Imalgene may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Ketamine hydrochloride (a derivative of Ketamine) is reported as an ingredient of Imalgene in the following countries:
International Drug Name Search
NP Thyroid (thyroid tablets, USP) for oral use is a natural preparation derived from porcine thyroid glands. They contain both tetraiodothyronine sodium (T4 levothyroxine) and triiodothyronine sodium (T3 liothyronine) providing 38 mcg levothyroxine (T4) and 9 mcg liothyronine (T3) per grain of thyroid (or per 65 mg of the labeled amount of thyroid). The inactive ingredients are calcium stearate, dextrose monohydrate, maltodextrin and mineral oil.
CLINICAL PHARMACOLOGY: The steps in the synthesis of the thyroid hormones are controlled by thyrotropin (Thyroid Stimulating Hormone, TSH) secreted by the anterior pituitary. This hormone’s secretion is in turn controlled by a feedback mechanism effected by the thyroid hormones themselves and by thyrotropin releasing hormone (TRH), a tripeptide of hypothalamic origin. Endogenous thyroid hormone secretion is suppressed when exogenous thyroid hormones are administered to euthyroid individuals in excess of the normal gland’s secretion. The mechanisms by which thyroid hormones exert their
physiologic action are not well understood. These hormones enhance oxygen consumption by most tissues of the body, increase the basal metabolic rate, and the metabolism of carbohydrates, lipids, and
proteins. Thus, they exert a profound influence on every organ system in the body and are of particular importance in the development of the central nervous system. The normal thyroid gland contains approximately 200 mcg of levothyroxine (T4) per gram of gland, and 15 mcg of liodothyronine (T3) per gram. The ratio of these two hormones in the circulation does not represent the ratio in the thyroid gland, since about 80 percent of peripheral triiodothyronine comes from monodeiodination of levothyroxine. Peripheral monodeiodination of levothyroxine at the 5 position (inner ring) also results in the formation of reverse triiodothyronine (T3), which is calorigenically inactive. Triiodothyronine (T3) levels are low in the fetus and newborn, in old age, in chronic caloric deprivation, hepatic cirrhosis, renal failure, surgical stress, and chronic illnesses representing what has been called the “T3 thyronine syndrome.”
Pharmacokinetics - Animal studies have shown that T4 is only partially absorbed from the gastrointestinal tract. The degree of absorption is dependent on the vehicle used for its administration and by the character of the intestinal contents, the intestinal flora, including plasma protein, and soluble dietary factors, all of which bind thyroid and thereby make it unavailable for diffusion. Only 41 percent is absorbed when given in a gelatin capsule as opposed to a 74 percent absorption when given with an lbumin carrier. Depending on other factors, absorption has varied from 48 to 79 percent of the administered dose. Fasting increases absorption. Malabsorption syndromes, as well as dietary factors, (children’s soybeanformula, concomitant use of anionic exchange resins such as cholestyramine) cause excessive fecal loss. T3 is almost totally absorbed, 95 percent in 4 hours. The hormones contained in the natural preparations are absorbed in a manner similar to the synthetic hormones. More than 99 percent of circulating hormones are bound to serum proteins, including thyroid-binding globulin (TBg), thyroid-binding prealbumin (TBPA), andalbumin (TBa), whose capacities and affinities vary for the hormones. The higher affinity of levothyroxine (T4) for both TBg and TBPA as compared to triiodothyronine (T3) partially explains the higher serum levels and longer half-life of the former hormone. Both protein-bound hormones exist in reverse equilibrium with minute amounts of free hormone, the latter accounting for the metabolic activity. deiodination of levothyroxine (T4) occurs at a number of sites, including liver, kidney, and other tissues. The conjugated hormone, in the form of glucuronide or sulfate, is found in the bile and gut where it may complete an enterohepatic circulation. Eighty-five percent of levothyroxine (T4) metabolized daily is deiodinated.
INDICATIONS AND USAGE: NP Thyroid tablets (thyroid tablets, USP) are indicated: 1. As replacement or supplemental therapy in patients with hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis. This category includes cretinism, myxedema, and ordinary hypothyroidism in patients of any age (children, adults, the elderly), or state (including pregnancy); primary hypothyroidism resulting from functional deficiency, primary atrophy, partial or total absence of thyroid gland, or the effects of surgery, radiation, or drugs, with or without the presence of goiter; and secondary (pituitary), or tertiary (hypothalamic) hypothyroidism (See WARNINGS). 2. As pituitary TSH suppressants, in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic Iymphocytic thyroiditis (Hashimoto’s), multinodular goiter, and in the management of thyroid cancer. 3. As diagnostic agents in suppression tests to differentiate suspected mild hyperthyroidism or thyroid gland autonomy.
CONTRAINDICATIONS: Thyroid hormone preparations are generally contraindicated in patients with diagnosed but as yet uncorrected adrenal cortical insufficiency, untreated thyrotoxicosis, and apparent hypersensitivity to any of their active or extraneous constituents. There is no well-documented evidence from the literature, however, of true allergic or idiosyncratic reactions to thyroid hormone.
WARNINGS
Drugs with thyroid hormone activity, alone or together with other therapeutic agents, have been used for the treatment of obesity. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life-threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.
The use of thyroid hormones in the therapy of obesity, alone or combined with other drugs, is unjustified and has been shown to be ineffective. Neither is their use justified for the treatment of male or female infertility unless this condition is accompanied by hypothyroidism.
PRECAUTIONS: General—Thyroid hormones should be used with great caution in a number of circumstances where the integrity of the cardiovascular system, particularly the coronary arteries, is suspected. These include patients with angina pectoris or the elderly, in whom there is a greater likelihood of acute cardiac disease. In these patients therapy should be initiated with low doses, i.e., 15-30 mg NP Thyroid. When, in such patients, a euthyroid state can only be reached at the expense of an aggravation of the cardiovascular disease, thyroid hormone dosage should be reduced. Thyroid hormone therapy in patients with concomitant diabetes mellitus or diabetes insipidus or adrenal cortical insufficiency aggravates the intensity of their symptoms. Appropriate adjustments of the various therapeutic measures directed at these concomitant endocrine diseases are required. The therapy of myxedema coma requires simultaneous administration of glucocorticoids (See DOSAGE AND ADMINISTRATION). Hypothyroidism decreases and hyperthyroidism increases the sensitivity to oral anticoagulants. Prothrombin time should be closely monitored in thyroid-treated patients on oral anticoagulants and dosage of the latter agents adjusted on the basis of frequent prothrombin time determinations. In infants, excessive doses of thyroid hormone preparations may produce craniosynostosis.
Information for the Patient—Patients on thyroid hormone preparations and parents of children on thyroid therapy should be informed that: 1. Replacement therapy is to be taken essentially for life, with the exception of cases of transient hypothyroidism, usually associated with thyroiditis, and in those patients receiving a therapeutic trial of the drug. 2. They should immediately report during the course of therapy any signs or symptoms of thyroid hormone toxicity, e.g., chest pain, increased pulse rate, palpitations, excessive sweating, heat intolerance, nervousness, or any other unusual event. 3. In case of concomitant diabetes mellitus, the daily dosage of antidiabetic medication may need readjustment as thyroid hormone replacement is achieved. If thyroid medication is stopped, a downward readjustment of the dosage of insulin or oral hypoglycemic agent may be necessary to avoid hypoglycemia. At all times, close monitoring of urinary glucose levels is mandatory in such patients. 4. In case of concomitant oral anticoagulant therapy, the prothrombin time should be measured frequently to determine if the dosage of oral anticoagulants is to be readjusted. 5. Partial loss of hair may be experienced by children in the first few months of thyroid therapy, but this is usually a transient phenomenon and later recovery is usually the rule.
Laboratory Tests — Treatment of patients with thyroid hormones requires the periodic assessment of thyroid status by means of appropriate laboratory tests besides the full clinical evaluation. The TSH suppression test can be used to test the effectiveness of any thyroid preparation bearing in mind the relative insensitivity of the infant pituitary to the negative feedback effect of thyroid hormones. Serum T4 levels can be used to test the effectiveness of all thyroid medications except T3. When the total serum T4 is low but TSH is normal, a test specific to assess unbound (free) T4 levels is warranted. Specific measurements of T4 and T3 by competitive protein binding or radioimmunoassay are not influenced by blood levels of organic or inorganic iodine.
Drug Interactions—Oral Anticoagulants—Thyroid hormones appear to increase catabolism of vitamin K-dependent clotting factors. If oral anticoagulants are also being given, compensatory increases in clotting factor synthesis are impaired. Patients stabilized on oral anticoagulants who are found to require thyroid replacement therapy should be watched very closely when thyroid is started. If a patient is truly hypothyroid, it is likely that a reduction in anticoagulant dosage will be required. No special precautions appear to be necessary when oral anticoagulant therapy is begun in a patient already stabilized on maintenance thyroid replacement therapy.
Insulin or Oral Hypoglycemics—Initiating thyroid replacement therapy may cause increases in insulin or oral hypoglycemic requirements. The effects seen are poorly understood and depend upon a variety of factors such as dose and type of thyroid preparations and endocrine status of the patient. Patients receiving insulin or oral hypoglycemics should be closely watched during initiation of thyroid replacement therapy.
Cholestyramine - Cholestyramine binds both T4 and T3 in the intestine, thus impairing absorption of these thyroid hormones. In vitro studies indicate that the binding is not easily removed. Therefore four to five hours should elapse between administration of cholestyramine and thyroid hormones.
Estrogen, Oral Contraceptives—Estrogens tend to increase serum thyroxine-binding globulin (TBg). In a patient with a nonfunctioning thyroid gland who is receiving thyroid replacement therapy, free levothyroxine may be decreased when estrogens are started thus increasing thyroid requirements. However, if the patient’s thyroid gland has sufficient function, the decreased free thyroxine will result in a compensatory increase in thyroxine output by the thyroid. Therefore, patients without a functioning thyroid gland who are on thyroid replacement therapy may need to increase their thyroid dose if estrogens or estrogen-containing oral contraceptives are given.
Drug/Laboratory Test Interactions—The following drugs or moieties are known to interfere with laboratory tests performed in patients on thyroid hormone therapy: androgens, corticosteroids, estrogens, oral contraceptives containing estrogens, iodine-containing preparations, and the numerous preparations containing salicylates. 1. Changes in TBg concentration should be taken into consideration in the interpretation of T4 and T3 values. In such cases, the unbound (free) hormone should be measured. Pregnancy, estrogens, and estrogencontaining oral contraceptives increase TBg concentrations. TBg may also be increased during infectious hepatitis. Decreases in TBg concentrations are observed in nephrosis, acromegaly, and after androgen or corticosteroid therapy. Familial hyper- or hypothyroxine-binding-globulinemias have been described. The incidence of TBg deficiency approximates 1 in 9,000. The binding of levothyroxine by TBPA is inhibited by salicylates. 2. Medicinal or dietary iodine interferes with all in vivo tests of radio-iodine uptake, producing low uptakes which may not be relative of a true decrease in hormone synthesis. 3. The persistence of clinical and laboratory evidence of hypothyroidism in spite of adequate dosage replacement indicates either poor patient compliance, poor absorption, excessive fecal loss, or inactivity of the preparation. Intracellular resistance to thyroid hormone is quite rare.
Carcinogenesis, Mutagenesis, and Impairment of Fertility—A reportedly apparent association between prolonged thyroid therapy and breast cancer has not been confirmed and patients on thyroid for established indications should not discontinue therapy. No confirmatory long-term studies in animals have been performed to evaluate carcinogenic potential, mutagenicity, or impairment of fertility in either males or females.
Pregnancy-Category A—Thyroid hormones do not readily cross the placental barrier. The clinical experience to date does not indicate any adverse effect on fetuses when thyroid hormones are administered to pregnant women. On the basis of current knowledge, thyroid replacement therapy to hypothyroid women should not be discontinued during pregnancy.
Nursing Mothers—Minimal amounts of thyroid hormones are excreted in human milk. Thyroid is not associated with serious adverse reactions and does not have a known tumorigenic potential. However, caution should be exercised when thyroid is administered to a nursing woman.
Pediatric Use—Pregnant mothers provide little or no thyroid hormone to the fetus. The incidence of congenital hypothyroidism is relatively high (1:4,000) and the hypothyroid fetus would not derive any benefit from the small amounts of hormone crossing the placental barrier. Routine determinations of serum T4 and/or TSH is strongly advised in neonates in view of the deleterious effects of thyroid deficiency on growth and development. Treatment should be initiated immediately upon diagnosis, and maintained for life, unless transient hypothyroidism is suspected; in which case, therapy may be interrupted for 2 to 8 weeks after the age of 3 years to reassess the condition. Cessation of therapy is justified in patients who have maintained a normal TSH during those 2 to 8 weeks.
ADVERSE REACTIONS: Adverse reactions other than those indicative of hyperthyroidism because of therapeutic overdosage, either initially or during the maintenance period, are rare (See OVERDOSAGE).
OVERDOSAGE: Signs and Symptoms—Excessive doses of thyroid result in a hypermetabolic state resembling in every respect the condition of endogenous origin. The condition may be selfinduced.
Treatment of Overdosage—Dosage should be reduced or therapy temporarily discontinued if signs and symptoms of overdosage appear. Treatment may be reinstituted at a lower dosage. In normal individuals, normal hypothalamic-pituitary-thyroid axis function is restored in 6 to 8 weeks after thyroid suppression. Treatment of acute massive thyroid hormone overdosage is aimed at reducing gastrointestinal absorption of the drugs and counteracting central and peripheral effects, mainly those of increased sympathetic activity. Vomiting may be induced initially if further gastrointestinal absorption can reasonably be prevented and barring contraindications such as coma, convulsions, or loss of the gagging reflex. Treatment is symptomatic and supportive. Oxygen may be administered and ventilation maintained. Cardiac glycosides may be indicated if congestive heart failure develops. Measures to control fever, hypoglycemia, or fluid loss should be instituted if needed. Antiadrenergic agents, particularly propranolol, have been used advantageously in the treatment of increased sympathetic activity. Propranolol may be administered intravenously at a dosage of 1 to 3 mg, over a 10-minute period or orally, 80 to 160 mg/day, initially, especially when no contraindications exist for its use.
DOSAGE AND ADMINISTRATION: The dosage of thyroid hormones is determined by the indication and must in every case be individualized according to patient response and laboratory findings. Thyroid hormones are given orally. In acute, emergency conditions, injectable levothyroxine sodium may be given intravenously when oral administration is not feasible or desirable, as in the treatment of myxedema coma, or during total parenteral nutrition. Intramuscular administration is not advisable because of reported poor absorption.
Hypothyroidism—Therapy is usually instituted using low doses, with increments which depend on the cardiovascular status of the patient. The usual starting dose is 30 mg NP Thyroid, with increments of 15 mg every 2 to 3 weeks. A lower starting dosage, 15 mg/day, is recommended in patients with long standing myxedema, particularly if cardiovascular impairment is suspected, in which case extreme caution is recommended. The appearance of angina is an indication for a reduction in dosage. Most patients require 60 to 120 mg/day. Failure to respond to doses of 180 mg suggests lack of compliance or malabsorption. Maintenance dosages 60 to 120 mg/day usually result in normal serum levothyroxine (T4) and triiodothyronine (T3) levels. Adequate therapy usually results in normal TSH and T4 levels after 2 to 3 weeks of therapy. Readjustment of thyroid hormone dosage should be made within the first four weeks of therapy, after proper clinical and laboratory evaluations, including serum levels of T4, bound and free, and TSH. T3 may be used in preference to levothyroxine (T4) during radio-isotope scanning procedures, since induction of hypothyroidism in those cases is more abrupt and can be of shorter duration. It may also be preferred when impairment of peripheral conversion of T4 and T3 is suspected.
Myxedema Coma—Myxedema coma is usually precipitated in the hypothyroid patient of longstanding by intercurrent illness or drugs such as sedatives and anesthetics and should be considered a medical emergency. Therapy should be directed at the correction of electrolyte disturbances and possible infection besides the administration of thyroid hormones. Corticosteroids should be administered routinely. T4 and T3 may be administered via a nasogastric tube but the preferred route of administration of both hormones is intravenous. Levothyroxine sodium (T4) is given at starting dose of 400 mcg (100 mcg/mL) given rapidly, and is usually well tolerated, even in the elderly. This initial dose is followed by daily supplements of 100 to 200 mcg given intravenously. Normal T4 levels are achieved in 24 hours followed in 3 days by threefold elevation of T3. Oral therapy with thyroid hormone would be resumed as soon as the clinical situation has been stabilized and the patient is able to take oral medication.
Thyroid Cancer—Exogenous thyroid hormone may produce regression of metastases from follicular and papillary carcinoma of the thyroid and is used as ancillary therapy of these conditions with radioactive iodine. TSH should be suppressed to low or undetectable levels. Therefore, larger amounts of thyroid hormone than those used for replacement therapy are required. Medullary carcinoma of the thyroid is usually unresponsive to this therapy.
Thyroid Suppression Therapy—Administration of thyroid hormone in doses higher than those produced physiologically by the gland results in suppression of the production of endogenous hormone. This is the basis for the thyroid suppression test and is used as an aid in the diagnosis of patients with signs of mild hyperthyroidism in whom base line laboratory tests appear normal, or to demonstrate thyroid gland autonomy in patients with Grave’s ophthalmopathy. 131I uptake is determined before and after the administration of the exogenous hormone. A 50 percent or greater suppression of uptake indicates a normal thyroid-pituitary axis and thus rules out thyroid gland autonomy. For adults, the usual suppressive dose of levothyroxine (T4) is 1.56 mcg/kg of body weight per day given for 7 to 10 days. These doses usually yield normal serum T4 and T3 levels and lack of response to TSH. Thyroid hormones should be administered cautiously to patients in whom there is strong suspicion of thyroid gland autonomy, in view of the fact that the exogenous hormone effects will be additive to the endogenous source.
Pediatric Dosage—Pediatric dosage should follow the recommendations summarized in Table 1. In infants with congenital hypothyroidism, therapy with full doses should be instituted as soon as the diagnosis has been made.
| NP Thyroid Tablets | ||
| Age | Dose per day | Daily dose per kg of body weight |
| 0 - 6 mos. | 15 - 30 mg | 4.8 - 6 mg |
| 6 - 12 mos. | 30 - 45 mg | 3.6 - 4.8 mg |
| 1 - 5 yrs. | 45 - 60 mg | 3 - 3.6 mg |
| 6 - 12 yrs. | 60 - 90 mg | 2.4 - 3 mg |
| Over 12 yrs. | Over 90 mg | 1.2 - 1.8 mg |
HOW SUPPLIED: NP Thyroid tablets (thyroid tablets, USP) are supplied as follows: 30 mg (1/2 gr) are available in bottles of 100 (NDC 42192-329-01), 60 mg (1 gr) are available in bottles of 100 (NDC 42192-330-01), and 90 mg (1 1/2 gr) are available in bottles of 100 (NDC 42192-331-01). NP Thyroid tablets are light tan, round tablets, debossed on one side with “AP” and a 3-digit code on the other side as follows:
30 mg (1/2 grain) - “329”
60 mg (1 grain) - “330”
90 mg (1 1/2 grain) - “331”
MANUFACTURED FOR:
Acella Pharmaceuticals, LLC
9005 Westside Parkway
Alpharetta, GA 30009
1-800-541-4802
Rev 1010v3
Store in a tight container protected from light and moisture. Store between 15° - 30°C (59° - 86°F).
All prescription substitutions and/or recommendations using this product shall be made subject to state and federal statutes as applicable. Please note: this is not an Orange Book product and has not been subjected to FDA therapeutic equivalency or other equivalency testing. No representation is made as to generic status or bioequivalency. Each person recommending a prescription substitution using this product shall make such recommendations based on each such person’s professional opinion and knowledge, upon evaluating the active ingredients, excipients, inactive ingredients and chemical information provided herein.
EACH TABLET CONTAINS:
DIRECTIONS FOR USE: See Insert.
USUAL DOSE: 15 mg - 180 mg once a day.
NP Thyroid is a natural product with a strong, characteristic odor.
MANUFACTURED FOR:
Acella Pharmaceuticals, LLC
Alpharetta, GA 30009
1-800-541-4802
Lot #/Exp. Date:
NDC 42192-329-01
NP Thyroid 30
Thyroid Tablets, USP
1/2 grain (30 mg)
Rx Only 100 Tablets
Acella PHARMACEUTICALS, LLC
| NP Thyroid 30 levothyroxine, liothyronine tablet | ||||||||||||||||||||
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| Marketing Information | |||
| Marketing Category | Application Number or Monograph Citation | Marketing Start Date | Marketing End Date |
| unapproved drug other | 11/11/2010 | ||
| Labeler - Acella Pharmaceuticals, LLC (825380939) |
Treating nasal allergy symptoms. It may also be used for other conditions as determined by your doctor.
Nasarel Spray is a topical adrenocortical steroid. It works by reducing inflammation (redness, swelling, itching, irritation) in the nasal passages in a way that is not clearly understood.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Nasarel Spray. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Nasarel Spray. Tell your health care provider if you are taking any other medicines, especially any of the following:
This may not be a complete list of all interactions that may occur. Ask your health care provider if Nasarel Spray may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.
Use Nasarel Spray as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Nasarel Spray.
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:
Aftertaste; cough; nasal burning, dryness, or stinging; nausea; nosebleed; sore throat.
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); decreased sense of smell; excessive sneezing; muscle weakness; nasal discomfort or irritation; repeated nosebleeds; unusual weight gain, especially in the face; white patches in the mouth, nose, or throat.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch .
See also: Nasarel side effects (in more detail)
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include increased thirst or urination; muscle weakness; severe or persistent headache or vomiting; trouble breathing; unusual weight gain, especially in the face.
Store Nasarel Spray at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not freeze. Do not store in the bathroom. Keep Nasarel Spray out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about Nasarel Spray. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.
Ferrous fumarate tablets are not USP for dissolution and assay.
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
norethindrone and ethinyl estradiol tablets, chewable and ferrous fumarate tablets 0.4 mg/35 mcg provides a regimen for oral contraception derived from 21 white tablets composed of norethindrone and ethinyl estradiol followed by 7 brown ferrous fumarate (placebo) tablets. The chemical name for norethindrone is 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one and for ethinyl estradiol the chemical name is 19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol. The structural formulas are:
NORETHINDRONE
ETHINYL ESTRADIOL
The active white norethindrone and ethinyl estradiol tablets, chewable and ferrous fumarate tablets 0.4 mg/35 mcg tablets contain 0.4 mg norethindrone and 0.035 mg ethinyl estradiol, and the following inactive ingredients: dibasic calcium phosphate, lactose, magnesium stearate, maltodextrin, povidone, sodium starch glycolate, spearmint flavor and sucralose.
The brown tablets contain ferrous fumarate, microcrystalline cellulose, magnesium stereate, povidone, sodium starch glycolate, and compressible sugar. The ferrous fumarate tablets do not serve any therapeutic purpose.
Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).
Ethinyl estradiol and norethindrone are rapidly absorbed with maximum plasma concentrations occurring within 2 hours after norethindrone and ethinyl estradiol tablets, chewable and ferrous fumarate tablets 0.4 mg/35 mcg administration (see Table 1). Norethindrone appears to be completely absorbed following oral administration; however, it is subject to first-pass metabolism resulting in an absolute bioavailability of approximately 65%. Large intersubject variability is reflected in a 3- to 5-fold variation in norethindrone bioavailability. Ethinyl estradiol bioavailability is approximately 43% due to small-intestinal and hepatic first-pass metabolism.
| an = 26 bn = 25 Cmax = maximum plasma concentration; tmax = time to reach Cmax; AUC = area under the curve; t1/2 = elimination half life. | ||||
| Norethindrone/Ethinyl Estradiol | tmax (h) | Cmax (pg/mL) | AUC0-∞ (pg•h/mL) | t1/2 (h) |
| Norethindrone 0.4 mg | 1.24 ± 0.40a | 4210.6 ± 1628.8a | 18034.9 ± 7852.9b | 8.6 ± 3.7b |
| Ethinyl Estradiol 35 mcg | 1.44 ± 0.33b | 131.4 ± 34.2b | 1065.8 ± 276.2b | 17.1 ± 4.4b |
Effect of Food. Single-dose administration of norethindrone and ethinyl estradiol tablets, chewable and ferrous fumarate tablets 0.4 mg/35 mcg tablets with food decreased the maximum norethindrone and ethinyl estradiol concentration by 53% and 47%, respectively; the extent of norethindrone and ethinyl estradiol absorption (AUC values) was not affected by food administration.
Norethindrone is 36% bound to sex hormone-binding globulin (SHBG) and 61% bound to albumin. Ethinyl estradiol is not bound to SHBG but is highly (98.5%) bound to albumin. Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg.
Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation; less than 5% of a norethindrone dose is excreted unchanged; greater than 50% and 20-40% of a dose is excreted in urine and feces, respectively. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites.
Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol, and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy-ethinyl estradiol which is formed by the CYP3A4 isoform of cytochrome P450.
Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Ethinyl estradiol and norethindrone are excreted in both urine and feces, primarily as metabolites. Ethinyl estradiol is excreted in urine and feces as glucuronides and sulfates, and about 28-43% undergoes enterohepatic circulation. The mean terminal elimination half-lives of norethindrone and ethinyl estradiol following single dose administration of norethindrone and ethinyl estradiol tablets, chewable and ferrous fumarate tablets 0.4 mg/35 mcg are approximately 9 hours and 17 hours, respectively.
Race. The effect of race on the disposition of norethindrone and ethinyl estradiol after norethindrone and ethinyl estradiol tablets, chewable and ferrous fumarate tablets 0.4 mg/35 mcg administration has not been evaluated.
Renal Insufficiency. The effect of renal disease on the disposition of norethindrone and ethinyl estradiol after norethindrone and ethinyl estradiol tablets, chewable and ferrous fumarate tablets 0.4 mg/35 mcg administration has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function.
Hepatic Insufficiency. The effect of hepatic disease on the disposition of norethindrone and ethinyl estradiol after norethindrone and ethinyl estradiol tablets, chewable and ferrous fumarate tablets 0.4 mg/35 mcg administration has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function.
See PRECAUTIONS section—DRUG INTERACTIONS
norethindrone and ethinyl estradiol tablets, chewable and ferrous fumarate tablets 0.4 mg/35 mcg is 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 2 lists the typical unintended pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, the IUD, and implants, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.
% of Women Experiencing an Unintended Pregnancy within the First Year of Use | % of Women Continuing Use at One Year3 | ||
Method (1) | Typical Use1 (2) | Perfect Use2 (3) | (4) |
| Chance4 | 85 | 85 | |
| Spermicides5 | 26 | 6 | 40 |
| Periodic abstinence | 25 | 63 | |
| Calendar | 9 | ||
| Ovulation Method | 3 | ||
| Sympto-thermal6 | 2 | ||
| Post-Ovulation | 1 | ||
| Cap7 | |||
| Parous Women | 40 | 26 | 42 |
| Nulliparous Women | 20 | 9 | 56 |
| Sponge | |||
| Parous Women | 40 | 20 | 42 |
| Nulliparous Women | 20 | 9 | 56 |
| Diaphragm7 | 20 | 6 | 56 |
| Withdrawal | 19 | 4 | |
| Condom8 | |||
| Female (reality) | 21 | 5 | 56 |
| Male | 14 | 3 | 61 |
| Pill | 5 | 71 | |
| Progestin only | 0.5 | ||
| Combined | 0.1 | ||
| IUD | |||
| Progesterone T | 2.0 | 1.5 | 81 |
| Copper T 380A | 0.8 | 0.6 | 78 |
| LNg 20 | 0.1 | 0.1 | 81 |
| Depo-Provera® | 0.3 | 0.3 | 70 |
| Norplant® and Norplant® 2 | 0.05 | 0.05 | 88 |
| Female Sterilization | 0.5 | 0.5 | 100 |
| Male Sterilization | 0.15 | 0.10 | 100 |
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces risk of pregnancy by at least 75%9
Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception10
Source: Trussell J, Stewart F, Contraceptive Efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York, NY: Irvington Publishers, 1998.
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 percentage of women becoming pregnant noted in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% became pregnant in one year. This estimate was lowered slightly (to 85%) to represent the percentage that would become pregnant within one year among women now relying on reversible methods of contraception if they abandon contraception altogether
5 Foams, creams, gels, vaginal suppositories and vaginal film
6 Cervical mucous (ovulation) method supplemented by calendar in the preovulatory and basal body temperature in the postovulatory phases
7 With spermicidal cream or jelly
8 Without spermicides
9 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)
10 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
Combination oral contraceptives should not be used in women who currently have the following conditions:
Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with the extent of smoking (in epidemiologic studies, 15 or more cigarettes per day was associated with a significantly increased risk) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.
The use of oral contraceptives is associated with increased risk of several serious conditions including venous and arterial thrombotic and thromboembolic events (such as myocardial infarction, thromboembolism, and stroke), hepatic neoplasia, gallbladder disease, and hypertension, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as certain inherited thrombophilias, hypertension, hyperlipidemias, obesity and diabetes.
Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks. The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with 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. 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. 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. Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and nonsmokers over the age of 40 (Figure 1) among women who use oral contraceptives.
Layde PM, Beral V. Lancet 1981;1:541-546.
Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age, and obesity. In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism. Oral contraceptives have been shown to increase blood pressure among users (see section 9 in WARNINGS). Such increases in risk factors have been associated with an increased risk of heart disease and the risk increases with the number of risk factors present. 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 non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The approximate incidence of deep-vein thrombosis and pulmonary embolism in users of low dose (<50 mcg ethinyl estradiol) combination oral contraceptives is up to 4 per 10,000 woman-years compared to 0.5-3 per 10,000 woman-years for non-users. However, the incidence is substantially less than that associated with pregnancy (6 per 10,000 woman-years). The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped.
A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives. The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions. If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four to six 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 risk of cerebrovascular events (thrombotic and hemorrhagic strokes) although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes.
In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension. The relative risk of hemorrhagic stroke is reported to be 1.2 for nonsmokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension. The attributable risk is also greater in older women. Oral contraceptives also increase the risk for stroke in women with other underlying risk factors such as certain inherited or acquired thrombophilias, hyperlipidemias, and obesity. Women with migraine (particularly migraine with aura) who take combination oral contraceptives may be at an increased risk of stroke.
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. A decline in serum high density lipoproteins (HDL) has been reported with many progestational agents. A decline in serum high density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the nature and absolute amount of progestogens used in the contraceptive. The amount of both hormones should be considered in the choice of an oral contraceptive.
Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular estrogen/progestogen combination, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with a low failure rate and the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest estrogen content which is judged appropriate for the individual patient.
e. Persistence of risk of vascular disease
There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40-49 years old who had used oral contraceptives for five or more years but this increased risk was not demonstrated in other age groups.
In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small. However, both studies were performed with oral contraceptive formulations containing 50 micrograms or higher of estrogens.
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 3).
| AGE | ||||||
Method of control and outcome | 15-19 | 20-24 | 25-29 | 30-34 | 35-39 | 40-44 |
| No fertility control methods* | 7.0 | 7.4 | 9.1 | 14.8 | 25.7 | 28.2 |
Oral contraceptives nonsmoker** | 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 |
| *Deaths are birth related | ||||||
| **Deaths are method related | ||||||
| Ory HW. Family Planning Perspectives 1983; 15:57-63. | ||||||
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 risk. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth.
The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970s but not reported until 1983. However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling.
Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular disease risk may be increased with oral contraceptive use after age 40 in healthy nonsmoking women (even with the newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.
Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.
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. Although the risk of breast cancer may be slightly increased among current users of oral contraceptives (RR = 1.24), this excess risk decreases over time after oral contraceptive discontinuation and by 10 years after cessation the increased risk disappears. The risk does not increase with duration of use, and no relationships have been found with dose or type of steroid. The patterns of risk are also similar regardless of a woman's reproductive history or her family breast cancer history. The subgroup for whom risk has been found to be significantly elevated is women who first used oral contraceptives before age 20, but because breast cancer is so rare at these young ages, the number of cases attributable to this early oral contraceptive use is extremely small. Breast cancers diagnosed in current or previous oral contraceptive users tend to be less advanced clinically than in never-users. Women who currently have or have had breast cancer should not use oral contraceptives because breast cancer is a hormone-sensitive tumor.
Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia or invasive cervical cancer in some populations of women. However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.
In spite of many studies of the relationship between oral contraceptive use and breast cancer and cervical cancers, a cause-and-effect relationship has not been established.
4. HEPATIC NEOPLASIA
Benign hepatic adenomas are associated with oral contraceptive use, although their occurrence is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.
Studies from Britain have shown an increased risk of developing hepatocellular carcinoma in long-term (>8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S. and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.
5. OCULAR LESIONS
There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives that may lead to partial or complete loss of vision. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.
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. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when taken inadvertently during early pregnancy (see CONTRAINDICATIONS section).
The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion.
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. More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal. The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.
8. CARBOHYDRATE AND LIPID METABOLIC EFFECTS
Oral contraceptives have been shown to cause glucose intolerance in a significant percentage of users. Oral contraceptives containing greater than 75 micrograms of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance. Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents. However, in the nondiabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see WARNINGS 1.a. and 1.d.), 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 contraceptives. An increase in blood pressure has been reported in women taking oral contraceptives, and this increase is more likely in older oral contraceptive users and with continued use. Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens.
Women with a history of hypertension or hypertension-related diseases, or renal disease should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued (see CONTRAINDICATIONS section). For most women, elevated blood pressure will return to normal after stopping oral contraceptives, and there is no difference in the occurrence of hypertension among ever- and never-users.
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 (see WARNINGS 1.c.).
11. BLEEDING IRREGULARITIES
Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. If bleeding persists or recurs, nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy or pregnancy 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 (possibly with anovulation), especially when such a condition was preexistent.
12. ECTOPIC PREGNANCY
Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.
1. SEXUALLY TRANSMITTED DISEASES
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
A periodic personal and family medical history and complete physical examination are appropriate for all women, 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. (See WARNINGS 1.d.)
In patients with familial defects of lipoprotein metabolism receiving estrogen-containing preparations, there have been case reports of significant elevations of plasma triglycerides leading to pancreatitis.
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. Patients becoming significantly depressed while taking oral contraceptives should stop the medication and use an alternate method of contraception in an attempt to determine whether the symptom is drug related. 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.
Changes
Improntal Topico may be available in the countries listed below.
Piroxicam is reported as an ingredient of Improntal Topico in the following countries:
International Drug Name Search
Reducing the appearance of fine wrinkles, certain dark and light spots, and certain lesions on the face. Avage Cream is used with a total skin care and sunlight avoidance program. It may also be used for other conditions as determined by your doctor.
Avage Cream is a retinoid. Exactly how Avage Cream works is unknown.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Avage Cream. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Avage Cream. Tell your health care provider if you are taking any other medicines, especially any of the following:
This may not be a complete list of all interactions that may occur. Ask your health care provider if Avage Cream may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.
Use Avage Cream as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Avage Cream.
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:
Burning; dry skin; irritation; itching; peeling; redness; scaling; skin inflammation; skin pain; stinging.
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); severe or prolonged itching, burning, redness, or peeling; sunburn; swelling of the skin, hands, or feet; swelling or cracking around the mouth; worsening of psoriasis.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.
See also: Avage side effects (in more detail)
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include severe redness, peeling, or discomfort. Avage Cream may be harmful if swallowed.
Store Avage Cream at 77 degrees F (25 degrees C). Brief storage at temperatures between 23 and 86 degrees F (-5 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Avage Cream out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about Avage Cream. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.
