Solescope

Solescope may be available in the countries listed below.

Ingredient matches for Solescope

Glutaral

Glutaral is reported as an ingredient of Solescope in the following countries:

• Japan

International Drug Name Search

Doxorubicin

In some countries, this medicine may only be approved for veterinary use.

In the US, Doxorubicin (doxorubicin systemic) is a member of the drug class antibiotics/antineoplastics and is used to treat Acute Lymphoblastic Leukemia, Acute Myeloblastic Leukemia, Bladder Cancer, Breast Cancer, Cancer, Hodgkin's Lymphoma, Lung Cancer, Lymphoma, Multiple Myeloma, Neuroblastoma, Osteosarcoma, Ovarian Cancer, Soft Tissue Sarcoma, Stomach Cancer, Thyroid Cancer and Wilms' Tumor.

US matches:

• Doxorubicin


• Doxorubicin Liposomal


• Doxorubicin Intravenous


• Doxorubicin hydrochloride liposome Intravenous


• Doxorubicin Hydrochloride


• Doxorubicin, Conventional


• Doxorubicin, Liposomal

UK matches:

• Doxorubicin Hydrochloride 2mg/ml solution for infusion (hameln) (SPC)
• Doxorubicin hydrochloride 50mg Powder for Injection (SPC)
• Doxorubicin Hydrochloride for Injection 10 mg and 50 mg (SPC)
• Doxorubicin Rapid Dissolution (SPC)
• Doxorubicin Solution for Injection (SPC)

Scheme

Rec.INN

ATC (Anatomical Therapeutic Chemical Classification)

L01DB01

CAS registry number (Chemical Abstracts Service)

0023214-92-8

Chemical Formula

C27-H29-N-O11

Molecular Weight

543

Therapeutic Category

Antineoplastic antibacterial

Chemical Name

5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, (8S-cis)-

Foreign Names

• Doxorubicinum (Latin)
• Doxorubicin (German)
• Doxorubicine (French)
• Doxorubicina (Spanish)

Generic Names

• Doxorubicin (OS: USAN, BAN)
• Doxorubicina (OS: DCIT)
• Doxorubicine (OS: DCF)
• ADM (IS)
• Adryamicin (IS)
• DOX (IS)
• FI 106 (IS)
• Hydroxy-14 daunomycine (IS)
• Hydroxydaunorubicin (IS)
• NSC 123127 (IS)
• Doxorubicin Hydrochloride (OS: BANM, JAN)
• Doxorubicin Hydrochloride (PH: BP 2010, Ph. Eur. 6, Ph. Int. 4, USP 32, JP XV)
• Doxorubicine (chlorhydrate de) (PH: Ph. Eur. 6)
• Doxorubicinhydrochlorid (PH: Ph. Eur. 6)
• Doxorubicini hydrochloridum (PH: Ph. Int. 4, Ph. Eur. 6)

Brand Names

• Adriamycin
  Pfizer, New Zealand



• Adriblastina RD
  Pharmacia, Poland



• Adriblastina
  Pfizer, Luxembourg; Pfizer, Slovenia; Pfizer, Tunisia



• Adrim
  Biogalenic, Venezuela



• Caelyx
  Schering-Plough, Portugal



• Dicladox
  Ivax, Argentina; Ivax, Peru



• Doxonolver
  Nolver, Venezuela



• Doxopeg
  Raffo, Argentina



• Doxorrubicina Farma-Aps
  Aps, Portugal



• Doxorubicin Ebewe
  Ebewe, Israel; Ebewe, Tunisia; Ebewe, Vietnam; InterPharma, New Zealand



• Doxorubicin
  Mayne, Ireland; Pharmachemie, Peru



• Doxorubicina Doxolem
  Lemery, Peru



• Doxorubicina
  Baxter, Chile; Kampar, Chile; Pfizer, Peru; Servycal, Peru



• Doxorubicin-KMP
  Arterium, Georgia



• Robanul
  Richmond, Peru



• Adriablastina
  Pfizer, Bosnia & Herzegowina



• Adriacin
  Kyowa Hakko Kirin, Japan



• Adriamycin RDF
  Pfizer, United States



• Adriamycin
  Bedford, United States; Pfizer, Australia; Pfizer, Denmark; Pfizer, Finland; Pfizer, Iceland; Pfizer, Norway; Pfizer, Singapore



• Adriamycin PFS
  Pfizer, Canada; Pfizer, United States



• Adriblastin
  Abic, Israel; Pfizer, Austria; Pfizer, Switzerland; Pfizer, Germany



• Adriblastina CS
  Pfizer, Colombia; Pfizer, Czech Republic



• Adriblastina PFS
  Pfizer, Croatia (Hrvatska); Pfizer, Israel; Pfizer, Poland; Pfizer, Romania; Pharmacia Enterprises, Slovakia; Sindan, Romania



• Adriblastina RD
  Pfizer, Bulgaria; Pfizer, Mexico; Pfizer, Romania; Pfizer, Serbia; Pfizer, Thailand; Pfizer, Taiwan; Pfizer, Vietnam; Sindan, Romania



• Adriblastina RTU
  Pfizer, Chile



• Adriblastina
  Deva, Turkey; Pfizer, Belgium; Pfizer, Estonia; Pfizer, Greece; Pfizer, Hungary; Pfizer, Italy; Pfizer, Lithuania; Pfizer, Latvia; Pfizer, Oman; Pfizer, Philippines; Pfizer, Singapore; Pfizer, Venezuela; Pfizer, South Africa; Pfizer Pharma, Ethiopia; Pharmacia, Bahrain; Pharmacia, Ghana; Pharmacia, Kenya; Pharmacia, Liberia; Pharmacia, Luxembourg; Pharmacia, Sierra Leone; Pharmacia, Tanzania; Pharmacia, Uganda; Pharmacia, Zimbabwe; Pharmacia & Upjohn, Georgia



• Adriblastine
  Pfizer, France



• Adricin
  Korea United Pharm, Georgia; Novell, Indonesia



• Adrim
  Dabur, Georgia; Dabur, India; Dabur, Sri Lanka; Dabur, Myanmar; Dabur, Philippines



• Adrimedac
  Medac, Germany; Medac, Luxembourg; Medac, Poland



• Biorrub
  Biosintética, Brazil



• Biorubina
  Inst. Biotechn. i Antybiotykow, Poland



• Caelyx
  Bayer Schering, Iran; Essex, Germany; Essex Chemie, Switzerland; Kirby, Ecuador; Schering, United Arab Emirates; Schering, Egypt; Schering, Iraq; Schering, Jordan; Schering, Kuwait; Schering, Lebanon; Schering, Qatar; Schering, Saudi Arabia; Schering, Yemen; Schering-Plough, Argentina; Schering-Plough, Australia; Schering-Plough, Bangladesh; Schering-Plough, Belgium; Schering-Plough, Bahrain; Schering-Plough, Brazil; Schering-Plough, Canada; Schering-Plough, Chile; Schering-Plough, Costa Rica; Schering-Plough, Czech Republic; Schering-Plough, Dominican Republic; Schering-Plough, Spain; Schering-Plough, Finland; Schering-Plough, France; Schering-Plough, United Kingdom; Schering-Plough, Greece; Schering-Plough, Guatemala; Schering-Plough, Hong Kong; Schering-Plough, Honduras; Schering-Plough, Hungary; Schering-Plough, Indonesia; Schering-Plough, Ireland; Schering-Plough, Iceland; Schering-Plough, Italy; Schering-Plough, Luxembourg; Schering-Plough, Mexico; Schering-Plough, Malaysia; Schering-Plough, Nicaragua; Schering-Plough, Norway; Schering-Plough, New Zealand; Schering-Plough, Oman; Schering-Plough, Panama; Schering-Plough, Peru; Schering-Plough, Philippines; Schering-Plough, Romania; Schering-Plough, Serbia; Schering-Plough, Russian Federation; Schering-Plough, Sweden; Schering-Plough, Singapore; Schering-Plough, Slovenia; Schering-Plough, Slovakia; Schering-Plough, El Salvador; Schering-Plough, Syria; Schering-Plough, Thailand; Schering-Plough, Turkey; Schering-Plough, Taiwan; Schering-Plough, Venezuela; Schering-Plough, South Africa; SP Europe, Austria; SP Europe, Denmark; SP Europe, Netherlands



• Colhidrol
  Teva, Argentina



• Daxotel
  Chile, Chile



• Doxil
  Alza, Israel; Ortho Biotech, United States



• Doxo Ebewe
  OncoCorp, Germany



• Doxo-cell
  Cell pharm, Germany; Eurogenerics, Luxembourg; Stada, Austria



• Doxocris
  LKM, Argentina



• Doxokebir
  Aspen, Argentina



• Doxolem
  Lemery, Peru; Lemery, Romania; Medicom, Czech Republic; Zodiac, Brazil



• Doxopeg
  Asofarma, Mexico; Tecnofarma, Chile



• Doxorrubicina Delta Farma
  Delta Farma, Argentina



• Doxorubicin Actavis
  Actavis, Switzerland



• Doxorubicin APP
  Abraxis, Switzerland



• Doxorubicin Bendalis
  Bendalis, Germany



• Doxorubicin Ebewe
  Ebewe, Austria; Ebewe, Bulgaria; Ebewe, Czech Republic; Ebewe, Estonia; Ebewe, Georgia; Ebewe, Hungary; Ebewe, Indonesia; Ebewe, Lithuania; Ebewe, Latvia; Ebewe, Myanmar; Ebewe, Poland; Ebewe, Romania; Ebewe, Serbia; Ebewe, Russian Federation; Ferron, Indonesia; Sandoz, Switzerland; Würth, Croatia (Hrvatska)



• Doxorubicin Hexal
  Hexal, Germany



• Doxorubicin Hydrochloride DBL
  Hospira, Indonesia; Tempo Scan Pacific, Indonesia



• Doxorubicin Hydrochloride Ebewe
  Pharmanel, Greece



• Doxorubicin Hydrochloride
  APP, United States; Baxter, United States; Bedford, United States; Hospira, Australia; Hospira, Canada; Hospira, New Zealand; Hospira, Singapore; Meiji, China; Pharmachemie, United States; Sicor, United States; Teva USA, United States



• Doxorubicin Hydrochloride-Shantou Meiji
  Shantou Meiji, China



• Doxorubicin Kalbe
  Kalbe, Indonesia



• Doxorubicin Lachema
  Lachema, Czech Republic; Pliva, Latvia



• Doxorubicin Meda
  Meda, Denmark; Meda, Sweden



• Doxorubicin Meiji
  Biochem, India



• Doxorubicin NC
  NeoCorp, Germany



• Doxorubicin PCH
  Pharmachemie, South Africa



• Doxorubicin Pfizer
  Pfizer, Philippines



• Doxorubicin Pharmachemie
  Pharmachemie, Sri Lanka



• Doxorubicin Pharmacia
  Pfizer, Vietnam



• Doxorubicin Pliva
  Pliva, Bosnia & Herzegowina; Pliva, Croatia (Hrvatska); Pliva, Slovenia; Pliva, Slovakia



• Doxorubicin Sandoz
  Sandoz, Switzerland



• Doxorubicin Stada
  Cell Pharm, Bulgaria; Stada, Austria



• Doxorubicin Teva
  Providens, Croatia (Hrvatska); Teva, Czech Republic; Teva, Hungary; Teva, Israel; Teva, Lithuania; Teva, Latvia; Teva, Romania; Teva, Sweden; Teva Pharma, Switzerland



• Doxorubicin
  Chemipharm, Greece; Combiphar, Indonesia; Khandelwal, India; Mayne, Ireland; Meda, Norway; Pfizer, United Kingdom; Pfizer, Malta; Pharmachemie, Iceland; Pliva, Bosnia & Herzegowina



• Doxorubicin (veterinary use)
  Pfizer Animal Health, United Kingdom



• Doxorubicina Asofarma
  Raffo, Argentina



• Doxorubicina Ebewe
  Ebewe, Italy



• Doxorubicina Ferrer Farm
  Ferrer, Spain



• Doxorubicina Filaxis
  Filaxis, Argentina



• Doxorubicina Gador
  Gador, Argentina



• Doxorubicina Rontag
  Rontag, Argentina



• Doxorubicina RU
  World Pharma, Peru



• Doxorubicina Servycal
  Servycal, Argentina



• Doxorubicina Tedec
  Tedec Meiji, Spain



• Doxorubicina
  Pfizer, Chile



• Doxorubicine Actavis
  Actavis, France



• Doxorubicine Baxter
  Baxter, France



• Doxorubicine CF
  Centrafarm, Netherlands



• Doxorubicine Dakota Pharm
  Sanofi-Aventis, France



• Doxorubicine Ebewe
  Ebewe, Belgium; Ebewe, France; Ebewe, Netherlands



• Doxorubicine G Gam
  Sandoz, France



• Doxorubicine HCl Kohne
  Kohne, Netherlands



• Doxorubicine HCl Sandoz
  Sandoz, Netherlands



• Doxorubicine PCH
  Pharmachemie, Netherlands



• Doxorubicine Teva
  Teva Santé, France



• Doxorubin
  Emporio, Slovenia; Khandelwal, Myanmar; Medac, United Arab Emirates; Medac, Bahrain; Medac, Egypt; Medac, United Kingdom; Medac, Iraq; Medac, Iran; Medac, Jordan; Medac, Kuwait; Medac, Lebanon; Medac, Oman; Medac, Qatar; Medac, Saudi Arabia; Medac, Syria; Medac, Yemen; Pharmachemie, Indonesia; Pharmachemie, Malaysia; Pharmachemie, Netherlands; Pharmachemie, Peru; Teva, Belgium



• Doxoteva
  Med, Turkey



• Doxotil
  Genepharm, Greece



• Doxtie
  Armstrong, Mexico; Bagó, Ecuador; Bioprofarma, Argentina



• Farmiblastina
  Pfizer, Spain



• Lipo-dox
  TTY Biopharm, Taiwan



• Myocet
  Cephalon, Germany; Cephalon, Spain; Cephalon, Finland; Cephalon, France; Cephalon, United Kingdom; Cephalon, Hungary; Cephalon, Ireland; Cephalon, Italy; Cephalon, Luxembourg; Cephalon, Sweden; Cephalon, Slovakia; Cephalon Pharma, Denmark; Elan, Netherlands; Elan, Norway; Wyeth, Greece; Zeneus, Austria; Zeneus, Belgium; Zeneus, Czech Republic



• Nagun
  Dosa, Argentina



• Onkostatil
  Microsules, Argentina



• Rastocin
  Pliva, Georgia; Pliva, Poland; Pliva, Russian Federation



• Ribodoxo
  Hikma, Germany



• Roxorin
  Richmond, Argentina; Richmond, Peru



• Rubex
  Bristol-Myers Squibb, United States



• Rubidox
  Medicus, Greece



• Sindroxocin
  Sindan, Romania



• Varidoxo
  Varifarma, Argentina

International Drug Name Search

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)
SPC	Summary of Product Characteristics (UK)
USAN	United States Adopted Name

Click for further information on drug naming conventions and International Nonproprietary Names.

Mogine

Mogine may be available in the countries listed below.

Ingredient matches for Mogine

Lamotrigine

Lamotrigine is reported as an ingredient of Mogine in the following countries:

• New Zealand

International Drug Name Search

Theofibrate

Theofibrate may be available in the countries listed below.

Ingredient matches for Theofibrate

Etofylline Clofibrate

Theofibrate (USAN) is also known as Etofylline Clofibrate (Rec.INN)

International Drug Name Search

Glossary

Rec.INN	Recommended International Nonproprietary Name (World Health Organization)
USAN	United States Adopted Name

Click for further information on drug naming conventions and International Nonproprietary Names.

Dealyd

Dealyd may be available in the countries listed below.

Ingredient matches for Dealyd

Phloroglucinol

Phloroglucinol polymer dihydrogen phosphate (a derivative of Phloroglucinol) is reported as an ingredient of Dealyd in the following countries:

• Austria

International Drug Name Search

Ortho-Novum

Dosage Form: tablets
Ortho-Novum® Tablets (norethindrone/ethinyl estradiol)

and MODICON® Tablets (norethindrone/ethinyl estradiol)

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

COMBINED ORAL CONTRACEPTIVES

Each of the following products is a combined oral contraceptive containing the progestational compound norethindrone and the estrogenic compound ethinyl estradiol.

Ortho-Novum® 7/7/7 Tablets

Each white tablet contains 0.5 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include lactose, magnesium stearate and pregelatinized corn starch. Each light peach tablet contains 0.75 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include FD&C Yellow No. 6, lactose, magnesium stearate and pregelatinized corn starch. Each peach tablet contains 1 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include FD&C Yellow No. 6, lactose, magnesium stearate and pregelatinized corn starch. Each green tablet contains only inert ingredients, as follows: D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, lactose, magnesium stearate, microcrystalline cellulose and pregelatinized corn starch.

Ortho-Novum® 1/35 Tablets

Each peach tablet contains 1 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include FD&C Yellow No. 6, lactose, magnesium stearate and pregelatinized corn starch. Each green tablet contains only inert ingredients, as listed under green tablets in Ortho-Novum® 7/7/7.

MODICON® Tablets

Each white tablet contains 0.5 mg of norethindrone and 0.035 mg of ethinyl estradiol. Inactive ingredients include lactose, magnesium stearate and pregelatinized corn starch. Each green tablet contains only inert ingredients, as listed under green tablets in Ortho-Novum® 7/7/7.

The chemical name for norethindrone is 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one, and for ethinyl estradiol is 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol. Their structural formulas are as follows:

Ortho-Novum - Clinical Pharmacology

COMBINED ORAL CONTRACEPTIVES

Combined 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).

Indications and Usage for Ortho-Novum

Ortho-Novum® 7/7/7, Ortho-Novum® 1/35, and MODICON® 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 I lists the typical accidental pregnancy rates for users of combined oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and the NORPLANT® System depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

Table 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*
Method (1)	Typical Use † (2)	Perfect Use‡ (3)	(4)
Adapted from Hatcher et al, 1998, Ref. # 1.
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.§
Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.¶
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.
* Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year. † Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. ‡ Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason. § The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral® (1 dose is 2 white pills), Alesse® (1 dose is 5 pink pills), Nordette® or Levlen® (1 dose is 2 light-orange pills), Lo/Ovral® (1 dose is 4 white pills), Triphasil® or Tri-Levlen® (1 dose is 4 yellow pills). ¶ However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches six months of age. # 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. Þ Foams, creams, gels, vaginal suppositories, and vaginal film. ß Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases. à With spermicidal cream or jelly. è Without spermicides.
Chance#	85	85
SpermicidesÞ	26	6	40
Periodic abstinence	25		63
Calendar		9
Ovulation Method		3
Sympto-Thermalß		2
Post-Ovulation		1
Capà
Parous Women	40	26	42
Nulliparous Women	20	9	56
Sponge
Parous Women	40	20	42
Nulliparous Women	20	9	56
Diaphragmà	20	6	56
Withdrawal	19	4
Condomè
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 T380A	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

Ortho-Novum® 7/7/7, Ortho-Novum® 1/35 and MODICON® have not been studied for and are not indicated for use in emergency contraception.

Contraindications

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

• Thrombophlebitis or thromboembolic disorders


• A past history of deep vein thrombophlebitis or thromboembolic disorders


• Cerebral vascular or coronary artery disease (current or history)


• Valvular heart disease with complications


• Severe hypertension


• Diabetes with vascular involvement


• Headaches with focal neurological symptoms


• Major surgery with prolonged immobilization


• 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


• Acute or chronic hepatocellular disease with abnormal liver function


• Hepatic adenomas or carcinomas


• Known or suspected pregnancy


• Hypersensitivity to any component of this product

Warnings

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with 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 higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined.

Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population (adapted from refs. 2 and 3 with the author's permission). For further information, the reader is referred to a text on epidemiological methods.

1. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS

a. Myocardial Infarction

An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six.4–10 The risk is very low under the age of 30.

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

(Adapted from P.M. Layde and V. Beral, ref. #12.)

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

b. Thromboembolism

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to 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.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

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

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, and smoking interacted to increase the risk of stroke.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 activity of the progestogen used in the contraceptives. The activity and amount of both hormones should be considered in the choice of an oral contraceptive.

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

e. Persistence of risk of vascular disease

There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40–49 years 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 higher of estrogens.

2. ESTIMATES OF MORTALITY FROM CONTRACEPTIVE USE

One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table 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's.35 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 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. 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.

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

Method of control and outcome	15–19	20–24	25–29	30–34	35–39	40–44
Adapted from H.W. Ory, ref. #35.
* Deaths are birth-related † Deaths are method-related
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

3. CARCINOMA OF THE REPRODUCTIVE ORGANS AND BREASTS

Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian and cervical cancer in women using oral contraceptives. The risk of having breast cancer diagnosed may be slightly increased among current and recent users of COCs. However, this excess risk appears to decrease over time after COC discontinuation and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have found a small increase in risk for women who first use COCs before age 20. Most studies show a similar pattern of risk with COC use regardless of a woman's reproductive history or her family breast cancer history.

Breast cancers diagnosed in current or previous OC users tend to be less clinically advanced than in nonusers.

Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is usually a hormonally-sensitive tumor.

Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women.45–48 However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.

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

4. HEPATIC NEOPLASIA

Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use especially with oral contraceptives of higher dose.49 Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage.50, 51

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

5. OCULAR LESIONS

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

6. ORAL CONTRACEPTIVE USE BEFORE OR DURING EARLY PREGNANCY

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.56,57 The majority of recent studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned,55,56,58,59 when 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. 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 if pregnancy is confirmed.

7. GALLBLADDER DISEASE

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.

8. CARBOHYDRATE AND LIPID METABOLIC EFFECTS

Oral contraceptives have been shown to cause a decrease in glucose tolerance in a significant percentage of users.17 This effect has been shown to be directly related to estrogen dose.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 in particular 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 1a and 1d), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.

9. ELEVATED BLOOD PRESSURE

Women with significant hypertension should not be started on hormonal contraception.92 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 use.61 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 contraceptives, and there is no difference in the occurrence of hypertension between former and never users.68–71

10. HEADACHE

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.

11. BLEEDING IRREGULARITIES

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 preexistent.

12. ECTOPIC PREGNANCY

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

Precautions

1. GENERAL

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

2. PHYSICAL EXAMINATION AND FOLLOW-UP

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.

3. LIPID DISORDERS

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.

4. LIVER FUNCTION

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.

5. FLUID RETENTION

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.

6. EMOTIONAL DISORDERS

Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.

7. CONTACT LENSES

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

8. DRUG INTERACTIONS

Changes in contraceptive effectiveness associated with co-administration of other products:

Contraceptive effectiveness may be reduced when hormonal contraceptives are co-administered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include rifampin, barbiturates, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin and bosentan. Several cases of contraceptive failure and breakthrough bleeding have been reported in the literature with concomitant administration of antibiotics such as ampicillin and tetracyclines. However, clinical pharmacology studies investigating drug interaction between combined oral contraceptives and these antibiotics have reported inconsistent results.

Several of the anti-HIV protease inhibitors have been studied with co-administration of oral combined hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of oral contraceptive products may be affected with co-administration of anti-HIV protease inhibitors. Healthcare professionals should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information.

Herbal products containing St. John's Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.

Concurrent use of bosentan and norethisterone/ethinyl estradiol may result in decreased concentrations of these contraceptive hormones, thereby increasing the risk of unintended pregnancy and unscheduled bleeding.

Increase in plasma levels associated with co-administered drugs:

Co-administration of atorvastatin and certain oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP 3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels.

Changes in plasma levels of co-administered drugs:

Combined hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporin, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine and clofibric acid, due to induction of conjugation, have been noted when these drugs were administered with oral contraceptives.

Combined hormonal contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.95

Healthcare professionals are advised to also refer to prescribing information of co-administered drugs for recommendations regarding management of concomitant therapy.

9. INTERACTIONS WITH LABORATORY TESTS

Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:

1. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.


2. 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.


3. Other binding proteins may be elevated in serum.


4. Sex-binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged.


5. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.


6. Glucose tolerance may be decreased.


7. 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.

10. CARCINOGENESIS

See WARNINGS.

11. PREGNANCY

Pregnancy Category X

See CONTRAINDICATIONS and WARNINGS.

12. NURSING MOTHERS

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, combined 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 combined oral contraceptives but to use other forms of contraception until she has completely weaned her child.

13. PEDIATRIC USE

Safety and efficacy of Ortho-Novum® Tablets and MODICON® 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.

14. GERIATRIC USE

This product has not been studied in women over 65 years of age and is not indicated in this population.

INFORMATION FOR THE PATIENT

See Patient Labeling printed below.

Adverse Reactions

An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (See WARNINGS).

• 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

There is evidence of an association between the following conditions and the use of oral contraceptives:

• Mesenteric thrombosis


• Retinal thrombosis

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


• Melasma which may persist


• Breast changes: tenderness, enlargement, secretion


• Change in weight (increase or decrease)


• Change in cervical erosion and secretion


• Diminution in lactation when given immediately postpartum


• Cholestatic jaundice


• Migraine


• Allergic reaction, including rash, urticaria, angioedema


• Mental depression


• Reduced tolerance to carbohydrates


• Vaginal candidiasis


• Change in corneal curvature (steepening)


• Intolerance to contact lenses

The following adverse reactions have been reported in users of oral contraceptives and a causal association has been neither confirmed nor refuted:

• Pre-menstrual syndrome


• Cataracts


• Changes in appetite


• Cystitis-like syndrome


• Headache


• Nervousness


• Dizziness


• Hirsutism


• Loss of scalp hair


• Erythema multiforme


• Erythema nodosum


• Hemorrhagic eruption


• Vaginitis


• Porphyria


• Impaired renal function


• Hemolytic uremic syndrome


• Acne


• Changes in libido


• Colitis


• Budd-Chiari Syndrome

Overdosage

Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females.

NON-CONTRACEPTIVE HEALTH BENEFITS

The following non-contraceptive health benefits related to the use of combined oral contraceptives are supported by epidemiological studies which largely utilized oral contraceptive formulations containing estrogen doses exceeding 0.035 mg of ethinyl estradiol or 0.05 mg mestranol.73–78

Effects on menses:

• increased menstrual cycle regularity


• decreased blood loss and decreased incidence of iron deficiency anemia


• decreased incidence of dysmenorrhea

Effects related to inhibition of ovulation:

• decreased incidence of functional ovarian cysts


• decreased incidence of ectopic pregnancies

Other effects:

• decreased incidence of fibroadenomas and fibrocystic disease of the breast


• decreased incidence of acute pelvic inflammatory disease


• decreased incidence of endometrial cancer


• decreased incidence of ovarian cancer

Ortho-Novum Dosage and Administration

To achieve maximum contraceptive effectiveness, Ortho-Novum® Tablets and MODICON® Tablets must be taken exactly as directed and at intervals not exceeding 24 hours. Ortho-Novum® Tablets and MODICON® Tablets are available with the DIALPAK® Tablet Dispenser which is preset for a Sunday Start. Day 1 Start is also available.

Sunday Start

When taking Ortho-Novum® 7/7/7, Ortho-Novum® 1/35, and MODICON®, the first "active" tablet should be taken on the first Sunday after menstruation begins. If the period begins on Sunday, the first "active" tablet should be taken that day. Take one active tablet daily for 21 days followed by one green "reminder" tablet daily for 7 days. After 28 tablets have been taken, a new course is started the next day (Sunday). For the first cycle of a Sunday Start regimen, another method of contraception such as

Lormetazepam FLX

Lormetazepam FLX may be available in the countries listed below.

Ingredient matches for Lormetazepam FLX

Lormetazepam

Lormetazepam is reported as an ingredient of Lormetazepam FLX in the following countries:

• Netherlands

International Drug Name Search