Daro Hoofdpijnpoeder may be available in the countries listed below.
Paracetamol is reported as an ingredient of Daro Hoofdpijnpoeder in the following countries:
Propyphenazone is reported as an ingredient of Daro Hoofdpijnpoeder in the following countries:
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Magnésie San Pellegrino Anisée may be available in the countries listed below.
Magnesium Hydroxide is reported as an ingredient of Magnésie San Pellegrino Anisée in the following countries:
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Progesterone Biologici may be available in the countries listed below.
Progesterone is reported as an ingredient of Progesterone Biologici in the following countries:
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Atenolol Eb may be available in the countries listed below.
Atenolol is reported as an ingredient of Atenolol Eb in the following countries:
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Metronidazol Richet may be available in the countries listed below.
Metronidazole is reported as an ingredient of Metronidazol Richet in the following countries:
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Panzol may be available in the countries listed below.
Pantoprazole is reported as an ingredient of Panzol in the following countries:
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In some countries, this medicine may only be approved for veterinary use.
Rec.INN
J01CE02
0000087-08-1
C16-H18-N2-O5-S
350
Antibacterial: Penicillin, penicillinase-sensitive
4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 3,3-dimethyl-7-oxo-6-[(phenoxyacetyl)amino]-, [2S-(2α,5α,6ß)]-
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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 |
Lincoln Sweet Itch Control may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Permethrin is reported as an ingredient of Lincoln Sweet Itch Control in the following countries:
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Procaine Penicillin. G may be available in the countries listed below.
Benzylpenicillin monohydrate (a derivative of Benzylpenicillin) is reported as an ingredient of Procaine Penicillin. G in the following countries:
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Xylonor may be available in the countries listed below.
Cetrimide is reported as an ingredient of Xylonor in the following countries:
Cetrimide bromide (a derivative of Cetrimide) is reported as an ingredient of Xylonor in the following countries:
Lidocaine is reported as an ingredient of Xylonor in the following countries:
Lidocaine hydrochloride (a derivative of Lidocaine) is reported as an ingredient of Xylonor in the following countries:
Norepinephrine is reported as an ingredient of Xylonor in the following countries:
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Nipruss may be available in the countries listed below.
Sodium Nitroprusside is reported as an ingredient of Nipruss in the following countries:
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Ratiodol Gel may be available in the countries listed below.
Ibuprofen is reported as an ingredient of Ratiodol Gel in the following countries:
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Procainamide Double-Crane Pharm may be available in the countries listed below.
Procainamide hydrochloride (a derivative of Procainamide) is reported as an ingredient of Procainamide Double-Crane Pharm in the following countries:
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Generic Name: phenazopyridine (fen AY zoe PIR i deen)
Brand Names: Azo-Gesic, Azo-Standard, Baridium, Phenazo, Prodium, Pyridiate, Pyridium, Re-Azo, Uricalm, Uristat
Phenazopyridine is a pain reliever that affects the lower part of your urinary tract (bladder and urethra).
Phenazopyridine is used to treat pain, burning, increased urination, and increased urge to urinate. These symptoms are usually caused by infection, injury, surgery, catheter, or other conditions that irritate the lower urinary tract.
Phenazopyridine may also be used for other purposes not listed in this medication guide.
Phenazopyridine will most likely darken the color of your urine to an orange or red color. This is a normal effect and is not cause for alarm unless you have other symptoms such as pale or yellowed skin, fever, stomach pain, nausea, and vomiting. Darkened urine may also cause stains to your underwear, which may or may not be removed by laundering.
Phenazopyridine can also permanently stain soft contact lenses, and you should not wear them while taking this medicine.
Stop taking this medication and call your doctor at once if you have pale skin, fever, confusion, yellowing of your skin or eyes, increased thirst, swelling, or if you urinate less than usual or not at all.
Before using phenazopyridine, tell your doctor if you are allergic to any drugs, or if you have:
liver disease;
diabetes; or
a condition called G6PD (glucose-6-phosphate dehydrogenase) deficiency.
If you have any of these conditions, you may need a dose adjustment or special tests to safely take phenazopyridine.
Take phenazopyridine 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.
Phenazopyridine will most likely darken the color of your urine to an orange or red color. This is a normal effect and is not cause for alarm unless you have other symptoms such as pale or yellowed skin, fever, stomach pain, nausea, and vomiting. Darkened urine may also cause stains to your underwear, which may or may not be removed by laundering.
Phenazopyridine can also permanently stain soft contact lenses, and you should not wear them while taking this medicine.
This medication can cause you to have false results with glucose or ketone urine tests. Tell any doctor who treats you that you are using phenazopyridine.
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.
Overdose symptoms may include yellowed skin, fever, confusion, weakness, urinating less than usual, nausea, vomiting, swelling, numbness, or blue-colored skin.
Avoid wearing soft contact lenses while you are taking phenazopyridine. The medication can cause permanent staining of soft contact lenses.
pale skin, fever, confusion or weakness;
jaundice (yellowing of your skin or eyes);
urinating less than usual or not at all;
drowsiness, confusion, mood changes, increased thirst, loss of appetite, nausea and vomiting;
swelling, weight gain, feeling short of breath; or
blue or purple coloring in your skin.
Less serious side effects may include:
headache;
dizziness;
stomach pain, upset stomach; or
skin 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.
There may be other drugs that can interact with phenazopyridine. 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.
See also: Re-Azo side effects (in more detail)
Ceftriaxona Labesfal may be available in the countries listed below.
Ceftriaxone disodium salt (a derivative of Ceftriaxone) is reported as an ingredient of Ceftriaxona Labesfal in the following countries:
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Ecovitamine B12 may be available in the countries listed below.
Cyanocobalamin is reported as an ingredient of Ecovitamine B12 in the following countries:
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Vita E may be available in the countries listed below.
Tocopherol, α- is reported as an ingredient of Vita E in the following countries:
Tocopherol, α- acetate (a derivative of Tocopherol, α-) is reported as an ingredient of Vita E in the following countries:
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Amitriptylin Valeant may be available in the countries listed below.
Amitriptyline hydrochloride (a derivative of Amitriptyline) is reported as an ingredient of Amitriptylin Valeant in the following countries:
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Hexamic may be available in the countries listed below.
Tranexamic Acid is reported as an ingredient of Hexamic in the following countries:
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Rubina may be available in the countries listed below.
Epirubicin hydrochloride (a derivative of Epirubicin) is reported as an ingredient of Rubina in the following countries:
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Pottie's Green Ointment may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Dichlorophen is reported as an ingredient of Pottie's Green Ointment in the following countries:
Salicylic Acid is reported as an ingredient of Pottie's Green Ointment in the following countries:
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In the US, Liberate is a member of the drug class miscellaneous coagulation modifiers and is used to treat Hemophilia A.
Coagulation Factor VIII, Human is reported as an ingredient of Liberate in the following countries:
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Microgynon 30 Dr.Fisher may be available in the countries listed below.
Ethinylestradiol is reported as an ingredient of Microgynon 30 Dr.Fisher in the following countries:
Levonorgestrel is reported as an ingredient of Microgynon 30 Dr.Fisher in the following countries:
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Timopress may be available in the countries listed below.
Timolol maleate (a derivative of Timolol) is reported as an ingredient of Timopress in the following countries:
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Plegomazin may be available in the countries listed below.
Chlorpromazine hydrochloride (a derivative of Chlorpromazine) is reported as an ingredient of Plegomazin in the following countries:
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Piperacillin DeltaSelect may be available in the countries listed below.
Piperacillin sodium salt (a derivative of Piperacillin) is reported as an ingredient of Piperacillin DeltaSelect in the following countries:
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Pantul may be available in the countries listed below.
Pantoprazole sodium (a derivative of Pantoprazole) is reported as an ingredient of Pantul in the following countries:
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Méquinol may be available in the countries listed below.
Méquinol (DCF) is known as Mequinol in the US.
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Glossary
| DCF | Dénomination Commune Française |
Opipra TAD may be available in the countries listed below.
Opipramol dihydrochloride (a derivative of Opipramol) is reported as an ingredient of Opipra TAD in the following countries:
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Phenaemal may be available in the countries listed below.
Phenobarbital is reported as an ingredient of Phenaemal in the following countries:
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Bétaméthasone EG may be available in the countries listed below.
Betamethasone is reported as an ingredient of Bétaméthasone EG in the following countries:
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Oxykel may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Oxytetracycline hydrochloride (a derivative of Oxytetracycline) is reported as an ingredient of Oxykel in the following countries:
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Vicks Paracetamol may be available in the countries listed below.
Paracetamol is reported as an ingredient of Vicks Paracetamol in the following countries:
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Paclitaxel Fresenius may be available in the countries listed below.
Paclitaxel is reported as an ingredient of Paclitaxel Fresenius in the following countries:
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In the US, Soma Compound (aspirin/carisoprodol systemic) is a member of the drug class skeletal muscle relaxant combinations and is used to treat Muscle Pain and Muscle Spasm.
US matches:
Acetylsalicylic Acid is reported as an ingredient of Soma Compound in the following countries:
Carisoprodol is reported as an ingredient of Soma Compound in the following countries:
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Prednison Galen may be available in the countries listed below.
Prednisone is reported as an ingredient of Prednison Galen in the following countries:
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Phenprocoumon ratiopharm may be available in the countries listed below.
Phenprocoumon is reported as an ingredient of Phenprocoumon ratiopharm in the following countries:
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Emovat may be available in the countries listed below.
Clobetasone 17α-butyrate (a derivative of Clobetasone) is reported as an ingredient of Emovat in the following countries:
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Prescribing Information
Patients should be counseled that this product doesnot protect against HIV infection (AIDS) and othersexually transmitted diseases.
Reclipsen™ 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) and 0.03 mg ethinyl estradiol (19-nor-17 alpha-pregna-1,3,5 (10)- trien-20-yne-3, 17, diol). Inactive ingredients include anhydrous lactose, colloidal silicon dioxide, corn starch, povidone, stearic acid and vitamin E. Reclipsen also contains 7 green tablets containing the following inactive ingredients: anhydrous lactose, D&C Yellow No. 10, FD&C Blue No. 2, magnesium stearate and microcrystalline cellulose.
desogestrel
ethinyl estradiol
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.
Receptor binding studies, as well as studies in animals, have shown that 3-keto-desogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with minimal intrinsic androgenicity91,92. The relevance of this latter finding in humans is unknown.
Desogestrel is rapidly and almost completely absorbed and converted into 3-keto-desogestrel, its biologically active metabolite. Following oral administration, the relative bioavailability of desogestrel, as measured by serum levels of 3-ketodesogestrel, is approximately 84%.
In the third cycle of use after a single dose of Reclipsen™, maximum concentrations of 3-ketodesogestrel of 2,805 ± 1,203 pg/mL (mean ± SD) are reached at 1.4 ± 0.8 hours. The area under the curve (AUC0-∞) is 33,858 ± 11,043 pg/mL•hr after a single dose. At steady state, attained from at least day 19 onwards, maximum concentrations of 5,840 ± 1,667 pg/mL are reached at 1.4 ± 0.9 hours. The minimum plasma levels of 3-keto-desogestrel at steady state are 1,400 ± 560 pg/mL. The AUC0-24 at steady state is 52,299 ± 17,878 pg/mL•hr. The mean AUC0-∞ for 3-keto-desogestrel at single dose is significantly lower than the mean AUC0-24 at steady state. This indicates that the kinetics of 3-keto-desogestrel are non-linear due to an increase in binding of 3-ketodesogestrel to sex hormone-binding globulin in the cycle, attributed to increased sex hormone-binding globulin levels which are induced by the daily administration of ethinyl estradiol. Sex hormonebinding globulin levels increased significantly in the third treatment cycle from day 1 (150 ± 64 nmol/L) to day 21 (230 ± 59 nmol/L).
The elimination half-life for 3-keto-desogestrel is approximately 38 ± 20 hours at steady state. In addition to 3-keto-desogestrel, other phase I metabolites are 3α-OH-desogestrel, 3β-OH-desogestrel, and 3α-OH-5α-H-desogestrel. These other metabolites are not known to have any pharmacologic effects, and are further converted in part by conjugation (phase II metabolism) into polar metabolites, mainly sulfates and glucuronides.
Ethinyl estradiol is rapidly and almost completely absorbed. In the third cycle of use after a single dose of Reclipsen, the relative bioavailability is approximately 83%.
In the third cycle of use after a single dose of Reclipsen, maximum concentrations of ethinyl estradiol of 95 ± 34 pg/mL are reached at 1.5 ± 0.8 hours. The AUC0-∞ is 1,471 ± 268 pg/mL•hr after a single dose. At steady state, attained from at least day 19 onwards, maximum ethinyl estradiol concentrations of 141 ± 48 pg/mL are reached at about 1.4 ± 0.7 hours. The minimum serum levels of ethinyl estradiol at steady state are 24 ± 8.3 pg/mL. The AUC0-24, at steady state is 1,117 ± 302 pg/mL•hr. The mean AUC0-∞ for ethinyl estradiol following a single dose during treatment cycle 3 does not significantly differ from the mean AUC0-24 at steady state. This finding indicates linear kinetics for ethinyl estradiol.
The elimination half-life is 26 ± 6.8 hours at steady state. 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.
Reclipsen™ Tablets are indicated for the prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception.
Oral contraceptives are highly effective. Table I 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.
| TABLE I: 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. | |||
| % of Women Experiencing an Unintended Pregnancy within the First Year of Use | % of Women Continuing Use at One Year 3 | ||
| Method (1) | Typical Use 1 (2) | Perfect Use 2 (3) | (4) |
| Chance 4 | 85 | 85 | |
| Spermicides 5 | 26 | 6 | 40 |
| Periodic abstinence | 25 | 63 | |
| Calendar | 9 | ||
| Ovulation Method | 3 | ||
| Sympto-Thermal 6 | 2 | ||
| Post-Ovulation | 1 | ||
| Withdrawal | 19 | 4 | |
| Cap 7 | |||
| Parous Women | 40 | 26 | 42 |
| Nulliparous Women | 20 | 9 | 56 |
| Sponge | |||
| Parous Women | 40 | 20 | 42 |
| Nulliparous Women | 20 | 9 | 56 |
| Diaphragm 7 | 20 | 6 | 56 |
| Condom 8 | |||
| 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 |
| Adapted from Hatcher et al,1998,Ref.#1. | |||
| 1 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. | |||
| 2 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. | |||
| 3 Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. | |||
| 4 The percents becoming pregnant 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% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percent who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether. | |||
| 5 Foams, creams, gels, vaginal suppositories, and vaginal film. | |||
| 6 Cervical mucus (ovulation) method supplemented by calendar in the preovulatory and basal body temperature in the post-ovulatory phases. | |||
| 7 With spermicidal cream or jelly. | |||
| 8 Without spermicides. | |||
In a clinical trial with desogestrel and ethinyl estradiol tablets USP, 1,195 subjects completed 11,656 cycles and a total of 10 pregnancies were reported. This represents an overall user-efficacy (typical user-efficacy) pregnancy rate of 1.12 per 100 women-years. This rate includes patients who did not take the drug correctly.
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
Known or suspected carcinoma of the breast
Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia
Undiagnosed abnormal genital bleeding
Cholestatic jaundice of pregnancy or jaundice with prior pill use
Hepatic adenomas or carcinomas
Known or suspected pregnancy
| 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 are 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, 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 (Adapted from refs. 2 and 3 with the author’s permission). For further information, the reader is referred to a text on epidemiological methods.
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 risk of thromboembolic disease associated with oral contraceptives is not related to length of use and disappears after pill use is stopped. Several epidemiologic studies indicate that third generation oral contraceptives, containing desogestrel, are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives. In general, these studies indicate an approximate 2-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 2-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 contraceptives9. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions26. 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.
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 six4-10. 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 infarctions in women in their midthirties or older with smoking accounting for the majority of excess cases11. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older among women who use oral contraceptives. (See Table II)
TABLE II (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 obesity13. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism14-18. 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.
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, and smoking interacted to increase the risk of stroke27-29.
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 hypertension30. 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 hypertension30. The attributable risk is also greater in older women3.
A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease31-33. A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents14-16. 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.
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 groups8. 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 small34. However, both studies were performed with oral contraceptive formulations containing 0.050 mg 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 III). 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 an increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970’s35. Current clinical recommendation involves the use of lower estrogen dose formulations and a careful consideration of risk factors. In 1989, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the use of oral contraceptives in women 40 years of age and over. The Committee concluded that although cardiovascular disease risk may be increased with oral contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are 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. 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 an oral contraceptive which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and individual patient needs.
| Method of control and outcome | 15-19 | 20-24 | 25-29 | 30-34 | 35-39 | 40-44 |
| No fertility | 7.0 | 7.4 | 9.1 | 14.8 | 25.7 | 28.2 |
| control methods* | ||||||
| Oral contraceptives | 0.3 | 0.5 | 0.9 | 1.9 | 13.8 | 31.6 |
| non-smoker ** | ||||||
| Oral contraceptives | 2.2 | 3.4 | 6.6 | 13.5 | 51.1 | 117.2 |
| smoker ** | ||||||
| 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/ | 1.9 | 1.2 | 1.2 | 1.3 | 2.2 | 2.8 |
| spermicide * | ||||||
| Periodic abstinence * | 2.5 | 1.6 | 1.6 | 1.7 | 2.9 | 3.6 |
| * Deaths are birth-related | ||||||
| ** Deaths are method-related | ||||||
| Adapted from H.W.Ory, ref. #35. | ||||||
Numerous epidemiological 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 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 has been reported to be related to duration of use36-44,79-89.
A meta-analysis of 54 studies found a small increase in the frequency of having breast cancer diagnosed for women who were currently using combined oral contraceptives or had used them within the past ten years. This increase in the frequency of breast cancer diagnosis, within ten years of stopping use, was generally accounted for by cancers localized to the breast. There was no increase in the frequency of having breast cancer diagnosed ten or more years after cessation of use101.
Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women45-48. 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 dose49. Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage50,51. Studies have shown an increased risk of developing hepatocellular carcinoma52-54,102 in oral contraceptive users. However, these cancers are rare in the U.S.
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 epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy56-57. The majority of recent studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned55,56,58,59, 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 time of 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 estrogens60,61. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal62-64. 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 users17. This effect has been shown to be directly related to estrogen dose65. In general, progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents17,66. In the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose67. 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 contraceptives68 and this increase is more likely in older oral contraceptive users69 and with extended duration of use61. Data from the Royal College of General Practitioners12 and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity.
Women with a history of hypertension or hypertension-related diseases, or renal disease70 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 contraceptives69, and there is no difference in the occurrence of hypertension among former and never users68,70,71.
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. Nonhormonal 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 failures.
It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.
Women who are being treated for hyperlipidemias should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult.
If jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.
Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.
Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.
Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.
Reduced efficacy and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin. A similar association, though less marked, has been suggested with barbiturates, phenylbutazone, phenytoin sodium, carbamazepine and possibly with griseofulvin, ampicillin and tetracyclines72.
Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:
Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.
Other binding proteins may be elevated in serum.
Sex hormone binding globulins are increased and result in elevated levels of total circulating sex steroids however, free or biologically active levels either decrease or remain unchanged.
High-density lipoprotein (HDL-C) and triglycerides may be increased, while low-density lipoprotein cholesterol (LDL-C) and total cholesterol (Total-C) may be decreased or unchanged.
Glucose tolerance may be decreased.
Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.
See WARNINGS section.
Pregnancy Category X. See CONTRAINDICATIONS and WARNINGS sections.
Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.
Safety and efficacy of Reclipsen Tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
INFORMATION FOR THE PATIENT
See Patient Labeling Printed Below
An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS section).
Thrombophlebitis and venous thrombosis with or without embolism
Arterial thromboembolism
Pulmonary embolism
Myocardial infarction
Cerebral hemorrhage
Cerebral thrombosis
Hypertension
Gallbladder disease
Hepatic adenomas or benign liver tumors
The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug-related:
Nausea
Vomiting
Gastrointestinal symptoms (such as abdominal cramps and bloating)
Breakthrough bleeding
Spotting
Change in menstrual flow
Amenorrhea
Temporary infertility after discontinuation of treatment
Edema
