Ceredase

Generic Name: alglucerase (Intravenous route)

al-GLOO-ser-ase

Commonly used brand name(s)

In the U.S.

• Ceredase

Available Dosage Forms:

• Solution

Therapeutic Class: Gastrointestinal Agent

Pharmacologic Class: Enzyme

Uses For Ceredase

Alglucerase is used to treat Gaucher's disease caused by the lack of a certain enzyme, glucocerebrosidase, in the body. This enzyme is necessary for your body to use fats.

Alglucerase is made from human placenta tissue that is collected after a baby is born. Before it is used, the tissue is tested for hepatitis and human immunodeficiency virus (HIV). This is similar to the testing that a blood bank does on donated blood before it is given to anyone else.

Alglucerase is available with your doctor's prescription.

Before Using Ceredase

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

This medicine has been tested in a limited number of children. In effective doses, the medicine has not been shown to cause different side effects or problems than it does in adults.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults or if they cause different side effects or problems in older people. There is no specific information comparing use of alglucerase in the elderly with use in other age groups.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Proper Use of Ceredase

This medicine will not cure Gaucher's disease but it does help control it. Therefore, you must continue to receive it if you expect to keep your condition under control. You may have to receive alglucerase for the rest of your life. If Gaucher's disease is not treated, it can cause serious blood, liver, skeletal, or spleen problems.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For Gaucher's disease:
  
  • For injection dosage form:
    
    • Adults and children—The dose is based on body weight. It is injected slowly into a vein over one to two hours. To start, some patients may receive 1.15 Units per kilogram (kg) (0.52 Units per pound) of body weight three times a week. Other patients may receive up to 60 Units per kg (27 Units per pound) of body weight as often as once a week or as seldom as every four weeks. Later, your doctor may raise or lower your dose.
    
    
  
  

Precautions While Using Ceredase

It is important that your doctor check your progress while you are receiving alglucerase to make sure that the dosage is correct for you.

Ceredase Side Effects

Since alglucerase is made from human tissue, it is possible that diseases caused by viruses could be passed on. Examples of such diseases are hepatitis and HIV infection. These problems have not been reported to date, however, and are unlikely since the tissue is tested before being used. If you have questions or concerns about this, check with your doctor.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

• Abdominal discomfort


• chills


• fever


• nausea and vomiting


• swelling at place of injection

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Ceredase side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Ceredase resources

• Ceredase Side Effects (in more detail)
• Ceredase Use in Pregnancy & Breastfeeding
• Ceredase Support Group
• 0 Reviews for Ceredase - Add your own review/rating

• Ceredase Prescribing Information (FDA)


• Ceredase MedFacts Consumer Leaflet (Wolters Kluwer)


• Ceredase Concise Consumer Information (Cerner Multum)


• Ceredase Monograph (AHFS DI)


• Alglucerase Professional Patient Advice (Wolters Kluwer)

Compare Ceredase with other medications

• Gaucher Disease

Voltaren Ophthalmic

diclofenac sodium

Dosage Form: ophthalmic solution
Voltaren

VOLTAREN OPHTHALMIC®

(diclofenac sodium ophthalmic solution) 0.1%

Sterile Ophthalmic Solution

Rx only

Prescribing Information

DESCRIPTION

Voltaren Ophthalmic (diclofenac sodium ophthalmic solution) 0.1% solution is a sterile, topical, nonsteroidal, anti-inflammatory product for ophthalmic use. Diclofenac sodium is designated chemically as 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt, with an empirical formula of C14H10Cl2NO2Na. The structural formula of diclofenac sodium is:

Voltaren Ophthalmic is available as a sterile solution which contains diclofenac sodium 0.1% (1 mg/mL).

Inactive Ingredients: polyoxyl 35 castor oil, Boric acid, tromethamine, sorbic acid (2 mg/mL), edetate disodium (1 mg/mL), and purified water.

Diclofenac sodium is a faintly yellow-white to light-beige, slightly hygroscopic crystalline powder. It is freely soluble in methanol, sparingly soluble in water, very slightly soluble in acetonitrile, and insoluble in chloroform and in 0.1N hydrochloric acid. Its molecular weight is 318.14. Voltaren Ophthalmic 0.1% is an iso-osmotic solution with an osmolality of about 300 mOsmol/1000 g, buffered at approximately pH 7.2. Voltaren Ophthalmic solution has a faint characteristic odor of castor oil.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Diclofenac sodium is one of a series of phenylacetic acids that has demonstrated anti-inflammatory and analgesic properties in pharmacological studies. It is thought to inhibit the enzyme cyclooxygenase, which is essential in the biosynthesis of prostaglandins.

Animal Studies

Prostaglandins have been shown in many animal models to be mediators of certain kinds of intraocular inflammation. In studies performed in animal eyes, prostaglandins have been shown to produce disruption of the blood-aqueous humor barrier, vasodilation, increased vascular permeability, leukocytosis, and increased intraocular pressure.

Pharmacokinetics

Results from a bioavailability study established that plasma levels of diclofenac following ocular instillation of two drops of Voltaren Ophthalmic to each eye were below the limit of quantification (10 ng/mL) over a 4-hour period. This study suggests that limited, if any, systemic absorption occurs with Voltaren Ophthalmic.

Clinical Trials

Postoperative Anti-Inflammatory Effects

In two double-masked, controlled, efficacy studies of postoperative inflammation, a total of 206 cataract patients were treated with Voltaren Ophthalmic and 103 patients were treated with vehicle placebo. Voltaren Ophthalmic was favored over vehicle placebo over a 2-week period for the clinical assessments of inflammation as measured by anterior chamber cells and flare.

In double-masked, controlled studies of corneal refractive surgery (radial keratotomy (RK) and laser photorefractive keratectomy (PRK)) patients were treated with Voltaren Ophthalmic and/or vehicle placebo. The efficacy of Voltaren Ophthalmic given before and shortly after surgery was favored over vehicle placebo during the 6-hour period following surgery for the clinical assessments of pain and photophobia. Patients were permitted to use a hydrogel soft contact lens with Voltaren Ophthalmic for up to three days after PRK.

INDICATIONS AND USAGE

Voltaren Ophthalmic is indicated for the treatment of postoperative inflammation in patients who have undergone cataract extraction and for the temporary relief of pain and photophobia in patients undergoing corneal refractive surgery.

CONTRAINDICATIONS

Voltaren Ophthalmic is contraindicated in patients who are hypersensitive to any component of the medication.

WARNINGS

The refractive stability of patients undergoing corneal refractive procedures and treated with Voltaren has not been established. Patients should be monitored for a year following use in this setting.

With some nonsteroidal anti-inflammatory drugs, there exists the potential for increased bleeding time due to interference with thrombocyte aggregation. There have been reports that ocularly applied nonsteroidal anti-inflammatory drugs may cause increased bleeding of ocular tissues (including hyphemas) in conjunction with ocular surgery.

There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other nonsteroidal anti-inflammatory agents. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs.

PRECAUTIONS

General

All topical nonsteroidal anti-inflammatory drugs (NSAIDs) may slow or delay healing. Topical corticosteroids are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems.

Use of topical NSAIDs may result in keratitis. In some susceptible patients continued use of topical NSAIDs may result in epithelial breakdown, corneal thinning, corneal infiltrates, corneal erosion, corneal ulceration, and corneal perforation. These events may be sight-threatening. Patients with evidence of corneal epithelial breakdown should immediately discontinue use of topical NSAIDs and should be closely monitored for corneal health.

Postmarketing experience with topical NSAIDs suggests that patients experiencing complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface disease (e.g., dry eye syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short period-of-time may be at increased risk for corneal adverse events, which may become sight threatening. Topical NSAIDs should be used with caution in these patients.

Postmarketing experience with topical NSAIDs also suggests that use more than 24 hours prior to surgery or use beyond 14 days postsurgery may increase patient risk for occurrence and severity of corneal adverse events.

It is recommended that Voltaren Ophthalmic, like other NSAIDs, be used with caution in patients with known bleeding tendencies or who are receiving other medications which may prolong bleeding time.

Results from clinical studies indicate that Voltaren Ophthalmic has no significant effect upon ocular pressure. However, elevations in intraocular pressure may occur following cataract surgery.

Information for Patients

Except for the use of a bandage hydrogel soft contact lens during the first 3 days following refractive surgery, Voltaren Ophthalmic should not be used by patients currently wearing soft contact lenses due to adverse events that have occurred in other circumstances.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies in rats given Voltaren in oral doses up to 2 mg/kg/day (approximately 500 times the human topical ophthalmic dose) revealed no significant increases in tumor incidence. A 2-year carcinogenicity study conducted in mice employing oral Voltaren up to 2 mg/kg/day did not reveal any oncogenic potential. Voltaren did not show mutagenic potential in various mutagenicity studies including the Ames test. Voltaren administered to male and female rats at 4 mg/kg/day (approximately 1000 times the human topical ophthalmic dose) did not affect fertility.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger adult patients.

PREGNANCY

Teratogenic Effects

Pregnancy Category C. Reproduction studies performed in mice at oral doses up to 5,000 times (20 mg/kg/day) and in rats and rabbits at oral doses up to 2,500 times (10 mg/kg/day) the human topical dose have revealed no evidence of teratogenicity due to Voltaren despite the induction of maternal toxicity and fetal toxicity. In rats, maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Voltaren has been shown to cross the placental barrier in mice and rats.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Non-teratogenic Effects

Because of the known effects of prostaglandin biosynthesis-inhibiting drugs on the fetal cardiovascular system (closure of ductus arteriosus), the use of Voltaren Ophthalmic during late pregnancy should be avoided.

Nursing Women

It is not known whether topical ophthalmic administration of Voltaren Ophthalmic could result in sufficient systemic absorption to produce detectable quantities in breast milk. Because many drugs are excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS

Clinical Practice

The following events have been identified during postmarketing use of topical diclofenac sodium ophthalmic solution, 0.1% in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to topical diclofenac sodium ophthalmic solution, 0.1%, or a combination of these factors, include corneal erosion, corneal infiltrates, corneal perforation, corneal thinning, corneal ulceration, epithelial breakdown, and superficial punctate keratitis, (see PRECAUTIONS, General).

Ocular

Transient burning and stinging were reported in approximately 15% of patients across studies with the use of Voltaren Ophthalmic. In cataract surgery studies, keratitis was reported in up to 28% of patients receiving Voltaren Ophthalmic, although in many of these cases keratitis was initially noted prior to the initiation of treatment. Elevated intraocular pressure following cataract surgery was reported in approximately 15% of patients undergoing cataract surgery. Lacrimation complaints were reported in approximately 30% of case studies undergoing incisional refractive surgery.

The following adverse reactions were reported in approximately 5% or less of patients: abnormal vision, acute elevated IOP, blurred vision, conjunctivitis, corneal deposits, corneal edema, corneal opacity, corneal lesions, discharge, eyelid swelling, injection (redness), iritis, irritation, itching, lacrimation disorder, and ocular allergy.

Systemic

The following adverse reactions were reported in 3% or less of patients: abdominal pain, asthenia, chills, dizziness, facial edema, fever, headache, insomnia, nausea, pain, rhinitis, viral infection, and vomiting.

OVERDOSAGE

Overdosage will not ordinarily cause acute problems. If Voltaren Ophthalmic is accidentally ingested, fluids should be taken to dilute the medication.

DOSAGE AND ADMINISTRATION

Cataract Surgery

One drop of Voltaren Ophthalmic should be applied to the affected eye, 4 times daily beginning 24 hours after cataract surgery and continuing throughout the first 2 weeks of the postoperative period.

Corneal Refractive Surgery

One or two drops of Voltaren Ophthalmic should be applied to the operative eye within the hour prior to corneal refractive surgery. Within 15 minutes after surgery, one or two drops should be applied to the operative eye and continued 4 times daily for up to 3 days.

HOW SUPPLIED

Voltaren Ophthalmic 0.1% (1 mg/mL) Sterile Solution is supplied in a low density polyethylene (LDPE) white bottle with a LDPE Dropper Tip and Polypropylene grey closure. The 2.5 mL fill is supplied in a 7.5 mL size bottle. The 5.0 mL fill is supplied in a 10.0 mL size bottle.

Bottles of 2.5 mL       NDC 0078-0477-61

Bottles of 5 mL       NDC 0078-0478-61

Store at 15ºC to 25ºC (59º to 77ºF).

Dispense in original, unopened container only.

Made in Canada

Manufactured for:

Novartis Pharmaceuticals Corporation

East Hanover, New Jersey 07936

© Novartis

T2011-80

April 2011

PRINCIPAL DISPLAY PANEL

Package Label – 2.5 mL

RX Only             NDC 0078-0477-61

VOLTAREN® Ophthalmic

(diclofenac sodium 0.1%)

Sterile Ophthalmic Solution

PRINCIPAL DISPLAY PANEL

Package Label – 5 mL

RX Only             NDC 0078-0478-61

VOLTAREN® Ophthalmic

(diclofenac sodium 0.1%)

Sterile Ophthalmic Solution

VOLTAREN  diclofenac sodium  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0078-0477 Route of Administration OPHTHALMIC DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DICLOFENAC SODIUM (DICLOFENAC) DICLOFENAC SODIUM 1 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength POLYOXYL 35 CASTOR OIL   BORIC ACID   TROMETHAMINE   SORBIC ACID 2 mg  in 1 mL EDETATE DISODIUM 1 mg  in 1 mL WATER

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0078-0477-61 2.5 mL In 1 BOTTLE, DROPPER None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA020037	03/28/1991

VOLTAREN  diclofenac sodium  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0078-0478 Route of Administration OPHTHALMIC DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DICLOFENAC SODIUM (DICLOFENAC) DICLOFENAC SODIUM 1 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength BORIC ACID   EDETATE DISODIUM 1 mg  in 1 mL POLYOXYL 35 CASTOR OIL   WATER   SORBIC ACID 2 mg  in 1 mL TROMETHAMINE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0078-0478-61 5 mL In 1 BOTTLE, DROPPER None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA020037	03/28/1991

Labeler - Novartis Pharmaceuticals Corporation (002147023)

Revised: 04/2011Novartis Pharmaceuticals Corporation

More Voltaren Ophthalmic resources

• Voltaren Ophthalmic Side Effects (in more detail)
• Voltaren Ophthalmic Dosage
• Voltaren Ophthalmic Use in Pregnancy & Breastfeeding
• Voltaren Ophthalmic Drug Interactions
• Voltaren Ophthalmic Support Group
• 0 Reviews for Voltaren Ophthalmic - Add your own review/rating

• Voltaren Ophthalmic Concise Consumer Information (Cerner Multum)

Compare Voltaren Ophthalmic with other medications

• Conjunctivitis
• Corneal Ulcer
• Inhibition of Intraoperative Miosis
• Keratoconjunctivitis
• Postoperative Ocular Inflammation

Jinteli

norethindrone acetate and ethinyl estradiol

Dosage Form: tablet
JinteliTM

(northindrone acetate and ethinyl estradiol tablets, USP)

WARNING

Estrogens and progestins should not be used for the prevention of cardiovascular disease or dementia. (See WARNINGS, Cardiovascular Disorders and Dementia.)

The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo. (See CLINICAL PHARMACOLOGY, Clinical Studies and WARNINGS, Cardiovascular Disorders and Malignant Neoplasms, Breast Cancer.)

The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.

(See CLINICAL PHARMACOLOGY, Clinical Studies, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)

Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Jinteli Description

JinteliTM (norethindrone acetate and ethinyl estradiol tablets, USP) is a continuous dosage regimen of a progestin-estrogen combination for oral administration.

Each white tablet contains 1 mg norethindrone acetate [19-Norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-, (17α)-] and 5 mcg ethinyl estradiol [19-Norpregna-1,3,5(10)-trien-20-yne-3, 17-diol, (17α)-]. Each tablet also contains the following ingredients: calcium stearate, lactose monohydrate, microcrystalline cellulose, pregelatinized starch, and sodium starch glycolate.

The structural formulas are as follows:

Norethindrone Acetate Ethinyl Estradiol C22H28O3 Molecular Weight: 340.47 C20H24O2 Molecular Weight: 296.41

Jinteli - Clinical Pharmacology

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites estrone and estriol at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. The pharmacologic effects of ethinyl estradiol are similar to those of endogenous estrogens.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, bone, skeletal tissue and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone.

Pharmacokinetics

Absorption

Norethindrone acetate (NA) is completely and rapidly deacetylated to norethindrone after oral administration, and the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol (EE) are rapidly absorbed from norethindrone acetate and ethinyl estradiol tablets, with maximum plasma concentrations of norethindrone and ethinyl estradiol generally occurring 1 to 2 hours postdose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 55% for ethinyl estradiol. Bioavailability of norethindrone acetate and ethinyl estradiol tablets is similar to that from solution for norethindrone and slightly less for ethinyl estradiol. Administration of norethindrone acetate and ethinyl estradiol tablets with a high fat meal decreases rate but not extent of ethinyl estradiol absorption. The extent of norethindrone absorption is increased by 27% following administration of norethindrone acetate and ethinyl estradiol tablets with food.

The full pharmacokinetic profile of norethindrone acetate and ethinyl estradiol tablets was not characterized due to assay sensitivity limitations. However, the multiple-dose pharmacokinetics were studied at a dose of 1 mg NA/10 mcg EE in 18 post-menopausal women. Mean plasma concentrations are shown below (Figure 1) and pharmacokinetic parameters are found in Table 1. Based on a population pharmacokinetic analysis, mean steady-state concentrations of norethindrone for 1 mg NA/5 mcg EE and 1/10 are slightly more than proportional to dose when compared to 0.5 mg NA/2.5 mcg EE tablets. It can be explained by higher sex hormone binding globulin (SHBG) concentrations. Mean steady-state plasma concentrations of ethinyl estradiol for the norethindrone acetate and ethinyl estradiol 0.5/2.5 tablets and norethindrone acetate and ethinyl estradiol 1/5 tablets are proportional to dose, but there is a less than proportional increase in steady-state concentrations for the NA/EE 1/10 tablet.

Figure 1: Mean Steady-State (Day 87) Plasma Norethindrone and Ethinyl Estradiol Concentrations Following Continuous Oral Administration of 1 mg NA/10 mcg EE Tablets

Table 1: Mean (SD) Single-Dose (Day 1) and Steady-State (Day 87) Pharmacokinetic Parameters*  Following Administration of 1 mg NA/10 mcg EE Tablets

* Cmax = Maximum plasma concentration; tmax = time of Cmax; AUC(0-24) = Area under the plasma concentration-time curve over the dosing interval; and CL/F = Apparent oral clearance; t½ = Elimination half-life † ND = Not determined
	Cmax	tmax	AUC(0-24)	CL/F	t½
Norethindrone	ng/mL	hr	ng·hr/mL	mL/min	hr
Day 1	6.0 (3.3)	1.8 (0.8)	29.7 (16.5)	588 (416)	10.3 (3.7)
Day 87	10.7 (3.6)	1.8 (0.8)	81.8 (36.7)	226 (139)	13.3 (4.5)
Ethinyl Estradiol	pg/mL	hr	pg•hr/mL	mL/min	hr
Day 1	33.5 (13.7)	2.2 (1.0)	339 (113)	ND†	ND†
Day 87	38.3 (11.9)	1.8 (0.7)	471 (132)	383 (119)	23.9 (7.1)

 Based on a population pharmacokinetic analysis, average steady-state concentrations (Css) of norethindrone and ethinyl estradiol for norethindrone acetate and ethinyl estradiol 1/5 tablets are estimated to be 2.6 ng/mL and 11.4 pg/mL, respectively. Css values of norethindrone and ethinyl estradiol for norethindrone acetate and ethinyl estradiol 0.5/2.5 tablets are estimated to be 1.1 ng/mL and 5.4 ng/mL, respectively.

The pharmacokinetics of ethinyl estradiol and norethindrone acetate were not affected by age, (age range 40-62 years), in the postmenopausal population studied.

Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (>95%); norethindrone binds to both albumin and sex hormone binding globulin (SHBG), whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis.

Metabolism

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol, such that exposure to ethinyl estradiol following administration of 1 mg of norethindrone acetate is equivalent to oral administration of 2.8 mcg ethinyl estradiol. 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, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation.

Excretion

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of 1 mg NA/10 mcg EE tablets are approximately 13 hours and 24 hours, respectively.

Special Populations

Pediatric

Norethindrone acetate and ethinyl estradiol is not indicated in children.

Geriatrics

The pharmacokinetics of norethindrone acetate and ethinyl estradiol have not been studied in a geriatric population.

Race

The effect of race on the pharmacokinetics of norethindrone acetate and ethinyl estradiol has not been studied.

Patients with Renal Insufficiency

The effect of renal disease on the disposition of norethindrone acetate and ethinyl estradiol 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 (see PRECAUTIONS, Fluid Retention).

Patients with Hepatic Impairment

The effect of hepatic disease on the disposition of norethindrone acetate and ethinyl estradiol has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function (see PRECAUTIONS).

Drug  Interactions

See PRECAUTIONS, Drug Interactions.

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

Clinical Studies

Effects on Vasomotor Symptoms

A 12-week placebo-controlled, multicenter, randomized clinical trial was conducted in 266 symptomatic women who had at least 56 moderate to severe hot flushes during the week prior to randomization. On average, patients had 12 hot flushes per day upon study entry.

A total of 66 women were randomized to receive norethindrone acetate and ethinyl estradiol  1/5, 67 women were randomized to receive norethindrone acetate and ethinyl estradiol 0.5/2.5 and 66 women were randomized to the placebo group. Norethindrone acetate and ethinyl estradiol 1/5 and norethindrone acetate and ethinyl estradiol 0.5/2.5 were shown to be statistically better than placebo at weeks 4 and 12 for relief of the frequency of moderate to severe vasomotor symptoms. See Table 2. In Table 3, norethindrone acetate and ethinyl estradiol 1/5 was shown to be statistically better than placebo at weeks 4 and 12 for relief of the severity of moderate to severe vasomotor symptoms; norethindrone acetate and ethinyl estradiol 0.5/2.5 was shown to be statistically better than placebo at weeks 5 and 12 for relief of the severity of moderate to severe vasomotor symptoms.

Table 2: Mean Change from Baseline in the Number of Moderate to Severe Vasomotor Symptoms per Week-ITT Population, LOCF

* Denotes statistical significance at the 0.05 level
Visit	Placebo (N=66)	Norethindrone Acetate and Ethinyl Estradiol 0.5/2.5 (N=67)	Norethindrone Acetate and Ethinyl Estradiol 1/5 (N=66)
Baseline [1]
Mean (SD)	76.5 (21.4)	77.6 (26.5)	70.0 (16.6)
Week 4
Mean (SD)	39.4 (27.6)	30.2 (26.1)	20.4 (22.7)
Mean Change from Baseline (SD)	-37.0 (26.6)	-47.4* (26.1)	-49.6* (22.1)
p-Value vs. Placebo (95% CI) [2]		0.041 (-20.0, -1.0)	<0.001 (-22.0,-6.0)
Week 12
Mean (SD)	31.1 (27.0)	13.8 (20.4)	11.3 (18.9)
Mean Change from Baseline (SD)	-45.3 (30.2)	-63.8* (27.5)	-58.7* (23.1)
p-Value vs. Placebo (95% CI) [2]		<0.001 (-27.0, -7.0)	<0.001 (-25.0, -5.0)

[1] The baseline number of moderate to severe vasomotor symptoms (MSVS) is the weekly average number of MSVS during the two week prerandomization observation period.

[2] ANCOVA - Analysis of Covariance model where the observation variable is change from baseline; independent variables include treatment, center and baseline as covariate. The 95% CI-Mann-Whitney confidence interval for the difference between means (not stratified by center).

ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval

2 randomized subjects (1 in Placebo and 1 in norethindrone acetate and ethinyl estradiol) did not return diaries.

Table 3: Mean Change from Baseline in the Daily Severity Score of Moderate to Severe Vasomotor Symptoms per Week-ITT Population, LOCF

* Denotes statistical significance at the 0.05 level
Visit	Placebo (N=66)	Norethindrone Acetate and Ethinyl Estradiol 0.5/2.5 (N=67)	Norethindrone Acetate and Ethinyl Estradiol 1/5 (N=66)
Baseline [1]
Mean (SD)	2.49 (0.26)	2.48 (0.22)	2.47 (0.23)
Week 4
Mean (SD)	2.13 (0.74)	1.88 (0.89)	1.45 (1.03)
Mean Change from Baseline (SD)	-0.36 (0.68)	-0.59 (0.83)	-1.02* (1.06)
p-Value vs. Placebo (95% CI) [2]	-	0.130 (-0.3, 0.0)	<0.001 (-0.9, -0.2)
Week 5
Mean (SD)	2.06 (0.79)	1.68 (0.99)	1.23 (1.03)
Mean Change from Baseline (SD)	-0.44 (0.74)	-0.80* (0.94)	-1.24* (1.07)
p-Value vs. Placebo (95% CI) [2]	-	0.041 (-0.4, -0.0)	<0.001 (-1.2, -0.3)
Week 12
Mean (SD)	1.82 (1.03)	1.22 (1.11)	1.02 (1.16)
Mean Change from Baseline (SD)	-0.67 (1.02)	-1.26* (1.08)	-1.45* (1.19)
p-Value vs. Placebo (95% CI) [2]	-	0.002 (-0.9, -0.2)	<0.001 (-1.4, -0.3)

[1] The baseline severity of moderate to severe vasomotor symptoms (MSVS) is the daily severity score of MSVS during the two week prerandomization observation period.

[2] ANCOVA - Analysis of Covariance model where the observation variable is change from baseline; independent variables include treatment, center and baseline as covariate. The 95% CI- Mann-Whitney confidence interval for the difference between means (not stratified by center).

ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval

2 randomized subjects (1 in Placebo and 1 in norethindrone acetate and ethinyl estradiol) did not return diaries.

Endometrial Hyperplasia

A 2-year, placebo-controlled, multicenter, randomized clinical trial was conducted to determine the safety and efficacy of norethindrone acetate and ethinyl estradiol on maintaining bone mineral density, protecting the endometrium, and to determine effects on lipids. A total of 1265 women were enrolled and randomized to either placebo, 0.2 mg NA/1 mcg EE, norethindrone acetate and ethinyl estradiol 0.5/2.5, norethindrone acetate and ethinyl estradiol 1/5 and 1 mg NA/10 mcg EE or matching unopposed EE doses (1, 2.5, 5, or 10 mcg) for a total of 9 treatment groups. All participants received 1000 mg of calcium supplementation daily. Of the 1265 women randomized to the various treatment arms of this study, 137 were randomized to placebo, 146 to norethindrone acetate and ethinyl estradiol 1/5, 136 to norethindrone acetate and ethinyl estradiol 0.5/2.5 and 141 to EE 5 mcg and 137 to EE 2.5 mcg. Of these, 134 placebo, 143 norethindrone acetate and ethinyl estradiol 1/5, 136 norethindrone acetate and ethinyl estradiol 0.5/2.5, 139 EE 5 mcg and 137 EE 2.5 mcg had a baseline endometrial result. Baseline biopsies were classified as normal (in approximately 95% of subjects), or insufficient tissue (in approximately 5% of subjects). Follow-up biopsies were obtained in approximately 70-80% of patients in each arm after 12 and 24 months of therapy. Results are shown in Table 4.

Table 4: Endometrial Biopsy Results After 12 and 24 Months of Treatment (CHART Study, 376-359)

*  All patients with endometrial hyperplasia were carried forward for all time points
Endometrial Status	Placebo	Norethindrone Acetate and Ethinyl Estradiol		EE Alone
		0.5/2.5	1/5	2.5 mcg	5 mcg
Number of Patients Biopsied at Baseline	N= 134	N=136	N= 143	N=137	N=139
MONTH 12 (% Patients)
Patients Biopsied (%)	113 (84)	103 (74)	110 (77)	100 (73)	114 (82)
Insufficient Tissue	30	34	45	20	20
Atrophic Tissue	60	41	41	15	2
Proliferative Tissue	23	28	24	65	91
Endometrial Hyperplasia*	0	0	0	0	1
MONTH 24 (% Patients)
Patients Biopsied (%)	94 (70)	99 (73)	102 (71)	89 (65)	107 (77)
Insufficient Tissue	35	42	37	23	17
Atrophic Tissue	38	30	33	6	2
Proliferative Tissue	20	27	32	60	86
Endometrial Hyperplasia*	1	0	0	0	2

Irregular Bleeding/Spotting

The cumulative incidence of amenorrhea, defined as no bleeding or spotting obtained from subject recall, was evaluated over 12 months for norethindrone acetate and ethinyl estradiol 0.5/2.5, norethindrone acetate and ethinyl estradiol 1/5 and placebo arms. Results are shown in Figure 2.

Effect on Bone Mineral Density

In the 2 year study, trabecular bone mineral density (BMD) was assessed at lumbar spine using quantitative computed tomography. A total of 419 postmenopausal primarily Caucasian women, aged 40 to 64 years, with intact uteri and non-osteoporotic bone mineral densities were randomized (1:1:1) to norethindrone acetate and ethinyl estradiol 1/5, norethindrone acetate and ethinyl estradiol 0.5/2.5 or placebo. Approximately 75% of the subjects in each group completed the two-year study. All patients received 1000 mg calcium in divided doses. Vitamin D was not supplemented.

As shown in Figure 3, women treated with norethindrone acetate and ethinyl estradiol 1/5 had an average increase of 3.1% in lumbar spine BMD from baseline to Month 24. Women treated with norethindrone acetate and ethinyl estradiol 0.5/2.5 and placebo had average decreases of –0.8% and –6.3%, respectively, in spinal BMD from baseline to Month 24. The differences in the changes from baseline to Month 24 in the two norethindrone acetate and ethinyl estradiol groups compared with the placebo group were statistically significant.

It should be noted that when measured by QCT, BMD gains and losses are greater than when measured by dual X-ray absorptiometry (DXA). Therefore, the differences in the changes in BMD between the placebo and active drug treated groups will be larger when measured by QCT compared with DXA. Changes in BMD measured by DXA should not be compared with changes in BMD measured by QCT.

Figure 3: Mean Percent Change (+ SE) From Baseline in Volumetric Bone Mineral Density* at Lumbar Spine Measured by Quantitative Computed Tomography after 12 and 24 Months of Treatment (Intent-to-Treat Population)

*It should be noted that when measured by QCT, BMD gains and losses are greater than when measured by dual X-ray absorptiometry (DXA). Therefore, the differences in the changes in BMD between the placebo and active drug treated groups will be larger when measured by QCT compared with DXA. Changes in BMD measured by DXA should not be compared with changes in BMD measured by QCT.

Women’s Health Initiative Studies

The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of oral 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 5 below:

Table 5: RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF WHI*

* nominal confidence intervals unadjusted for multiple looks and multiple comparisons
*  adapted from JAMA, 2002; 288:321-333 †  a subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes ‡ includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer § not included in Global Index
Event†	Relative Risk CE/MPA vs placebo at 5.2 Years (95% CI*)	Placebo n = 8102	CE/MPA n = 8506
		Absolute Risk per 10,000 Women-years
CHD events	1.29 (1.02-1.63)	30	37
Non-fatal MI	1.32 (1.02-1.72)	23	30
CHD death	1.18 (0.70-1.97)	6	7
Invasive breast cancer‡	1.26 (1.00-1.59)	30	38
Stroke	1.41 (1.07-1.85)	21	29
Pulmonary embolism	2.13 (1.39-3.25)	8	16
Colorectal cancer	0.63 (0.43-0.92)	16	10
Endometrial cancer	0.83 (0.47-1.47)	6	5
Hip fracture	0.66 (0.45-0.98)	15	10
Death due to causes other than the events above	0.92 (0.74-1.14)	40	37
Global Index†	1.15 (1.03-1.28)	151	170
Deep vein thrombosis§	2.07 (1.49-2.87)	13	26
Vertebral fractures§	0.66 (0.44-0.98)	15	9

Trimetrexate

Pronunciation: TRY-meh-TREK-sate
Generic Name: Trimetrexate
Brand Name: Neutrexin

Trimetrexate must be used with another medicine called leucovorin to protect against potentially serious or life-threatening reactions, such as kidney or liver problems; infected stomach, intestinal or mouth sores; or a decreased ability to fight infections.

Trimetrexate is used for:

Treating moderate to severe Pneumocystis carinii pneumonia (PCP) in patients with weak immune systems, including those with AIDS, who are not able to take the standard treatment. Trimetrexate is used in combination with leucovorin.

Trimetrexate is an anti-infective agent. It works by inhibiting DNA, RNA, and protein synthesis, leading to cell death.

Do NOT use Trimetrexate if:

• you are allergic to any ingredient in Trimetrexate, leucovorin, or methotrexate


• you are taking a nonsteroidal anti-inflammatory drug (NSAID) (eg, ibuprofen) or pristinamycin

Contact your doctor or health care provider right away if any of these apply to you.

Before using Trimetrexate:

Some medical conditions may interact with Trimetrexate. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have bone marrow depression, a blood disorder, or kidney or liver problems

Some MEDICINES MAY INTERACT with Trimetrexate. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Cisplatin, corticosteroids (eg, prednisone), cyclosporine, etretinate, NSAIDs (eg, ibuprofen), penicillins (eg, amoxicillin), pristinamycin, probenecid, quinolones (eg, ciprofloxacin), salicylates (eg, aspirin), sulfonamides (eg, sulfamethoxazole), tetracyclines (eg, doxycycline), or trimethoprim because the actions and side effects of Trimetrexate may be increased, possibly leading to toxicities


• Digoxin or hydantoins (eg, phenytoin) because the effectiveness of these medicines may be decreased

This may not be a complete list of all interactions that may occur. Ask your health care provider if Trimetrexate 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.

How to use Trimetrexate:

Use Trimetrexate as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Trimetrexate is usually administered as an injection at your doctor's office, hospital, or clinic. If you are using Trimetrexate at home, carefully follow the injection procedures taught to you by your health care provider.


• Trimetrexate should not be given at the same time as fluorouracil. Doses should be separated as directed.


• If Trimetrexate contains particles or is discolored, or if the vial is cracked or damaged in any way, do not use it.


• Trimetrexate must be used with another medicine, leucovorin, as protection against potentially serious or life-threatening reactions. Treatment with leucovorin must extend 72 hours past the last dose of Trimetrexate. Use all leucovorin doses as instructed. If you fail to use the correct dose and all doses of leucovorin, it may cause fatal toxicity.


• Keep this product, as well as syringes and needles, out of the reach of children and away from pets. Do not reuse needles, syringes, or other materials. Dispose of properly after use. Ask your doctor or pharmacist to explain local regulations for proper disposal.


• If you miss a dose of Trimetrexate, contact your doctor immediately.

Ask your health care provider any questions you may have about how to use Trimetrexate.

Important safety information:

• Do not drink alcohol while you are using Trimetrexate.


• Trimetrexate may reduce the number of clot-forming cells (platelets) in your blood. To prevent bleeding, avoid situations in which bruising or injury may occur. Report any unusual bleeding, bruising, blood in stools, or dark, tarry stools to your doctor.


• Trimetrexate may lower your body's ability to fight infection. Prevent infection by avoiding contact with people with colds or other infections. Notify your doctor of any signs of infection including fever, sore throat, rashes, or chills.


• LAB TESTS, including neutrophil counts, platelet counts, liver function, and kidney function, may be performed to monitor your progress or to check for side effects. Be sure to keep all doctor and lab appointments.


• Use Trimetrexate with caution in the ELDERLY because they may be more sensitive to its effects.


• Trimetrexate is not recommended for use in CHILDREN. Safety and effectiveness have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Trimetrexate has been shown to cause harm to the fetus. Avoid becoming pregnant while taking Trimetrexate. If you think you may be pregnant, discuss with your doctor the benefits and risks of using Trimetrexate during pregnancy. It is unknown if Trimetrexate is excreted in breast milk. Do not breast-feed while taking Trimetrexate.

Possible side effects of Trimetrexate:

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:

Confusion; fatigue.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chills; drops in counts of blood cells; fever; itching; nausea; sores in mouth; symptoms of a new infection; unusual bruising or bleeding; unusual tiredness or weakness; vomiting; yellow discoloration of skin or eyes.

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: Trimetrexate side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include blood disorders.

Proper storage of Trimetrexate:

Store Trimetrexate at room temperature, between 68 to 77 degrees F (20 to 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Trimetrexate out of the reach of children and away from pets.

General information:

• If you have any questions about Trimetrexate, please talk with your doctor, pharmacist, or other health care provider.


• Trimetrexate is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Trimetrexate. 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.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Trimetrexate resources

• Trimetrexate Side Effects (in more detail)
• Trimetrexate Use in Pregnancy & Breastfeeding
• Trimetrexate Drug Interactions
• Trimetrexate Support Group
• 0 Reviews for Trimetrexate - Add your own review/rating

• trimetrexate Intravenous Advanced Consumer (Micromedex) - Includes Dosage Information


• Neutrexin Prescribing Information (FDA)

Compare Trimetrexate with other medications

• Pneumocystis Pneumonia

Xanodyne Pharmaceuticals, Inc

Address Xanodyne Pharmaceuticals, Inc, 1 Riverfront Place Newport, KY 41071-4563 Contact Details Phone: (859) 371-6383 Website: http://www.xanodyne.com Careers: http://www.xanodyne.com/careers.asp

Imodium Original 2mg Capsules

1. Name Of The Medicinal Product

Imodium Original 2 mg Capsules.

2. Qualitative And Quantitative Composition

Each capsule contains 2 mg Loperamide hydrochloride.

Excipient: lactose

For a full list of excipients, see Section 6.1

3. Pharmaceutical Form

Capsule, hard.

Opaque green cap and grey body, hard gelatin capsule imprinted with 'Imodium' on cap and 'Janssen' on body containing white powder.

4. Clinical Particulars

4.1 Therapeutic Indications

For the symptomatic treatment of acute diarrhoea in adults and children aged 12 years and over.

For the symptomatic treatment of acute episodes of diarrhoea associated with Irritable Bowel Syndrome in adults aged 18 years and over following initial diagnosis by a doctor.

4.2 Posology And Method Of Administration

The capsules should be taken with liquid.

ACUTE DIARRHOEA

Adults and children over 12:

2 capsules (4 mg) initially followed by 1 capsule (2 mg) after every loose stool.

The maximum daily dose should not exceed 6 capsules (12 mg).

SYMPTOMATIC TREATMENT OF ACUTE EPISODES OF DIARRHOEA ASSOCIATED WITH IRRITABLE BOWEL SYNDROME IN ADULTS AGED 18 YEARS AND OVER

Two capsules (4 mg) to be taken initially, followed by 1 capsule (2 mg) after every loose stool, or as previously advised by your doctor. The maximum daily dose should not exceed 6 capsules (12 mg).

USE IN ELDERLY

No dose adjustment is required for the elderly.

RENAL IMPAIRMENT

No dose adjustment is required for patients with renal impairment.

HEPATIC IMPAIRMENT

Although no pharmacokinetic data are available in patients with hepatic impairment, Imodium should be used with caution in such patients because of reduced first pass metabolism. (see 4.4 Special warnings and special precautions for use).

Method of administration

Oral use.

4.3 Contraindications

This medicine is contraindicated:

• in patients with a known hypersensitivity to loperamide hydrochloride or to any of the excipients.

• in children less than 12 years of age.

• in patients with acute dysentery, which is characterised by blood in stools and high fever.

• in patients with acute ulcerative colitis.

• in patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella and Campylobacter.

• in patients with pseudomembranous colitis associated with the use of broad-spectrum antibiotics.

Imodium must not be used when inhibition of peristalsis is to be avoided due to the possible risk of significant sequelae including ileus, megacolon and toxic megacolon. Imodium must be discontinued promptly when ileus, constipation or abdominal distension develop.

4.4 Special Warnings And Precautions For Use

Treatment of diarrhoea with Imodium is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate. The priority in acute diarrhoea is the prevention or reversal of fluid and electrolyte depletion. This is particularly important in young children and in frail and elderly patients with acute diarrhoea. Use of this medicine does not preclude the administration of appropriate fluid and electrolyte replacement therapy.

Since persistent diarrhoea can be an indicator of potentially more serious conditions, this medicine should not be used for prolonged periods until the underlying cause of the diarrhoea has been investigated.

In acute diarrhoea, if clinical improvement is not observed within 24 hours, the administration of Imodium should be discontinued and patients should be advised to consult their doctor.

Patients with AIDS treated with this medicine for diarrhoea should have therapy stopped at the earliest signs of abdominal distension. There have been isolated reports of obstipation with an increased risk for toxic megacolon in AIDS patients with infectious colitis from both viral and bacterial pathogens treated with loperamide hydrochloride.

Although no pharmacokinetic data are available in patients with hepatic impairment, this medicine should be used with caution in such patients because of reduced first pass metabolism, as it may result in a relative overdose leading to CNS toxicity.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine because it contains lactose.

If you are taking this medicine to control episodes of diarrhoea associated with Irritable Bowel Syndrome previously diagnosed by your doctor, you should return to him/her if the pattern of your symptoms changes. You should also return to your doctor if your episodes of diarrhoea continue for more than two weeks or there is a need for continued treatment of more than two weeks.

Special Warnings to be included on the leaflet:

Only take this medicine to treat acute episodes of diarrhoea associated with Irritable Bowel Syndrome if your doctor has previously diagnosed IBS.

If any of the following now apply, do not use the product without first consulting your doctor, even if you know you have IBS:

• If you are 40 years or over and it is some time since your last attack of IBS or the symptoms are different this time

• If you have recently passed blood from the bowel

• If you suffer from severe constipation

• If you are feeling sick or vomiting

• If you have lost your appetite or lost weight

• If you have difficulty or pain passing urine

• If you have a fever

• If you have recently travelled abroad

Consult your doctor if you develop new symptoms, or if your symptoms worsen, or your symptoms have not improved over two weeks.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Non-clinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant administration of loperamide (16 mg single dose) with quinidine, or ritonavir, which are both P-glycoprotein inhibitors, resulted in a 2 to 3-fold increase in loperamide plasma levels. The clinical relevance of this pharmacokinetic interaction with P-glycoprotein inhibitors, when loperamide is given at recommended dosages, is unknown.

The concomitant administration of loperamide (4 mg single dose) and itraconazole, an inhibitor of CYP3A4 and P-glycoprotein, resulted in a 3 to 4-fold increase in loperamide plasma concentrations. In the same study a CYP2C8 inhibitor, gemfibrozil, increased loperamide by approximately 2-fold. The combination of itraconazole and gemfibrozil resulted in a 4-fold increase in peak plasma levels of loperamide and a 13-fold increase in total plasma exposure. These increases were not associated with central nervous system (CNS) effects as measured by psychomotor tests (i.e. subjective drowsiness and the Digit Symbol Substitution Test).

The concomitant administration of loperamide (16 mg single dose) and ketoconazole, an inhibitor of CYP3A4 and P-glycoprotein, resulted in a 5-fold increase in loperamide plasma concentrations. This increase was not associated with increased pharmacodynamic effects as measured by pupillometry.

Concomitant treatment with oral desmopressin resulted in a 3-fold increase of desmopressin plasma concentrations, presumably due to slower gastrointestinal motility.

It is expected that drugs with similar pharmacological properties may potentiate loperamide's effect and that drugs that accelerate gastrointestinal transit may decrease its effect.

4.6 Pregnancy And Lactation

Safety in human pregnancy has not been established, although from animal studies there are no indications that loperamide HCl posseses any teratogenic or embryotoxic properties. As with other drugs, it is not advisable to administer this medicine in pregnancy, especially during the first trimester.

Small amounts of loperamide may appear in human breast milk. Therefore, this medicine is not recommended during breast-feeding.

Women who are pregnant or breast feeding infants should therefore be advised to consult their doctor for appropriate treatment.

4.7 Effects On Ability To Drive And Use Machines

Loss of consciousness, depressed level of consciousness, tiredness, dizziness, or drowsiness may occur when diarrhoea is treated with this medicine. Therefore, it is advisable to use caution when driving a car or operating machinery. See Section 4.8, Undesirable Effects.

4.8 Undesirable Effects

Adults and children aged

The safety of loperamide HCl was evaluated in 2755 adults and children aged

The most commonly reported (i.e.

Table 1 displays ADRs that have been reported with the use of loperamide HCl from either clinical trial (acute diarrhoea) or post-marketing experience.

The frequency categories use the following convention: very common (

Table 1: Adverse Drug Reactions

System Organ Class	Indication
Common	Uncommon	Rare
Immune System Disorders			Hypersensitivity reactiona Anaphylactic reaction (including Anaphylactic shock)a Anaphylactoid reactiona
Nervous System Disorders	Headache	Dizziness Somnolencea	Loss of consciousnessa Stupora Depressed level of consciousnessa Hypertoniaa Coordination abnormalitya
Eye Disorders			Miosisa
Gastrointestinal Disorders	Constipation Nausea Flatulence	Abdominal pain Abdominal discomfort Dry mouth Abdominal pain upper Vomiting Dyspepsiaa	Ileusa (including paralytic ileus) Megacolona (including toxic megacolonb) Abdominal distension
Skin and Subcutaneous Tissue Disorders		Rash	Bullous eruptiona (including Stevens-Johnson syndrome, Toxic epidermal necrolysis and Erythema multiforme) Angioedemaa Urticariaa Pruritusa
Renal and Urinary Disorders			Urinary retentiona
General Disorders and Administration Site Conditions			Fatiguea
a: Inclusion of this term is based on post-marketing reports for loperamide HCl. As the process for determining post marketing ADRs did not differentiate between chronic and acute indications or adults and children, the frequency is estimated from all clinical trials with loperamide HCl (acute and chronic), including trials in children b: See section 4.4 Special Warnings and Special Precautions for use.

4.9 Overdose

Symptoms:

In case of overdose (including relative overdose due to hepatic dysfunction), CNS depression (stupor, coordination abnormality, somnolence, miosis, muscular hypertonia and respiratory depression), constipation, urinary retention and ileus may occur. Children, and patients with hepatic dysfunction, may be more sensitive to CNS effects.

Treatment:

If symptoms of overdose occur, naloxone can be given as an antidote. Since the duration of action of loperamide is longer than that of naloxone (1 to 3 hours), repeated treatment with naloxone might be indicated. Therefore, the patient should be monitored closely for at least 48 hours in order to detect possible CNS depression.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Antipropulsives: ATC code: A07DA03

Loperamide binds to the opiate receptor in the gut wall, reducing propulsive peristalsis and increasing intestinal transit time. Loperamide increases the tone of the anal sphincter.

In a double blind randomised clinical trial in 56 patients with acute diarrhoea receiving loperamide, onset of anti-diarrhoeal action was observed within one hour following a single 4 mg dose. Clinical comparisons with other antidiarrhoeal drugs confirmed this exceptionally rapid onset of action of loperamide.

5.2 Pharmacokinetic Properties

The half-life of loperamide in man is 10.8 hours with a range of 9-14 hours. Studies on distribution in rats show high affinity for the gut wall with preference for binding to the receptors in the longitudinal muscle layer. Loperamide is well absorbed from the gut, but is almost completely extracted and metabolised by the liver where it is conjugated and excreted via the bile. Due to its high affinity for the gut wall and its high first pass metabolism, very little loperamide reaches the systemic circulation.

5.3 Preclinical Safety Data

No relevant information additional to that contained elsewhere in the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose

Maize starch

Talc

Magnesium stearate (E572)

Capsule cap:

Titanium dioxide (E171)

Yellow ferric oxide (E172)

Indigo carmine (E132)

Gelatin

Capsule body:

Titanium dioxide (E171)

Black ferrous oxide (E172)

Indigo carmine (E132)

Erythrosine (E127)

Gelatin

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

Blister packs consisting of aluminium foil, hermetalu and polyvinyl chloride genotherm glass clear.

The blister strips are packed in cardboard cartons to contain 2, 4 or 6 capsules.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

McNeil Products Limited

Foundation Park

Roxborough Way

Maidenhead

Berkshire

SL6 3UG

United Kingdom

8. Marketing Authorisation Number(S)

PL 15513/0310

9. Date Of First Authorisation/Renewal Of The Authorisation

15/12/2009

10. Date Of Revision Of The Text

27/07/2011