination Commune Française |
| DCIT | Denominazione Comune Italiana |
| IS | Inofficial Synonym |
| JAN | Japanese Accepted Name |
| OS | Official Synonym |
| PH | Pharmacopoeia Name |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
| USAN | United States Adopted Name |
Heparina may be available in the countries listed below.
Heparin sodium salt (a derivative of Heparin) is reported as an ingredient of Heparina in the following countries:
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Sulfaguanidine Actavis may be available in the countries listed below.
Sulfaguanidine is reported as an ingredient of Sulfaguanidine Actavis in the following countries:
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Perlutal may be available in the countries listed below.
Algestone 16α,17α-acetonide (a derivative of Algestone) is reported as an ingredient of Perlutal in the following countries:
Estradiol 17ß-enantate (a derivative of Estradiol) is reported as an ingredient of Perlutal in the following countries:
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P&U Etoposide may be available in the countries listed below.
Etoposide is reported as an ingredient of P&U Etoposide in the following countries:
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Clenbuterol Sopharma may be available in the countries listed below.
Clenbuterol hydrochloride (a derivative of Clenbuterol) is reported as an ingredient of Clenbuterol Sopharma in the following countries:
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Calas de Glycerina Cifsa may be available in the countries listed below.
Glycerol is reported as an ingredient of Calas de Glycerina Cifsa in the following countries:
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The following drugs and medications are in some way related to, or used in the treatment of COPD, Maintenance. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.
Medical Encyclopedia:
Doxorubicin is for intravenous (IV) use only and should only be given under the supervision of a doctor experienced in the use of cancer chemotherapy agents. If Doxorubicin accidentally leaks into surrounding tissue, the skin and/or muscle may be severely damaged. Notify your doctor immediately if redness, pain, or swelling at or around the injection site occur.
Doxorubicin may cause severe and possibly life-threatening heart problems (eg, heart failure). These problems may occur during therapy or sometimes months to years after receiving Doxorubicin. In some cases, heart problems are irreversible. The risk may be increased if you are using certain medicines that may affect heart function (eg, trastuzumab), or have a history of heart problems, radiation treatment to the chest area, or previous therapy with other anthracyclines (eg, epirubicin). The risk of developing heart problems varies depending on your dose and condition, although it can occur at any dose whether or not you are at risk. Notify your doctor immediately if you develop cough; fast, slow, or irregular heartbeat; shortness of breath; sudden, unexplained weight gain; or swelling of the hands, ankles, or feet.
Another type of cancer (acute myelogenous leukemia [AML]) and a certain blood problem (myelodysplastic syndrome [MDS]) have been reported in patients treated with anthracyclines, including Doxorubicin. The risk varies depending on your dose and other medicines and/or radiation therapy. Discuss any questions or concerns with your doctor.
Doxorubicin may cause bone marrow suppression. Notify your doctor immediately if you develop easy bruising or bleeding, unusual tiredness or weakness, or signs of an infection (eg, fever, chills, persistent sore throat).
Tell your doctor if you have liver problems because your dose will have to be decreased. Your doctor will closely monitor you while you are using Doxorubicin.
Treating various types of cancer.
Doxorubicin is an antineoplastic antibiotic. It works by killing cancer cells.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Doxorubicin. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Doxorubicin. Tell your health care provider if you are taking any other medicines, especially any of the following:
This may not be a complete list of all interactions that may occur. Ask your health care provider if Doxorubicin may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.
Use Doxorubicin as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Doxorubicin.
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:
Diarrhea; hair loss; loss of appetite; nausea; stomach pain; tiredness; weakness; weight changes.
Severe allergic reactions (rash; hives; itching; difficulty breathing; dizziness; flushed face; tightness in the chest; swelling of the mouth, face, lips, or tongue); absence of menstrual cycle; black, tarry stools; chest pain; fainting; fast, slow, or irregular heartbeat; headache; loose or bloody stools; pain, redness, burning, stinging, swelling, or open sores at the injection site; rectal bleeding or irritation; redness or discharge of the eyes; redness, pain, swelling, peeling, tingling, or blistering of the palms of the hands and the soles of the feet; severe or persistent nausea or vomiting; shortness of breath; sudden, unexplained weight gain; swelling of the hands, ankles, or feet; swelling or soreness of the mouth or tongue; symptoms of dehydration (eg, dry mouth or eyes, decreased urination, fast heartbeat, sluggishness, unusual thirst); symptoms of infection (eg, fever, chills, cough, sore throat, burning or painful urination); unusual bruising or bleeding; unusual tiredness or weakness; vomiting.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include swelling or soreness of the mouth or tongue; unusual bruising or bleeding.
Doxorubicin is usually handled and stored by a health care provider. If you are using Doxorubicin at home, store Doxorubicin as directed by your pharmacist or health care provider. Keep Doxorubicin out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about Doxorubicin. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.
Cyprotérone Biogaran may be available in the countries listed below.
Cyproterone 17α-acetate (a derivative of Cyproterone) is reported as an ingredient of Cyprotérone Biogaran in the following countries:
International Drug Name Search
Fluoxétine Sandoz may be available in the countries listed below.
Fluoxetine hydrochloride (a derivative of Fluoxetine) is reported as an ingredient of Fluoxétine Sandoz in the following countries:
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Drug Facts
Active Ingredient Purpose
Lanolin 30% Skin protectant
Purpose - Skin protectant
Uses
For Body and Legs, Head and Face
Temporarily protects and helps relieve minor cuts, lacerations, scrapes, burns and sores.
Keeps affected areas soft and supple
Soothes dry skin, chapping, sunburns, and skin irritations.
Warnings
If conditions persist or become worse, or in case of deep wounds, or serious burns, consult y our veterinarian
For external use only
for veterinary use only
Keep out of reach of children
Directions:
For minor wounds: Clean the area and apply a thick coat at least once daily. Repeat as needed
Other Information
Sore at 20 - 25 degrees C (68-77 degrees F)
Inactive Ingredients
Beeswax (yellow wax), Disodium EDTA, Fragrance, Lanolin Alcohol, Mineral Oil, Oxyquinoline, Petralatum, Purified Water, Sodium Borate, Sorbitan Sesquioleate.
For questions or comments
call 1-800-241-6996 or visit www.coronastable.com
FOR CUTS SORES CHAPPING
SCRAPES DRY SKIN
SINCE 1096
CORONA
MULTI-PURPOSE OINTMENT
Helps promote healing
Ensures moisture balance
Lanolin-based protection
Prevents drying and cracking
Soothes chapping and sunburns
CORONA MULTIPURPOSE OINTMENT
Used since 1906 for:
Horses, Cattle, Small Animals, and Pets
SUMMIT INDUSTRIES, INC.
P.O. BOX 7329
Marietta, GA 30065
| CORONA MULTI-PURPOSE lanolin ointment | ||||||||||||||||||||||||
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| unapproved drug other | 09/17/2010 | ||
| Labeler - SUMMIT INDUSTRIES (003279189) |
| Registrant - SUMMIT INDUSTRIES (003279189) |
| Establishment | |||
| Name | Address | ID/FEI | Operations |
| SUMMIT INDUSTRIES | 003279189 | manufacture | |
Cyprotérone/Ethinylestradiol Bayer may be available in the countries listed below.
Cyproterone 17α-acetate (a derivative of Cyproterone) is reported as an ingredient of Cyprotérone/Ethinylestradiol Bayer in the following countries:
Ethinylestradiol is reported as an ingredient of Cyprotérone/Ethinylestradiol Bayer in the following countries:
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Clanil may be available in the countries listed below.
Clarithromycin is reported as an ingredient of Clanil in the following countries:
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Farmacortix may be available in the countries listed below.
Deflazacort is reported as an ingredient of Farmacortix in the following countries:
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Selukos may be available in the countries listed below.
Selenium Sulfide is reported as an ingredient of Selukos in the following countries:
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Rx only
Iss. 12/2009
11001578
PATIENTS SHOULD BE COUNSELED THAT THIS PRODUCT DOES NOT PROTECT AGAINST HIV INFECTION (AIDS) AND OTHER SEXUALLY TRANSMITTED DISEASES.
Kariva® (desogestrel/ethinyl estradiol and ethinyl estradiol) Tablets provide an oral contraceptive regimen of 21 white round tablets each containing 0.15 mg desogestrel (13-ethyl-11-methylene-18,19-dinor-17 alpha-pregn-4-en- 20-yn-17-ol), 0.02 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5(10)-trien-20-yne-3,17-diol), and inactive ingredients which include colloidal silicon dioxide, hypromellose, lactose monohydrate, polyethylene glycol, povidone, pregelatinized starch, stearic acid and vitamin E, followed by 2 inert light-green round tablets with the following inactive ingredients: FD&C Blue No. 1 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose and pregelatinized starch. Kariva® also contains 5 light-blue round tablets containing 0.01 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol) and inactive ingredients which include colloidal silicon dioxide, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, hypromellose, lactose monohydrate, polydextrose, polyethylene glycol, povidone, pregelatinized starch, stearic acid, titanium dioxide, triacetin and vitamin E. The molecular weight for desogestrel and ethinyl estradiol are 310.48 and 296.40 respectively. The structural formulas are as follows:
DESOGESTREL M.W. 310.48 MF: C22H30O
ETHINYL ESTRADIOL M.W. 296.40 MF: C20H24O2
The 21 white tablets meet USP Dissolution Test 2.
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.
Desogestrel is rapidly and almost completely absorbed and converted into etonogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel compared to a solution, as measured by serum levels of etonogestrel, is approximately 100%. Kariva® (desogestrel/ethinyl estradiol and ethinyl estradiol) Tablets provide two different regimens of ethinyl estradiol; 0.02 mg in the combination tablet [white] as well as 0.01 mg in the light-blue tablet. Ethinyl estradiol is rapidly and almost completely absorbed. After a single dose of Kariva® combination tablet [white], the relative bioavailability of ethinyl estradiol is approximately 93% while the relative bioavailability of the 0.01 mg tablet [light-blue] is 99%. The effect of food on the bioavailability of Kariva® Tablets following oral administration has not been evaluated.
The pharmacokinetics of etonogestrel and ethinyl estradiol following multiple dose administration of Kariva® was determined during the third cycle in 17 subjects. Plasma concentrations of etonogestrel and ethinyl estradiol reached steady-state by Day 21. The AUC(0–24) for etonogestrel at steady-state on Day 21 was approximately 2.2 times higher than AUC(0–24) on Day 1 of the third cycle. The pharmacokinetic parameters of etonogestrel and ethinyl estradiol during the third cycle following multiple dose administration of Kariva® are summarized in Table I.
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| Etonorgestrel | ||||||
| Day | Dose* mg | Cmax pg/mL | Tmax h | t1/2 h | AUC0–24 pg/mL•hr | CL/F L/h |
| 1 | 0.15 | 2503.6 (987.6) | 2.4 (1.0) | 29.8 (16.3) | 17832 (5674) | 5.4 (2.5) |
| 21 | 0.15 | 4091.2 (1186.2) | 1.6 (0.7) | 27.8 (7.2) | 39391 (12134) | 4.4 (1.4) |
| Cmax - measured peak concentration Tmax - observed time of peak concentration t1/2 - elimation half-life, calculated by 0.693/Kelim AUC0-24 - area under the concentration-time curve calculated by the linear trapezoidal rule (Time 0 to 24 hours) CL/F - apparent clearance | ||||||
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| Ethinyl Estradiol | ||||||
| Day | Dose mg | Cmax pg/mL | Tmax h | t1/2 h | AUC0–24 pg/mL•hr | CL/F L/h |
| 1 | 0.02 | 51.9 (15.4) | 2.9 (1.2) | 16.5 (4.8) | 566 (173)* | 25.7 (9.1) |
| 21 | 0.02 | 62.2 (25.9) | 2.0 (0.8) | 23.9 (25.5) | 597 (127)* | 35.1 (8.2) |
| 24 | 0.01 | 24.6 (10.8) | 2.4 (1.0) | 18.8 (10.3) | 246 (65) | 43.6 (12.2) |
| 28 | 0.01 | 35.3 (27.5) | 2.1 (1.3) | 18.9 (8.3) | 312 (62) | 33.2 (6.6) |
Etonogestrel, the active metabolite of desogestrel, was found to be 99% protein bound, primarily to sex hormone-binding globulin (SHBG). Ethinyl estradiol is approximately 98.3% bound, mainly 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).
Desogestrel: Desogestrel is rapidly and completely metabolized by hydroxylation in the intestinal mucosa and on first pass through the liver to etonogestrel. Other metabolites (i.e., 3a-OH-desogestrel, 3ß-OH-desogestrel, and 3a-OH-5a-H-desogestrel) with no pharmacologic actions 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.
Etonogestrel and ethinyl estradiol are excreted in urine, bile, and feces. At steady state, on Day 21, the elimination half-life of etonogestrel is 27.8±7.2 hours and the elimination half-life of ethinyl estradiol for the combination tablet is 23.9±25.5 hours. For the 0.01 mg ethinyl estradiol tablet [light-blue], the elimination half-life at steady state, Day 28, is 18.9±8.3 hours.
There is no information to determine the effect of race on the pharmacokinetics of Kariva®.
No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of Kariva®.
No formal studies were conducted to evaluate the effect of renal disease on the disposition of Kariva®.
Interactions between desogestrel/ethinyl estradiol and other drugs have been reported in the literature. No formal drug-drug interaction studies were conducted (see PRECAUTIONS section).
Kariva® (desogestrel/ethinyl estradiol and ethinyl estradiol) 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 accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of these methods can result in lower failure rates.
| Adapted from Hatcher et al., 1998, ref #1. | |||
| |||
| % 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 | |
| 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 |
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 risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, 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 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 author’s permission). For further information, the reader is referred to a text on epidemiologic methods.
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 thromboembolic disease, 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 2-fold increased risk, which corresponds to an additional 1 to 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 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 (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. Elevated blood pressure). 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 nonusers, 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).
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 preparations containing 0.035 mg or less of estrogen.
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 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 (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.
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 consideration of risk factors.
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.
| Adapted from H.W. Ory, ref. #35. | ||||||
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| 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 |
Numerous epidemiologic studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives. While there are conflicting reports, most studies suggest that the use of oral contraceptives is not associated with an overall increase in the risk of developing breast cancer. Some studies have reported an increased relative risk of developing breast cancer, particularly at a younger age. This increased relative risk appears to be related to duration of use (36–43, 79–89).
Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intra-epithelial 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.
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.
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. Appropriate diagnostic and therapeutic measures should be undertaken immediately.
Extensive epidemiologic studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy (55–57). Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned (55,56,58,59), when oral contraceptives are taken inadvertently during early pregnancy.
The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the first missed period. Oral contraceptive use should be discontinued until pregnancy is ruled out.
Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens (60,61). More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal (62–64). 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 a decrease in glucose tolerance in a significant percentage of users (17). Oral contraceptives containing greater than 75 micrograms of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance (65). Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents (17,66). However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose (67). Because of these demonstrated effects, prediabetic and diabetic women should be carefully monitored while taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1.a. and 1.d.), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.
An increase in blood pressure has been reported in women taking oral contraceptives (68) and this increase is more likely in older oral contraceptive users (69) and with continued use (61). Data from the Royal College of General Practitioners (12) and subsequent randomized trials have shown that the incidence of hypertension increases with increasing quantities of progestogens.
Women with a history of hypertension or hypertension-related diseases, or renal disease (70) should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives (69), and there is no difference in the occurrence of hypertension between ever- and never-users (68,70,71).
The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause.
Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Non-hormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out.
Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was pre-existent.
Ectopic as well as intrauterine pregnancy may occur in contraceptive fail
