Zyprexa

Generic Name: olanzapine (Oral route)

oh-LAN-za-peen

Oral route(Tablet;Tablet, Disintegrating)

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared to placebo. Although the causes of death in clinical trials were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Observational studies suggest that antipsychotic drugs may increase mortality. It is unclear from these studies to what extent the mortality findings may be attributed to the antipsychotic drug as opposed to patient characteristics. Olanzapine is not approved for the treatment of patients with dementia-related psychosis .

Commonly used brand name(s)

In the U.S.

• Zyprexa


• Zyprexa Zydis

Available Dosage Forms:

• Tablet


• Tablet, Disintegrating

Therapeutic Class: Antipsychotic

Chemical Class: Thienobenzodiazepine

Uses For Zyprexa

Olanzapine is used to treat nervous, emotional, and mental conditions (e.g., schizophrenia). It may also be used alone or with other medicines (e.g., lithium or valproate) to treat bipolar disorder (manic-depressive illness) or mania that is part of bipolar disorder. This medicine should not be used to treat behavioral problems in older adult patients who have dementia or Alzheimer's disease.

This medicine is available only with your doctor's prescription.

Before Using Zyprexa

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

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of olanzapine in teenagers 13 to 17 years of age. However, safety and efficacy of olanzapine in children younger than 13 years of age have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of olanzapine in the elderly. However, elderly patients are more likely to have dementia or age-related liver, kidney, or heart problems, which may require caution or an adjustment in the dose for patients receiving olanzapine.

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. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Levomethadyl


• Metoclopramide

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Clomipramine


• Hydromorphone


• Lithium


• Milnacipran


• Mirtazapine


• Tetrabenazine


• Tramadol

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Betel Nut


• Carbamazepine


• Ciprofloxacin


• Fluvoxamine


• Haloperidol


• Valproic Acid

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. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Blood vessel disease or circulation problems or


• Dehydration or


• Heart attack or stroke, history of or


• Heart disease or


• Heart failure or


• Heart rhythm problems or


• Hypotension (low blood pressure) or


• Hypovolemia (low blood volume)—May cause side effects to become worse.

• Breast cancer, prolactin-dependent or


• Glaucoma, narrow-angle or


• Hyperlipidemia (high cholesterol or fat in the blood) or


• Hyperprolactinemia (high prolactin in the blood) or


• Liver disease or


• Paralytic ileus (severe intestinal problem), history of or


• Prostatic hypertrophy (enlarged prostate) or


• Seizures, history of—Use with caution. This medicine may make these conditions worse.

• Diabetes or


• Hyperglycemia (high blood sugar)—This medicine may raise your blood sugar levels.

• Phenylketonuria (PKU, a genetic disease of metabolism)—The orally disintegrating tablet (Zyprexa® Zydis®) contains phenylalanine, which can make this condition worse.

Proper Use of olanzapine

This section provides information on the proper use of a number of products that contain olanzapine. It may not be specific to Zyprexa. Please read with care.

Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This medicine should come with a medication guide. Read and follow these instructions carefully. Ask your doctor or pharmacist if you have any questions. Ask your pharmacist for the medication guide if you do not have one.

If you are using the orally disintegrating tablet (Zyprexa® Zydis®), make sure your hands are dry before you handle the tablet. Do not open the blister pack that contains the tablet until you are ready to take it. Remove the tablet from the blister pack by peeling back the foil, then taking the tablet out. Do not push the tablet through the foil. Place the tablet in your mouth. It should melt quickly. After the tablet has melted, swallow or take a sip of water.

You may take this medicine with or without food.

Tell your doctor if you smoke tobacco. You might need a different amount of this medicine if you smoke.

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 oral dosage form (orally disintegrating tablets, regular tablets):
  
  • For treatment of schizophrenia:
    
    • Adults—At first, 5 to 10 milligrams (mg) once a day. Your doctor may adjust your dose if needed. However, the dose is usually not more than 20 mg per day.
    
    
    • Teenagers and children 13 to 17 years of age—At first, 2.5 or 5 milligrams (mg) once a day. Your doctor may adjust your dose if needed. However, the dose is usually not more than 20 mg per day.
    
    
    • Children younger than 13 years of age—Use and dose must be determined by your doctor.
    
    
  
  
  • For treatment of bipolar disorder:
    
    • Adults—At first, 5 to 15 milligrams (mg) once a day. Your doctor may adjust your dose if needed. However, the dose is usually not more than 20 mg per day.
    
    
    • Teenagers and children 13 to 17 years of age—At first, 2.5 or 5 milligrams (mg) once a day. Your doctor may adjust your dose if needed. However, the dose is usually not more than 20 mg per day.
    
    
    • Children younger than 13 years of age—Use and dose must be determined by your doctor.
    
    
  
  
  • For treatment of mania with bipolar disorder:
    
    • Adults—At first, 10 to 15 milligrams (mg) once a day. Your doctor may adjust your dose if needed. However, the dose is usually not more than 20 mg per day.
    
    
    • Teenagers and children 13 to 17 years of age—At first, 2.5 or 5 milligrams (mg) once a day. Your doctor may adjust your dose if needed. However, the dose is usually not more than 20 mg per day.
    
    
    • Children younger than 13 years of age—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Zyprexa

It is very important that your doctor check your or your child's progress at regular visits to make sure this medicine is working properly. Blood tests may be needed to check for unwanted effects.

For some patients, this medicine can increase thoughts of suicide. Tell your doctor right away if you or your child start to feel more depressed and have thoughts about hurting yourself. Report any unusual thoughts or behaviors that trouble you, especially if they are new or are getting worse quickly. Make sure the doctor knows if you or your child have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. Also tell the doctor if you have sudden or strong feelings, such as feeling nervous, angry, restless, violent, or scared. Let the doctor know if you or anyone in your family has bipolar disorder (manic-depressive illness) or has tried to commit suicide.

This medicine may increase the amount of sugar in your blood. Check with your doctor right away if you have increased thirst or increased urination. If you or your child have diabetes, you may notice a change in the results of your urine or blood sugar tests. If you have any questions, check with your doctor.

This medicine may increase your cholesterol and fats in the blood. If this condition occurs, your doctor may give you or your child some medicines that can lower the amount of cholesterol and fats in the blood.

This medicine may increase your weight. Your doctor may need to check your or your child's weight on a regular basis while you are using this medicine.

Stop taking this medicine and check with your doctor right away if you or your child have any of the following symptoms while using this medicine: convulsions (seizures), difficulty with breathing, a fast heartbeat, a high fever, high or low blood pressure, increased sweating, loss of bladder control, severe muscle stiffness, unusually pale skin, or tiredness. These could be symptoms of a serious condition called neuroleptic malignant syndrome (NMS).

This medicine may cause tardive dyskinesia (a movement disorder). Check with your doctor right away if you or your child have any of the following symptoms while taking this medicine: lip smacking or puckering, puffing of the cheeks, rapid or worm-like movements of the tongue, uncontrolled chewing movements, or uncontrolled movements of the arms and legs.

Dizziness, lightheadedness, or fainting may occur, especially when you get up from a lying or sitting position. Getting up slowly may help. If this problem continues or gets worse, check with your doctor.

This medicine can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. If you can, avoid people with infections. Check with your doctor immediately if you or your child think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.

Olanzapine may cause drowsiness, trouble with thinking, trouble with controlling body movements, or trouble with your vision. Make sure you know how you react to this medicine before you drive, use machines, or do other jobs that require you to be alert, well-coordinated, or able to think or see well.

This medicine may add to the effects of alcohol and other central nervous system (CNS) depressants (medicines that make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicines for allergies or colds; sedatives, tranquilizers, or sleeping medicines; prescription pain medicines or narcotics; medicines for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before taking any CNS depressants while you are taking this medicine.

This medicine may make it more difficult for your body to cool down. It might reduce how much you sweat. Your body could get too hot if you do not sweat enough. If your body gets too hot, you might feel dizzy, weak, tired, or confused. You might vomit or have an upset stomach. Do not get too hot while you are exercising. Avoid places that are very hot. Call your doctor if you are too hot and can not cool down.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines) and herbal or vitamin supplements.

Zyprexa Side Effects

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.

Check with your doctor immediately if any of the following side effects occur:

More common

• Bloating or swelling of the face, arms, hands, lower legs, or feet


• blurred vision


• change in vision


• change in walking and balance


• clumsiness or unsteadiness


• difficulty with speaking


• difficulty with swallowing


• drooling


• impaired vision


• inability to sit still


• loss of balance control


• mask-like face


• muscle trembling, jerking, or stiffness


• need to keep moving


• rapid weight gain


• restlessness


• shakiness in the legs, arms, hands, or feet


• shuffling walk


• slowed movements


• slurred speech


• stiffness of the arms and legs


• tic-like (jerky) movements of the head, face, mouth, and neck


• tingling of the hands or feet


• trembling or shaking of the fingers, hands, or feet


• twisting movements of the body


• uncontrolled movements, especially of the face, neck, and back


• unusual weight gain or loss

Less common

• Bladder pain


• bloody or cloudy urine


• bruising


• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings


• chest pain


• difficult or labored breathing


• difficult, burning, or painful urination


• dizziness


• excessive muscle tone


• frequent urge to urinate


• headache


• inability to move the eyes


• increased blinking or spasms of the eyelid


• itching of the vagina or genital area


• lack of coordination


• large, flat, blue, or purplish patches in the skin


• loss of bladder control


• loss of memory


• lower back or side pain


• muscle tension or tightness


• nervousness


• pain during sexual intercourse


• pounding in the ears


• problems with memory


• rhythmic movement of the muscles


• shortness of breath


• slow, fast, pounding, or irregular heartbeat or pulse


• speaking is less clear than usual


• sticking out the tongue


• thick, white vaginal discharge with no odor or with a mild odor


• tightness in the chest


• trouble with breathing, speaking, or swallowing


• twitching


• uncontrolled twisting movements of the neck, trunk, arms, or legs


• unusual or incomplete body or facial movements


• weakness of the arms and legs


• wheezing

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

• Anxiety


• attacking, assaulting, or using force


• change in consciousness


• change in patterns and rhythms of speech


• confusion as to time, place, or person


• convulsions (seizures)


• dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly


• drowsiness


• dry mouth


• fainting


• hallucinations


• heart stops beating


• high fever


• high or low blood pressure


• holding false beliefs that cannot be changed by fact


• increased sweating


• irregular, fast or slow, or shallow breathing


• irritability


• lightheadedness


• loss of consciousness


• mood or mental changes


• no breathing


• no pulse or blood pressure


• pale or blue lips, fingernails, or skin


• rapid breathing


• relaxed and calm


• severe muscle stiffness


• shaking or trembling


• sleepiness


• trouble with sleeping


• unconscious


• unusual excitement, nervousness, or restlessness


• unusual tiredness or weakness


• unusually pale skin

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:

More common

• Acid or sour stomach


• back pain


• belching


• change in personality


• difficulty having a bowel movement (stool)


• discouragement


• feeling sad or empty


• fever


• heartburn


• increased appetite


• increased cough


• indigestion


• lack of appetite


• lack or loss of strength


• loss of interest or pleasure


• runny nose


• sleeplessness


• sneezing


• stomach discomfort, upset, or pain


• stuffy nose


• thirst


• trouble with concentrating


• unable to sleep


• watering of the mouth


• weight gain

Less common

• Blemishes on the skin


• body aches or pain


• chills


• cold sweats


• congestion


• cough


• dry skin


• dryness or soreness of the throat


• false or unusual sense of well-being


• joint pain


• heavy menstrual bleeding (periods)


• hoarseness


• lack of feeling or emotion


• leg cramps


• pain in the arms or legs


• pimples


• sweating


• tender, swollen glands in the neck


• uncaring feelings


• voice change


• vomiting

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: Zyprexa side effects (in more detail)

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More Zyprexa resources

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

• Zyprexa Prescribing Information (FDA)


• Zyprexa Consumer Overview


• Zyprexa MedFacts Consumer Leaflet (Wolters Kluwer)


• Olanzapine Monograph (AHFS DI)


• Olanzapine MedFacts Consumer Leaflet (Wolters Kluwer)


• Olanzapine Professional Patient Advice (Wolters Kluwer)


• Zyprexa Relprevv Prescribing Information (FDA)


• Zyprexa Relprevv MedFacts Consumer Leaflet (Wolters Kluwer)


• Zyprexa Relprevv Consumer Overview


• Zyprexa Zydis Orally Disintegrating Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Zyprexa with other medications

• Anorexia
• Asperger Syndrome
• Bipolar Disorder
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• Insomnia
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• Paranoid Disorder
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• Schizophrenia
• Tourette's Syndrome

Kapanol

Kapanol may be available in the countries listed below.

Ingredient matches for Kapanol

Morphine

Morphine sulphate pentahydrate (a derivative of Morphine) is reported as an ingredient of Kapanol in the following countries:

• Australia


• Belgium


• Bosnia & Herzegowina


• Germany


• Luxembourg


• Netherlands


• Switzerland

International Drug Name Search

Zarah

drospirenone and ethinyl estradiol

Dosage Form: tablets
Zarah™

(Drospirenone and Ethinyl Estradiol Tablets, 3 mg / 0.03 mg)

Issued: May 2010

Rx only

PATIENTS SHOULD BE COUNSELED THAT THIS PRODUCT DOES NOT PROTECT AGAINST HIV INFECTION (AIDS) AND OTHER SEXUALLY TRANSMITTED DISEASES.

DESCRIPTION

Zarah™ (Drospirenone and ethinyl estradiol tablets) provides an oral contraceptive regimen consisting of 21 active tablets each containing 3 mg of drospirenone and 0.030 mg of ethinyl estradiol and 7 inert tablets. The inactive ingredients are lactose monohydrate, corn starch, pregelatinized starch, magnesium stearate, Vitamin E, FD&C Blue #1 Aluminum Lake. The inert tablets contain lactose anhydrous, microcrystalline cellulose, FD&C Yellow #6 Aluminum Lake and magnesium stearate.

Drospirenone (6R,7R,8R,9S,10R,13S,14S,15S,16S,17S) - 1,3’,4’,6,6a,7,8,9,10,11,12,13,14,15,15a,16 - hexadecahydro - 10,13 - dimethylspiro - [17H - dicyclopropa - 6,7:15,16]cyclopenta[a]phenanthrene - 17,2’(5H) - furan] - 3,5’(2H) - dione) is a synthetic progestational compound and has a molecular weight of 366.5 and a molecular formula of C24H30O3. Ethinyl estradiol (19-nor-17α-pregna 1,3,5(10)-triene-20-yne-3,17-diol) is a synthetic estrogenic compound and has a molecular weight of 296.4 and a molecular formula of C20H24O2. The structural formulas are as follows:

Drospirenone                                                   Ethinyl estradiol

CLINICAL PHARMACOLOGY

Pharmacodynamics

Combination oral contraceptives (COCs) 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 increases the difficulty of sperm entry into the uterus) and the endometrium (which reduces the likelihood of implantation).

Drospirenone is a spironolactone analogue with antimineralocorticoid activity. Preclinical studies in animals and in vitro have shown that drospirenone has no androgenic, estrogenic, glucocorticoid, and antiglucocorticoid activity. Preclinical studies in animals have also shown that drospirenone has antiandrogenic activity.

Pharmacokinetics

Absorption

The absolute bioavailability of drospirenone (DRSP) from a single entity tablet is about 76%. The absolute bioavailability of ethinyl estradiol (EE) is approximately 40% as a result of presystemic conjugation and first-pass metabolism. The absolute bioavailability of a combination tablet of drospirenone and ethinyl estradiol has not been evaluated. Serum concentrations of DRSP and EE reached peak levels within 1 to 3 hours after administration of drospirenone and ethinyl estradiol. After single dose administration of drospirenone and ethinyl estradiol, the relative bioavailability, compared to a suspension, was 107% and 117% for DRSP and EE, respectively.

The pharmacokinetics of DRSP are dose proportional following single doses ranging from 1 to 10 mg. Following daily dosing of drospirenone and ethinyl estradiol, steady-state DRSP concentrations were observed after 10 days. There was about 2 to 3 fold accumulation in serum Cmax and AUC (0 to 24h) values of DRSP following multiple dose administration of drospirenone and ethinyl estradiol (see Table 1).

For EE, steady-state conditions are reported during the second half of a treatment cycle. Following daily administration of drospirenone and ethinyl estradiol serum Cmax and AUC (0 to 24h) values of EE accumulate by a factor of about 1.5 to 2.0.

TABLE 1: Mean Pharmacokinetic Parameters of Drospirenone and Ethinyl Estradiol (3 mg / 0.03 mg)

Drospirenone Mean (%CV) Values
Cycle / Day	No. of Subjects	Cmax (ng/mL)	Tmax (h)	AUC(0 to 24h) (ng•h/mL)	t1/2 (h)
NA = Not available
1/1	12	36.9 (13)	1.7 (47)	288 (25)	NA
1/21	12	87.5 (59)	1.7 (20)	827 (23)	30.9 (44)
6/21	12	84.2 (19)	1.8 (19)	930 (19)	32.5 (38)
9/21	12	81.3 (19)	1.6 (38)	957 (23)	31.4 (39)
13/21	12	78.7 (18)	1.6 (26)	968 (24)	31.1 (36)
Ethinyl Estradiol Mean (%CV) Values
Cycle / Day	No. of Subjects	Cmax (pg/mL)	Tmax (h)	AUC(0 to 24h) (pg•h/mL)	t1/2 (h)
1/1	11	53.5 (43)	1.9 (45)	280.3 (87)	NA
1/21	11	92.1 (35)	1.5 (40)	461.3 (94)	NA
6/21	11	99.1 (45)	1.5 (47)	346.4 (74)	NA
9/21	11	87.0 (43)	1.5 (42)	485.3 (92)	NA
13/21	10	90.5 (45)	1.6 (38)	469.5 (83)	NA

Effect of Food

The rate of absorption of DRSP and EE following single administration of two drospirenone and ethinyl estradiol tablets was slower under fed conditions with the serum Cmax being reduced about 40% for both components. The extent of absorption of DRSP, however, remained unchanged. In contrast the extent of absorption of EE was reduced by about 20% under fed conditions.

Distribution

DRSP and EE serum levels decline in two phases. The apparent volume of distribution of DRSP is approximately 4 L/kg and that of EE is reported to be approximately 4 to 5 L/kg.

DRSP does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG) but binds about 97% to other serum proteins. Multiple dosing over 3 cycles resulted in no change in the free fraction (as measured at trough levels). EE is reported to be highly but non-specifically bound to serum albumin (approximately 98.5 %) and induces an increase in the serum concentrations of both SHBG and CBG. EE induced effects on SHBG and CBG were not affected by variation of the DRSP dosage in the range of 2 to 3 mg.

Metabolism

The two main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate. These metabolites were shown not to be pharmacologically active. In in vitro studies with human liver microsomes, DRSP was metabolized only to a minor extent mainly by Cytochrome P450 3A4 (CyP3A4)

EE has been reported to be subject to presystemic conjugation in both small bowel mucosa and the liver. Metabolism occurs primarily by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed. These are present as free metabolites and as conjugates with glucuronide and sulfate. CYP3A4 in the liver are responsible for the 2-hydroxylation which is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion.

Excretion

DRSP serum levels are characterized by a terminal disposition phase half-life of approximately 30 hours after both single and multiple dose regimens. Excretion of DRSP was nearly complete after ten days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least 20 different metabolites were observed in urine and feces. About 38 to 47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17 to 20 % of the metabolites were excreted as glucuronides and sulfates.

For EE the terminal disposition phase half life has been reported to be approximately 24 hours. EE is not excreted unchanged. EE is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic circulation.

Special Populations

Race

The effect of race on the disposition of drospirenone and ethinyl estradiol has not been evaluated.

Hepatic Dysfunction

Drospirenone and ethinyl estradiol is contraindicated in patients with hepatic dysfunction (also see BOLDED WARNING). The mean exposure to DRSP in women with moderate liver impairment is approximately three times the exposure in women with normal liver function.

Renal Insufficiency

Drospirenone and ethinyl estradiol is contraindicated in patients with renal insufficiency (also see BOLDED WARNING).

The effect of renal insufficiency on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the effect of DRSP on serum potassium levels were investigated in female subjects (n = 28, age 30 to 65) with normal renal function and mild and moderate renal impairment. All subjects were on a low potassium diet. During the study 7 subjects continued the use of potassium sparing drugs for the treatment of the underlying illness. On the 14th day (steady-state) of DRSP treatment, serum DRSP levels in the group with mild renal impairment (creatinine clearance CLcr, 50 to 80 mL/min) were comparable to those in the group with normal renal function (CLcr, >80 mL/min). The serum DRSP levels were on average 37% higher in the group with moderate renal impairment (CLcr, 30 to 50 mL/min) compared to those in the group with normal renal function. DRSP treatment was well tolerated by all groups. DRSP treatment did not show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not observed in the study, in five of the seven subjects who continued use of potassium sparing drugs during the study, mean serum potassium levels increased by up to 0.33 mEq/L. Therefore, potential exists for hyperkalemia to occur in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium sparing drugs.

INDICATIONS AND USAGE

Zarah (Drospirenone and ethinyl estradiol tablets) is indicated for the prevention of pregnancy in women who elect to use an oral contraceptive.

Oral contraceptives are highly effective. Table 2 lists the typical accidental pregnancy rates for users of combination oral contraceptives and other methods of contraception. The efficacy of these contraceptive methods, except sterilization, depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.

TABLE 2: Percentage of women experiencing an unintended pregnancy during the first year of typical use and first year of perfect use of contraception and the percentage continuing use at the end of the first year: United States.

	% of Women Experiencing an Accidental Pregnancy within the First Year of Use		% of Women Continuing Use at One Year3
Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.9
Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.10 Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F, Contraceptive Technology: Seventeenth Revised Edition. New York, NY: Irvington Publishers, 1998.
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 reason.
3   Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.
4   The percents becoming pregnant in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percentage who would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.
5   Foams, creams, gels, vaginal suppositories, and vaginal film.
6   Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory 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.
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
Withdrawal	19	4
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
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 T380A	0.8	0.6	78
Lng 20	0.1	0.1	81
Depo-Provera®*	0.3	0.3	70
Norplant®* and Norplant®* II	0.05	0.05	88
Female sterilization	0.5	0.5	100
Male sterilization	0.15	0.10	100

In clinical efficacy studies of drospirenone and ethinyl estradiol tablets of up to 2 years duration, 2,629 subjects completed 33,160 cycles of use without any other contraception. The mean age of the subjects was 25.5 ± 4.7 years. The age range was 16 to 37 years. The racial demographic was: 83% Caucasians, 1% Hispanic, 1% Black, < 1% Asian, < 1% other, < 1% missing data, 14% not inquired and <1% unspecified. Pregnancy rates in the clinical trials were less than one per 100 woman-years of use.

CONTRAINDICATIONS

Drospirenone and ethinyl estradiol tablets should not be used in women who have the following:

• Renal insufficiency


• Hepatic dysfunction


• Adrenal Insufficiency


• Thrombophlebitis or thromboembolic disorders


• A past history of deep-vein thrombophlebitis or thromboembolic disorders


• Cerebral-vascular or coronary-artery disease


• Valvular heart disease with thrombogenic complications


• Severe hypertension


• Diabetes with vascular involvement


• Headaches with focal neurological symptoms


• Known or suspected carcinoma of the breast


• Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia


• Undiagnosed abnormal genital bleeding


• Cholestatic jaundice of pregnancy or jaundice with prior pill use


• Liver tumor (benign or malignant) or active liver disease


• Known or suspected pregnancy


• Heavy smoking (> 15 cigarettes per day) and over age 35

WARNINGS

Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

Drospirenone and ethinyl estradiol tablets contain 3 mg of the progestin drospirenone that has antimineralocorticoid activity, including the potential for hyperkalemia in high-risk patients, comparable to a 25 mg dose of spironolactone. Drospirenone and ethinyl estradiol tablets should not be used in patients with conditions that predispose to hyperkalemia (i.e. renal insufficiency, hepatic dysfunction and adrenal insufficiency). Women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium should have their serum potassium level checked during the first treatment cycle. Drugs that may increase serum potassium include ACE inhibitors, angiotensin – II receptor antagonists, potassium-sparing diuretics, heparin, aldosterone antagonists, and NSAIDs.

The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, 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 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 based principally 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, epidemiologic studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among 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 epidemiologic 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 (Table 3) among women who use oral contraceptives.

TABLE 3: (Adapted from P.M. Layde and V. Beral) Circulatory Disease Mortality Rates Per 100,000 Woman-Years By Age, Smoking Status and Oral Contraceptive Use

AGE	EVER-USERS NON- SMOKERS	EVER-USERS SMOKERS	CONTROLS NON-SMOKERS	CONTROL SMOKERS
15 to 24	0.0	10.5	0.0	0.0
25 to 34	4.4	14.2	2.7	4.2
35 to 44	21.5	63.4	6.4	15.2
45+	52.4	206.7	11.4	27.9

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"). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

b. Thromboembolism

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease. Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization. The risk of thromboembolic disease 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 the relative risk of post-operative 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 from 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.

Several studies have investigated the relative risks of thromboembolism in women using drospirenone and ethinyl estradiol tablets compared to those in women using COCs containing other progestins. Two prospective cohort studies, both evaluating the risk of venous and arterial thromboembolism and death, were initiated at the time of drospirenone and ethinyl estradiol tablets approval.1, 2 The first (EURAS) showed the risk of thromboembolism (particularly venous thromboembolism) and death in drospirenone and ethinyl estradiol tablets users to be comparable to that of other oral contraceptive preparations, including those containing levonorgestrel (a so-called second generation COC). The second prospective cohort study (Ingenix) also showed a comparable risk of thromboembolism in drospirenone and ethinyl estradiol tablets users compared to users of other COCs, including those containing levonorgestrel. In the second study, COC comparator groups were selected based on their having similar characteristics to those being prescribed drospirenone and ethinyl estradiol tablets.

Two additional epidemiological studies, one case-control study (van Hylckama Vlieg et al.3) and one retrospective cohort study (Lidegaard et al.4) suggested that the risk of venous thromboembolism occurring in drospirenone and ethinyl estradiol tablets users was higher than that for users of levonorgestrel-containing COCs and lower than that for users of desogestrel/gestodene-containing COCs (so-called third generation COCs). In the case-control study, however, the number of drospirenone and ethinyl estradiol tablets cases was very small (1.2% of all cases) making the risk estimates unreliable. The relative risk for drospirenone and ethinyl estradiol tablets users in the retrospective cohort study was greater than that for users of other COC products when considering women who used the products for less than one year. However, these one-year estimates may not be reliable because the analysis may include women of varying risk levels. Among women who used the product for 1 to 4 years, the relative risk was similar for users of drospirenone and ethinyl estradiol tablets to that for users of other COC products.

c. Cerebrovascular diseases

Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor, for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes.

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.

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 progestogen 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 provides satisfactory results in the individual.

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 aged 40 to 49 years 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 4). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is below that associated with childbirth.

The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's - but not reported until 1983. 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 risks 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, women of all ages who take oral contraceptives should take the lowest possible dose formulation that is effective.

TABLE 4: Annual Number of Birth-Related or Method-Related Deaths Associated With Control of Fertility per 100,000 Nonsterile Women, by Fertility Control Method According to Age

Method of Control and Outcome	AGE
	15 to 19	20 to 24	25 to 29	30 to 34	35 to 39	40 to 44
1 Deaths are birth related
2 Deaths are method related
Adapted from H.W. Ory, Family Planning Perspectives, 15:57 to 63, 1983.
No fertility control methods1	7.0	7.4	9.1	14.8	25.7	28.2
Oral contraceptives
Nonsmoker 2	0.3	0.5	0.9	1.9	13.8	31.6
Oral contraceptives
Smoker 2	2.2	3.4	6.6	13.5	51.1	117.2
lUD 2	0.8	0.8	1	1	1.4	1.4
Condom 1	1.1	1.6	0.7	0.2	0.3	0.4
Diaphragm/ spermicide 1	1.9	1.2	1.2	1.3	2.2	2.8
Periodic abstinence 1	2.5	1.6	1.6	1.7	2.9	3.6

3. CARCINOMA OF THE REPRODUCTIVE ORGANS AND BREASTS

Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian and cervical cancer in women using oral contraceptives.

The risk of having breast cancer diagnosed may be slightly increased among current and recent users of COCs. However this excess risk appears to decrease over time after COC discontinuation and by 10 years after cessation the increased risk disappears. The risk does not appear to increase with duration of use and no consistent relationships have been found with dose or type of steroid. Most studies show a similar pattern of risk with

Cromax

Cromax may be available in the countries listed below.

Ingredient matches for Cromax

Cromoglicic Acid

Cromoglicic Acid disodium salt (a derivative of Cromoglicic Acid) is reported as an ingredient of Cromax in the following countries:

• Colombia

International Drug Name Search

Ziox Ointment

Pronunciation: pap-ANE/you-REE-ah/KLOR-oh-FILL-in
Generic Name: Papain/Urea/Chlorophyllin
Brand Name: Examples include Panafil and Ziox

Ziox Ointment is used for:

Removing dead tissue and thinning the pus in lesions such as ulcers, burns, wounds, and carbuncles.

Ziox Ointment is a debriding agent. It works by helping the breakdown of dead skin and pus, which helps improve the recovery time of open wounds. It also helps to control wound inflammation and odor.

Do NOT use Ziox Ointment if:

• you are allergic to any ingredient in Ziox Ointment

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

Before using Ziox Ointment:

Some medical conditions may interact with Ziox Ointment. 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

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

• Medicines containing silver, lead, or mercury because they may decrease Ziox Ointment's effectiveness

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

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

• Ziox Ointment is for external use only.


• Before each use of Ziox Ointment, clean the affected area with saline or another mild wound cleansing solution. Do not use hydrogen peroxide.


• Apply Ziox Ointment directly to the lesion, cover with appropriate dressing (eg, bandages), and secure into place. Wash the lesion each time the dressing is changed.


• Change wound dressings according to the schedule set by your doctor.


• If irritation occurs, talk with your doctor about changing the dressings more often.


• If you miss a dose of Ziox Ointment, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

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

Important safety information:

• Ziox Ointment is for external use only. Do not get it in the eyes or mouth. If you get Ziox Ointment in the eyes, rinse them immediately with a generous amount of cool water.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Ziox Ointment while you are pregnant. It is not known if Ziox Ointment is found in breast milk. If you are or will be breast-feeding while you use Ziox Ointment, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Ziox Ointment:

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:

Mild skin irritation; temporary burning sensation.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue).

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: Ziox 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.

Proper storage of Ziox Ointment:

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

General information:

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


• Ziox Ointment 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 Ziox Ointment. 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 Ziox resources

• Ziox Side Effects (in more detail)
• Ziox Use in Pregnancy & Breastfeeding
• Ziox Drug Interactions
• Ziox Support Group
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• Burns, External
• Dermatologic Lesion
• Wound Cleansing

Next Choice

levonorgestrel
FULL PRESCRIBING INFORMATION

 INDICATIONS AND USAGE

Next ChoiceTM is a progestin-only emergency contraceptive indicated for prevention of pregnancy following unprotected intercourse or a known or suspected contraceptive failure. To obtain optimal efficacy, the first tablet should be taken as soon as possible within 72 hours of intercourse. The second tablet should be taken 12 hours later.

Next ChoiceTM is available only by prescription for women younger than age 17 years, and available over the counter for women 17 years and older.

Next ChoiceTM is not indicated for routine use as a contraceptive.

 DOSAGE AND ADMINISTRATION

Take one levonorgestrel tablet orally as soon as possible within 72 hours after unprotected intercourse or a known or suspected contraceptive failure. Efficacy is better if the tablet is taken as soon as possible after unprotected intercourse. The second tablet should be taken 12 hours after the first dose. Next ChoiceTM can be used at any time during the menstrual cycle.

If vomiting occurs within two hours of taking either dose of medication, consideration should be given to repeating the dose.

 DOSAGE FORMS AND STRENGTHS

Each Next ChoiceTM tablet is supplied as a peach, round, bevel edged, flat faced tablet containing 0.75 mg of levonorgestrel and is embossed with “475” on one side and “WATSON” on the other side.

 CONTRAINDICATIONS

Next ChoiceTM is contraindicated for use in the case of known or suspected pregnancy.

 WARNINGS AND PRECAUTIONS

Ectopic Pregnancy

Ectopic pregnancies account for approximately 2% of all reported pregnancies. Up to 10% of pregnancies reported in clinical studies of routine use of progestin-only contraceptives are ectopic.

A history of ectopic pregnancy is not a contraindication to use of this emergency contraceptive method. Healthcare providers, however, should consider the possibility of an ectopic pregnancy in women who become pregnant or complain of lower abdominal pain after taking Next ChoiceTM. A follow-up physical or pelvic examination is recommended if there is any doubt concerning the general health or pregnancy status of any woman after taking Next ChoiceTM.

Existing Pregnancy

Next ChoiceTM is not effective in terminating an existing pregnancy.

 Effects on Menses

Some women may experience spotting a few days after taking Next ChoiceTM. Menstrual bleeding patterns are often irregular among women using progestin-only oral contraceptives and women using levonorgestrel for postcoital and emergency contraception. If there is a delay in the onset of expected menses beyond 1 week, consider the possibility of pregnancy.

 STI/HIV

Next ChoiceTM does not protect against HIV infection (AIDS) or other sexually transmitted infections (STIs).

 Physical Examination and Follow-up

A physical examination is not required prior to prescribing Next ChoiceTM. A follow-up physical or pelvic examination is recommended if there is any doubt concerning the general health or pregnancy status of any woman after taking Next ChoiceTM.

 Fertility Following Discontinuation

A rapid return of fertility is likely following treatment with Next ChoiceTM for emergency contraception; therefore, routine contraception should be continued or initiated as soon as possible following use of Next ChoiceTM to ensure ongoing prevention of pregnancy.

 Presence of FD&C Yellow #6

Next ChoiceTM contains FD&C Yellow #6 as a color additive.

Adverse Reactions

 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A double-blind, controlled clinical trial in 1,955 evaluable women compared the efficacy and safety of levonorgestrel tablets (one 0.75 mg tablet of levonorgestrel taken within 72 hours of unprotected intercourse, and one tablet taken 12 hours later) to the Yuzpe regimen (two tablets each containing 0.25 mg levonorgestrel and 0.05 mg ethinyl estradiol, taken within 72 hours of intercourse, and two tablets taken 12 hours later).

The most common adverse events (>10%) in the clinical trial for women receiving levonorgestrel tablets included menstrual changes (26%), nausea (23%), abdominal pain (18%), fatigue (17%), headache (17%), dizziness (11%), and breast tenderness (11%). Table 1 lists those adverse events that were reported in >5% of levonorgestrel tablets users.

Table 1: Adverse Events in >5% of Women, by % Frequency

Most Common Adverse Events	Levonorgestrel N=977 (%)
Nausea	23.1
Abdominal Pain	17.6
Fatigue	16.9
Headache	16.8
Heavier Menstrual Bleeding	13.8
Lighter Menstrual Bleeding	12.5
Dizziness	11.2
Breast Tenderness	10.7
Other complaints	9.7
Vomiting	5.6
Diarrhea	5.0

 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Next ChoiceTM. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal Disorders

Abdominal Pain, Nausea, Vomiting

General Disorders and Administration Site Conditions

Fatigue

Nervous System Disorders

Dizziness, Headache

Reproductive System and Breast Disorders

Dysmenorrhea, Irregular Menstruation, Oligomenorrhea, Pelvic Pain

Drug Interactions

Drugs or herbal products that induce enzymes, including CYP3A4, that metabolize progestins may decrease the plasma concentrations of progestins, and may decrease the effectiveness of progestin-only pills. Some drugs or herbal products that may decrease the effectiveness of progestin-only pills include:

• barbiturates
  


• bosentan
  


• carbamazepine
  


• felbamate
  


• griseofulvin
  


• oxcarbazepine
  


• phenytoin
  


• rifampin
  


• St. John’s wort
  


• topiramate

Significant changes (increase or decrease) in the plasma levels of the progestin have been noted in some cases of coadministration with HIV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.

Consult the labeling of all concurrently used drugs to obtain further information about interactions with progestin-only pills or the potential for enzyme alterations.

USE IN SPECIFIC POPULATIONS

 Pregnancy

Many studies have found no harmful effects on fetal development associated with longterm use of contraceptive doses of oral progestins. The few studies of infant growth and development that have been conducted with progestin-only pills have not demonstrated significant adverse effects.

 Nursing Mothers

In general, no adverse effects of progestin-only pills have been found on breastfeeding performance or on the health, growth or development of the infant. However, isolated post-marketing cases of decreased milk production have been reported. Small amounts of progestins pass into the breast milk of nursing mothers taking progestin-only pills for long-term contraception, resulting in detectable steroid levels in infant plasma.

 Pediatric Use

Safety and efficacy of progestin-only pills for long-term contraception have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents less than 17 years and for users 17 years and older. Use of Next ChoiceTM emergency contraception before menarche is not indicated.

 Geriatric Use

This product is not intended for use in postmenopausal women.

 Race

No formal studies have evaluated the effect of race. However, clinical trials demonstrated a higher pregnancy rate in Chinese women with both levonorgestrel tablets and the Yuzpe regimen (another form of emergency contraception). The reason for this apparent increase in the pregnancy rate with emergency contraceptives in Chinese women is unknown.

 Hepatic Impairment

No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of levonorgestrel tablets.

 Renal Impairment

No formal studies were conducted to evaluate the effect of renal disease on the disposition of levonorgestrel tablets.

Drug Abuse and Dependence

Levonorgestrel is not a controlled substance. There is no information about dependence associated with the use of Next ChoiceTM.

Overdosage

There are no data on overdosage of levonorgestrel tablets, although the common adverse event of nausea and associated vomiting may be anticipated.

Next Choice Description

Each Next ChoiceTM tablet contains 0.75 mg of a single active steroid ingredient, levonorgestrel [18,19-Dinorpregn-4-en-20-yn-3-one-13-ethyl-1 7-hydroxy-, (17α)-(-)-], a totally synthetic progestogen. The inactive ingredients present are colloidal silicon dioxide, corn starch, FD&C Yellow #6, magnesium stearate, povidone, and lactose monohydrate. Levonorgestrel has a molecular weight of 312.45, and the following structural and molecular formulas:

Next Choice - Clinical Pharmacology

 Mechanism of Action

Emergency contraceptive pills are not effective if a woman is already pregnant. Next ChoiceTM is believed to act as an emergency contraceptive principally by preventing ovulation or fertilization (by altering tubal transport of sperm and/or ova). In addition, they may inhibit implantation (by altering the endometrium). It is not effective once the process of implantation has begun.

 Pharmacokinetics

Absorption

No specific investigation of the absolute bioavailability of levonorgestrel tablets in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability about 100%) and is not subject to first pass metabolism.

After a single dose of levonorgestrel tablets (0.75 mg) administered to 16 women under fasting conditions, the mean maximum serum concentration of levonorgestrel was 14.1 ng/mL at an average of 1.6 hours. See Table 2.

Table 2: Pharmacokinetic Parameter Values Following Single Dose Administration of Levonorgestrel Tablets 0.75 mg to Healthy Female Volunteers under Fasting Conditions

	Mean (± SD)
	Cmax	Tmax	CL	Vd	t1/2	AUCinf
	(ng/mL)	(h)	(L/h)	(L)	(h)	(ng·hr/mL)
Levonorgestrel	14.1 (7.7)	1.6 (0.7)	7.7 (2.7)	260.0	24.4 (5.3)	123.1 (50.1)

Cmax = maximum concentration

Tmax = time to maximum concentration

CL = clearance

Vd = volume of distribution

t1/2 = elimination half life

AUCinf = area under the drug concentration curve from time 0 to infinity

Effect of Food: The effect of food on the rate and the extent of levonorgestrel absorption following single oral administration of levonorgestrel has not been evaluated.

Distribution

The apparent volume of distribution of levonorgestrel is reported to be approximately 1.8 L/kg. It is about 97.5 to 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin.

Metabolism

Following absorption, levonorgestrel is conjugated at the 17β-OH position to form sulfate conjugates and, to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3α, 5β-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3α, 5α-tetrahydrolevonorgestrel and 16βhydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users.

Excretion

About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates.

Specific Populations

Pediatric: This product is not intended for use in the premenarcheal population, and pharmacokinetic data are not available for this population.

Geriatric: This product is not intended for use in postmenopausal women and pharmacokinetic data are not available for this population.

Race: No formal studies have evaluated the effect of race on pharmacokinetics of levonorgestrel tablets. However, clinical trials demonstrated a higher pregnancy rate in Chinese women with both levonorgestrel tablets and the Yuzpe regimen (another form of emergency contraception). The reason for this apparent increase in the pregnancy rate with emergency contraceptives in Chinese women is unknown [see USE IN SPECIFIC POPULATIONS (8.6)].

Hepatic Impairment: No formal studies were conducted to evaluate the effect of hepatic disease on the disposition of levonorgestrel tablets.

Renal Impairment: No formal studies were conducted to evaluate the effect of renal disease on the disposition of levonorgestrel tablets.

Drug-Drug Interactions

No formal drug-drug interaction studies were conducted with levonorgestrel tablets [see DRUG INTERACTIONS (7)].

Nonclinical Toxicology

 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity: There is no evidence of increased risk of cancer with short-term use of progestins. There was no increase in tumorgenicity following administration of levonorgestrel to rats for 2 years at approximately 5 μg/day, to dogs for 7 years at up to 0.125 mg/kg/day, or to rhesus monkeys for 10 years at up to 250 μg/kg/day. In another 7 year dog study, administration of levonorgestrel at 0.5 mg/kg/day did increase the number of mammary adenomas in treated dogs compared to controls. There were no malignancies.

Genotoxicity: Levonorgestrel was not found to be mutagenic or genotoxic in the Ames Assay, in vitro mammalian culture assays utilizing mouse lymphoma cells and Chinese hamster ovary cells, and in an in vivo micronucleus assay in mice.

Fertility: There are no irreversible effects on fertility following cessation of exposures to levonorgestrel or progestins in general.

Clinical Studies

A double-blind, randomized, multinational controlled clinical trial in 1,955 evaluable women (mean age 27) compared the efficacy and safety of levonorgestrel tablets (one 0.75 mg tablet of levonorgestrel taken within 72 hours of unprotected intercourse, and one tablet taken 12 hours later) to the Yuzpe regimen (two tablets each containing 0.25 mg levonorgestrel and 0.05 mg ethinyl estradiol, taken within 72 hours of intercourse, and two additional tablets taken 12 hours later). After a single act of intercourse occurring anytime during the menstrual cycle, the expected pregnancy rate of 8% (with no contraceptive use) was reduced to approximately 1% with levonorgestrel tablets.

Emergency contraceptives are not as effective as routine hormonal contraception since their failure rate, while low based on a single use, would accumulate over time with repeated use [see INDICATIONS AND USAGE (1)].

At the time of expected menses, approximately 74% of women using levonorgestrel tablets had vaginal bleeding similar to their normal menses, 14% bled more than usual, and 12% bled less than usual. The majority of women (87%) had their next menstrual period at the expected time or within + 7 days, while 13% had a delay of more than 7 days beyond the anticipated onset of menses.

How Supplied/Storage and Handling

Next ChoiceTM (levonorgestrel) tablets, 0.75 mg, are available for a single course of treatment in PVC/aluminum foil blister packages of two tablets each. Each tablet is peach, round, bevel edged, and flat faced and embossed with “475” on one side and “WATSON” on the other side.

Available as: Unit-of-use NDC 52544-275-36

Store Next ChoiceTM tablets at 20° to 25°C (68° to 77°F) [see USP controlled room temperature].

Patient Counseling Information

 Information for Patients

• Take Next ChoiceTM as soon as possible and not more than 72 hours after unprotected intercourse or a known or suspected contraceptive failure.
  


• If you vomit within two hours of taking either tablet, immediately contact your healthcare provider to discuss whether to take another tablet.
  


• Seek medical attention if you experience severe lower abdominal pain 3 to 5 weeks after taking Next ChoiceTM, in order to be evaluated for an ectopic pregnancy.
  


• After taking Next ChoiceTM, consider the possibility of pregnancy if your period is delayed more than one week beyond the date you expected your period.
  


• Do not use Next ChoiceTM as routine contraception.
  


• Next ChoiceTM is not effective in terminating an existing pregnancy.
  


• Next ChoiceTM does not protect against HIV-infection (AIDS) and other sexually transmitted diseases/infections.
  


• For women younger than age 17 years, Next ChoiceTM is available only by prescription.
  


• Next ChoiceTM contains FD&C Yellow #6 as a color additive.

Manufactured by: Watson Laboratories, Inc.

Corona, CA 92880 USA

Distributed by: Watson Pharma, Inc.

Corona, CA 92880 USA

Phone: 1 -866-9WATSON (1-866-992-8766)

www.mynextchoice.com

Issued: August 2009

190229-1

0809B

PRINCIPAL DISPLAY PANEL

NDC 52544-275-36

Next Choice™ 

(Levonorgestrel) tablets 0.75 mg 

Emergency Contraceptive

Reduces the chance of pregnancy after unprotected sex (if a regular birth control method fails or after sex without birth control).

Not for regular birth control.

Next Choice™ should be used only in emergencies.

2 Levonorgestrel Tablets

0.75 mg each

Next Choice  levonorgestrel  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 52544-275 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LEVONORGESTREL (LEVONORGESTREL) LEVONORGESTREL 0.75 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE   STARCH, CORN   FD&C YELLOW NO. 6   MAGNESIUM STEARATE   POVIDONE   LACTOSE MONOHYDRATE

Product Characteristics Color ORANGE (peach) Score no score Shape ROUND (bevel edged, flat faced) Size 6mm Flavor Imprint Code 475;WATSON Contains

Packaging # NDC Package Description Multilevel Packaging 1 52544-275-36 1 BLISTER PACK In 1 CARTON contains a BLISTER PACK 1 2 TABLET In 1 BLISTER PACK This package is contained within the CARTON (52544-275-36)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA078665	09/04/2009

Labeler - Watson Pharma, Inc. (966714656)

Revised: 12/2009Watson Pharma, Inc.

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