Rapamune

Pronunciation: sir-OH-li-mus
Generic Name: Sirolimus
Brand Name: Rapamune

Rapamune decreases the action of the immune system. This may increase your risk of infection. It may also increase your risk of developing certain types of cancer (eg, lymphoma, skin cancer). Tell your doctor right away if you notice signs of infection (eg, persistent sore throat, chills, fever), any changes in the appearance or size of a mole, night sweats, unusual growths or lumps, or unusual tiredness or weakness.

Rapamune may increase the risk of severe side effects, including death, when used with certain other immunosuppressants in liver or lung transplant patients. Use of Rapamune in liver or lung transplant patients is not recommended.

Rapamune is used for:

Preventing organ rejection after a kidney transplant. It is used with other medicines. It may also be used for other conditions as determined by your doctor.

Rapamune is an immunosuppressant. It works by blocking the action of certain blood cells (eg, T lymphocytes) that can cause the body to reject the transplanted organ.

Do NOT use Rapamune if:

• you are allergic to any ingredient in Rapamune


• you have had a liver or lung transplant


• you are taking astemizole, certain azole antifungals (eg, itraconazole, ketoconazole, voriconazole), certain macrolide antibiotics (eg, clarithromycin, erythromycin), rifabutin, rifampin, tacrolimus, telithromycin, or terfenadine

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

Before using Rapamune:

Some medical conditions may interact with Rapamune. 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 able to become pregnant


• 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 liver problems, kidney problems, high cholesterol or triglycerides, low blood platelet levels, diabetes, or a history of lung or breathing problems


• if you are on dialysis, have recently received or are scheduled to receive a vaccine, or have a history of tuberculosis (TB) or have ever had a positive TB skin test


• if you have had multiple organ transplants, an organ retransplanted, or a previous transplant that was rejected


• if you or a family member has a history of skin cancer


• if you previously took cyclosporine and have recently stopped taking it

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

• Angiotensin-converting enzyme (ACE) inhibitors (eg, lisinopril) because the risk of a serious side effect (angioedema) involving swelling of the mouth, face, lips, tongue, throat, and hands; trouble swallowing or breathing; and unexplained hoarseness may be increased


• Amiodarone, azole antifungals (eg, fluconazole, itraconazole, ketoconazole, voriconazole), bromocriptine, cimetidine, cisapride, cyclosporine, danazol, diltiazem, dronedarone, hepatitis C virus (HCV) protease inhibitors (eg, boceprevir), HIV protease inhibitors (eg, ritonavir), macrolide antibiotics (eg, clarithromycin, erythromycin), metoclopramide, mibefradil, nicardipine, streptogramins (eg, dalfopristin), telithromycin, troleandomycin, or verapamil because they may increase the risk of Rapamune's side effects, including kidney problems


• Medicines that may harm the kidney (eg, aminoglycosides [eg, gentamicin], amphotericin B, nonsteroidal anti-inflammatory drugs [NSAIDs] [eg, ibuprofen], vancomycin) because the risk of kidney side effects may be increased. Ask your doctor if you are unsure if any of your medicines might harm the kidney


• Carbamazepine, hydantoins (eg, phenytoin), phenobarbital, rifamycins (eg, rifabutin, rifampin, rifapentine), or St. John's wort because they may decrease Rapamune's effectiveness


• Astemizole, calcineurin inhibitors (eg, tacrolimus ), fibrates (eg, fenofibrate), HMG-CoA reductase inhibitors (eg, atorvastatin), mycophenolate, or terfenadine because the risk of their side effects may be increased by Rapamune

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

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

• Rapamune comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Rapamune refilled.


• You may take Rapamune by mouth on an empty stomach or with food. However, you must take it the same way each time for it to work best. If you take Rapamune on an empty stomach, always take it on an empty stomach. If you take it with food, always take it with food.


• Swallow Rapamune whole. Do not break, crush, or chew before swallowing. If you cannot swallow Rapamune whole, check with your doctor.


• Wash your hands immediately after taking Rapamune.


• If you are also taking cyclosporine, take Rapamune 4 hours after your cyclosporine dose unless your doctor tells you otherwise.


• Grapefruit and grapefruit juice may increase the risk of side effects from Rapamune. Do not eat grapefruit or drink grapefruit juice while taking Rapamune.


• Rapamune works best if it is taken at the same time each day. Continue to take Rapamune even if you feel well. Do not miss any doses.


• Do not stop taking Rapamune without first checking with your doctor.


• If you miss a dose of Rapamune, take 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 take 2 doses at once.

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

Important safety information:

• Do not change your dose of Rapamune without first checking with your doctor.


• Rapamune may lower the ability of your body to fight infection. Avoid contact with people who have colds or infections. Tell your doctor if you notice signs of infection like fever, sore throat, rash, or chills.


• Some patients treated with Rapamune have developed severe and sometimes fatal infections, such as progressive multifocal leukoencephalopathy (PML) or severe kidney problems associated with BK virus infection. In kidney transplant patients, BK virus infection may cause loss of the transplanted kidney. Tell your doctor right away if you notice symptoms of PML (eg, confusion; disorientation; depression; changes in thinking, strength, or vision; one-sided weakness; trouble walking or talking; loss of balance or coordination) or kidney problems (eg, change in the amount of urine, difficult or painful urination, blood in the urine). Discuss any questions or concerns with your doctor.


• Rapamune may increase your risk of developing certain types of cancer (eg, lymphoma, skin cancer). Discuss any questions or concerns with your doctor.


• To decrease your risk of skin cancer, avoid using sunlamps or tanning booths. Limit your exposure to the sun. Use a sunscreen or wear protective clothing if you must be outside for more than a short time.


• Do not receive a live vaccine (eg, measles, mumps) while you are taking Rapamune. Talk with your doctor before you receive any vaccine.


• Rapamune may reduce the number of clot-forming cells (platelets) in your blood. Avoid activities that may cause bruising or injury. Tell your doctor if you have unusual bruising or bleeding. Tell your doctor if you have dark, tarry, or bloody stools.


• Do not switch between the tablet and solution forms of Rapamune without first checking with your doctor. The same doses may not be equally effective.


• Tell your doctor or dentist that you take Rapamune before you receive any medical or dental care, emergency care, or surgery.


• If you may become pregnant, you must use an effective form of birth control before you start taking Rapamune. You will need to continue to use birth control while you take Rapamune and for 12 weeks after you stop taking it. If you have questions about effective birth control, talk with your doctor.


• Decreased sperm production has occurred in some men taking Rapamune. Normal sperm production has usually returned when Rapamune was stopped. Discuss any questions or concerns with your doctor.


• Patients who take Rapamune after an organ transplant may have an increased risk of developing high blood sugar or diabetes. High blood sugar may make you feel confused, drowsy, or thirsty. It can also make you flush, breathe faster, or have a fruit-like breath odor. If these symptoms occur, tell your doctor right away.


• Lab tests, including complete blood cell counts, kidney function, urine protein, blood cholesterol and triglyceride levels, and sirolimus blood levels, may be performed while you take Rapamune. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Rapamune should be used with extreme caution in CHILDREN younger than 13 years old; safety and effectiveness in these children have not been confirmed.


• Rapamune should be used with extreme caution in CHILDREN younger than 18 years old who are considered to be at high immunological risk; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Rapamune may cause harm to the fetus. Do not become pregnant while you are taking it. If you think you may be pregnant, contact your doctor. You will need to discuss the benefits and risks of taking Rapamune while you are pregnant. It is not known if Rapamune is found in breast milk. Do not breast-feed while taking Rapamune.

Possible side effects of Rapamune:

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:

Acne; constipation; diarrhea; headache; joint pain; nausea; stomach pain.

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 or throat; swelling of the mouth, face, lips, or tongue; unusual hoarseness; wheezing); calf or leg pain, redness, tenderness, or swelling; chest pain; fainting; fast or irregular heartbeat; mental or mood changes; muscle pain, cramps, or tenderness; new or worsening breathing problems (eg, shortness of breath); new or worsening cough; night sweats; red, swollen, blistered, or peeling skin; severe or persistent headache or dizziness; skin growths or discoloration; swelling of the hands, ankles, feet, or stomach; swelling or soreness of the mouth or tongue; swollen glands or veins; symptoms of infection (eg, chills, fever, frequent or painful urination, sore throat, unusual vaginal discharge or odor); symptoms of kidney problems (eg, change in the amount of urine, difficult or painful urination, blood in the urine); symptoms of liver problems (eg, dark urine, loss of appetite, pale stools, yellowing of the skin or eyes); symptoms of PML (eg, changes in thinking, strength, or vision; confusion; depression; disorientation; loss of balance or coordination; one-sided weakness; trouble walking or talking); tremor; unusual bleeding or bruising; unusual lumps; unusual tiredness or weakness; unusual weight gain or loss; vision changes; wound healing problems.

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: Rapamune 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 Rapamune:

Store Rapamune at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store in a tightly closed container, away from heat, moisture, and light. Do not store in the bathroom. If Rapamune comes in a blister container, keep the tablets in the original container and use the outer carton to protect from light. Do not use after the expiration date. Keep Rapamune out of the reach of children and away from pets.

General information:

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


• Rapamune 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 Rapamune. 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 Rapamune resources

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

• Rapamune Prescribing Information (FDA)


• Rapamune Advanced Consumer (Micromedex) - Includes Dosage Information


• Rapamune Concise Consumer Information (Cerner Multum)


• Rapamune Monograph (AHFS DI)


• Sirolimus Professional Patient Advice (Wolters Kluwer)

Compare Rapamune with other medications

• Organ Transplant, Rejection Prophylaxis

Chemosef

Chemosef may be available in the countries listed below.

Ingredient matches for Chemosef

Cefalexin

Cefalexin is reported as an ingredient of Chemosef in the following countries:

• Bangladesh

International Drug Name Search

Fantezole

Fantezole may be available in the countries listed below.

Ingredient matches for Fantezole

Cilostazol

Cilostazol is reported as an ingredient of Fantezole in the following countries:

• Japan

International Drug Name Search

Renapril Plus

Renapril Plus may be available in the countries listed below.

Ingredient matches for Renapril Plus

Enalapril

Enalapril maleate (a derivative of Enalapril) is reported as an ingredient of Renapril Plus in the following countries:

• Hungary

Hydrochlorothiazide

Hydrochlorothiazide is reported as an ingredient of Renapril Plus in the following countries:

• Hungary

International Drug Name Search

Olanzapine Tablets

Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Olanzapine is not approved for the treatment of patients with dementia-related psychosis. [See Warnings and Precautions (5.1 , 5.14) and Patient Counseling Information (17.2)]. When using olanzapine and fluoxetine in combination, also refer to the Boxed Warning of the package insert for olanzapine and fluoxetine in combination.

Indications and Usage for Olanzapine Tablets

Schizophrenia

Olanzapine Tablets USP are indicated for the treatment of schizophrenia. Efficacy was established in three clinical trials in adult patients with schizophrenia: two 6-week trials and one maintenance trial [see Clinical Studies (14.1)].

When deciding among the alternative treatments for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and hyperlipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see Warnings and Precautions (5.5, 5.6)].

Information describing the use of Olanzapine Tablets in pediatric patients with schizophrenia is approved for Eli Lilly and Company’s olanzapine drug product labeling. However, due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Bipolar I Disorder (Manic or Mixed Episodes)

Monotherapy

Olanzapine Tablets USP are indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder. Efficacy was established in three clinical trials in adult patients with manic or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one monotherapy maintenance trial [see Clinical Studies (14.2)].

When deciding among the alternative treatments for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and hyperlipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents [see Warnings and Precautions (5.5, 5.6)].

Information describing the use of Olanzapine Tablets in pediatric patients with bipolar I disorder is approved for Eli Lilly and Company’s olanzapine drug product labeling. However, due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Adjunctive Therapy to Lithium or Valproate

Olanzapine Tablets USP are indicated for the treatment of manic or mixed episodes associated with bipolar I disorder as an adjunct to lithium or valproate. Efficacy was established in two 6-week clinical trials in adults. The effectiveness of adjunctive therapy for longer-term use has not been systematically evaluated in controlled trials [see Clinical Studies (14.2)].

Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder

Information on treating pediatric patients with schizophrenia and bipolar I disorder is approved for Eli Lilly and Company’s olanzapine drug product labeling. However, due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Olanzapine and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder

Oral olanzapine and fluoxetine in combination is indicated for the treatment of depressive episodes associated with bipolar I disorder, based on clinical studies in adult patients. When using olanzapine and fluoxetine in combination, refer to the Clinical Studies section of the package insert for olanzapine and fluoxetine in combination.

Olanzapine monotherapy is not indicated for the treatment depressive episodes associated with bipolar I disorder.

Olanzapine Tablets Dosage and Administration

Schizophrenia

Adults

Dose Selection

Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 5 to 10 mg initially, with a target dose of 10 mg/day within several days. Further dosage adjustments, if indicated, should generally occur at intervals of not less than 1 week, since steady state for olanzapine would not be achieved for approximately 1 week in the typical patient. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended.

Efficacy in schizophrenia was demonstrated in a dose range of 10 to 15 mg/day in clinical trials. However, doses above 10 mg/day were not demonstrated to be more efficacious than the 10 mg/day dose. An increase to a dose greater than the target dose of 10 mg/day (i.e., to a dose of 15 mg/day or greater) is recommended only after clinical assessment. Olanzapine is not indicated for use in doses above 20 mg/day.

Dosing in Special Populations

The recommended starting dose is 5 mg in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients ≥65 years of age), or who may be more pharmacodynamically sensitive to olanzapine [see Warnings and Precautions (5.14), Drug Interactions (7), and Clinical Pharmacology (12.3)]. When indicated, dose escalation should be performed with caution in these patients.

Maintenance Treatment

The effectiveness of oral olanzapine, 10 mg/day to 20 mg/day, in maintaining treatment response in schizophrenic patients who had been stable on olanzapine for approximately 8 weeks and were then followed for relapse has been demonstrated in a placebo-controlled trial [see Clinical Studies (14.1)]. The physician who elects to use olanzapine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Adolescents

Pediatric dosing information in pediatric patients with schizophrenia is approved for Eli Lilly and Company’s olanzapine drug product labeling. However, due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Bipolar I Disorder (Manic or Mixed Episodes)

Adults

Dose Selection for Monotherapy

Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 10 or 15 mg. Dosage adjustments, if indicated, should generally occur at intervals of not less than 24 hours, reflecting the procedures in the placebo-controlled trials. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended.

Short-term (3 to 4 weeks) antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials. The safety of doses above 20 mg/day has not been evaluated in clinical trials [see Clinical Studies (14.2)].

Maintenance Monotherapy

The benefit of maintaining bipolar I patients on monotherapy with oral olanzapine at a dose of 5 to 20 mg/day, after achieving a responder status for an average duration of 2 weeks, was demonstrated in a controlled trial [see Clinical Studies (14.2)]. The physician who elects to use olanzapine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Dose Selection for Adjunctive Treatment

When administered as adjunctive treatment to lithium or valproate, oral olanzapine dosing should generally begin with 10 mg once-a-day without regard to meals.

Antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials [see Clinical Studies (14.2)]. The safety of doses above 20 mg/day has not been evaluated in clinical trials.

Adolescents

Pediatric dosing information in pediatric patients with bipolar I disorder is approved for Eli Lilly and Company’s olanzapine drug product labeling. However, due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Olanzapine and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder

When using olanzapine and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for olanzapine and fluoxetine in combination.

Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 to 12.5 mg and fluoxetine 20 to 50 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg.

Safety and efficacy of olanzapine and fluoxetine in combination was determined in clinical trials supporting approval of olanzapine and fluoxetine in combination. Olanzapine and fluoxetine in combination is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of olanzapine and fluoxetine versus olanzapine and fluoxetine in combination. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

Table 1: Approximate Dose Correspondence Between Olanzapine and Fluoxetine in Combination and the Combination of Olanzapine and Fluoxetine

For	Use in Combination
olanzapine and fluoxetine in combination (mg/day)	Olanzapine (mg/day)	Fluoxetine (mg/day)
3 mg olanzapine/25 mg fluoxetine 6 mg olanzapine/25 mg fluoxetine 12 mg olanzapine/25 mg fluoxetine 6 mg olanzapine/50 mg fluoxetine 12 mg olanzapine/50 mg fluoxetine	2.5 5 10+2.5 5 10+2.5	20 20 20 40+10 40+10

 While there is no body of evidence to answer the question of how long a patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that bipolar I disorder, including the depressive episodes associated with bipolar I disorder, is a chronic illness requiring chronic treatment. The physician should periodically reexamine the need for continued pharmacotherapy.

Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.

Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.

Olanzapine and Fluoxetine in Combination: Dosing in Special Populations

The starting dose of oral olanzapine 2.5 to 5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, nonsmoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Dosing modification may be necessary in patients who exhibit a combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. Olanzapine and fluoxetine in combination have not been systematically studied in patients over 65 years of age or in patients < 18 years of age [see Warnings and Precautions (5.14), Drug Interactions (7), and Clinical Pharmacology (12.3)].

Dosage Forms and Strengths

Olanzapine Tablets USP, 2.5 mg are available as off-white, round, unscored, film-coated tablets, debossed with “TEVA” on one side and “5767” on the other side.

Olanzapine Tablets USP, 5 mg are available as off-white, round, unscored, film-coated tablets, debossed with “TEVA” on one side and "5768” on the other side.

Olanzapine Tablets USP, 7.5 mg are available as off-white, round, unscored, film-coated tablets, debossed with “TEVA” on one side and "5769” on the other side.

Olanzapine Tablets USP, 10 mg are available as off-white, round, unscored, film-coated tablets, debossed with “TEVA” on one side and "5770” on the other side.

Olanzapine Tablets USP, 15 mg are available as blue, capsule-shaped, unscored, film-coated tablets, debossed with “TEVA” on one side and “5771” on the other side.

Contraindications

• None with olanzapine monotherapy.


• When using olanzapine and fluoxetine in combination, also refer to the Contraindications section of the package insert for olanzapine and fluoxetine in combination.


• For specific information about the contraindications of lithium or valproate, refer to the Contraindications section of the package inserts for these other products.

Warnings and Precautions

When using olanzapine and fluoxetine in combination, also refer to the Warnings and Precautions section of the package insert for olanzapine and fluoxetine in combination.

Elderly Patients with Dementia-Related Psychosis

Increased Mortality

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.14), and Patient Counseling Information (17.2)].

In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively).

Cerebrovascular Adverse Events (CVAE), Including Stroke

Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with olanzapine compared to patients treated with placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Patient Counseling Information (17.2)].

Suicide

The possibility of a suicide attempt is inherent in Schizophrenia and in Bipolar I Disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for olanzapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported [see Patient Counseling Information (17.3)].

Hyperglycemia

Physicians should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level (fasting 100 to 126 mg/dL, non-fasting 140 to 200 mg/dL). Patients taking olanzapine should be monitored regularly for worsening of glucose control. Patients starting treatment with olanzapine should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug [see Patient Counseling Information (17.4)].

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including olanzapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics.

Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15 mg/dL.

In a study of healthy volunteers, subjects who received olanzapine (N = 22) for 3 weeks had a mean increase compared to baseline in fasting blood glucose of 2.3 mg/dL. Placebo-treated subjects (N = 19) had a mean increase in fasting blood glucose compared to baseline of 0.34 mg/dL.

Olanzapine Monotherapy in Adults

In an analysis of 5 placebo-controlled adult olanzapine monotherapy studies with a median treatment duration of approximately 3 weeks, olanzapine was associated with a greater mean change in fasting glucose levels compared to placebo (2.76 mg/dL versus 0.17 mg/dL). The difference in mean changes between olanzapine and placebo was greater in patients with evidence of glucose dysregulation at baseline (patients diagnosed with diabetes mellitus or related adverse reactions, patients treated with anti-diabetic agents, patients with a baseline random glucose level ≥ 200 mg/dL, and/or a baseline fasting glucose level ≥ 126 mg/dL). Olanzapine-treated patients had a greater mean HbA1c increase from baseline of 0.04% (median exposure 21 days), compared to a mean HbA1c decrease of 0.06% in placebo-treated subjects (median exposure 17 days).

In an analysis of 8 placebo-controlled studies (median treatment exposure 4 to 5 weeks), 6.1% of olanzapine-treated subjects (N = 855) had treatment-emergent glycosuria compared to 2.8% of placebo-treated subjects (N = 599). Table 2 shows short-term and long-term changes in fasting glucose levels from adult olanzapine monotherapy studies.

Table 2: Changes in Fasting Glucose Levels from Adult Olanzapine Monotherapy Studies

* Not Applicable
			Up to 12 weeks exposure		At least 48 weeks exposure
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	N	Patients	N	Patients
Fasting Glucose	Normal to High (< 100 mg/dL to ≥ 126 mg/dL)	Olanzapine	543	2.2%	345	12.8%
		Placebo	293	3.4%	NA*	NA*
	Borderline to High (≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL)	Olanzapine	178	17.4%	127	26%
		Placebo	96	11.5%	NA*	NA*

The mean change in fasting glucose for patients exposed at least 48 weeks was 4.2 mg/dL (N = 487). In analyses of patients who completed 9 to 12 months of olanzapine therapy, mean change in fasting and nonfasting glucose levels continued to increase over time.

Olanzapine Monotherapy in Adolescents

The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescent patients, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a greater mean change from baseline in fasting glucose levels compared to placebo (2.68 mg/dL versus -2.59 mg/dL). The mean change in fasting glucose for adolescents exposed at least 24 weeks was 3.1 mg/dL (N = 121). Table 3 shows short-term and long-term changes in fasting blood glucose from adolescent olanzapine monotherapy studies.

Table 3: Changes in Fasting Glucose Levels from Adolescent Olanzapine Monotherapy Studies

			Up to 12 weeks exposure		At least 24 weeks exposure
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	N	Patients	N	Patients
Fasting Glucose	Normal to High (< 100 mg/dL to ≥ 126 mg/dL)	Olanzapine	124	0%	108	0.9%
		Placebo	53	1.9%	NAa	NAa
	Borderline to High (≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL)	Olanzapine	14	14.3%	13	23.1%
		Placebo	13	0%	NAa	NAa

a) Not Applicable.

 5.5 Hyperlipidemia

Undesirable alterations in lipids have been observed with olanzapine use. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using olanzapine, is recommended [see Patient Counseling Information (17.5)].

Clinically significant, and sometimes very high (> 500 mg/dL), elevations in triglyceride levels have been observed with olanzapine use. Modest mean increases in total cholesterol have also been seen with olanzapine use.

Olanzapine Monotherapy in Adults

In an analysis of 5 placebo-controlled olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine-treated patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.3 mg/dL, 3 mg/dL, and 20.8 mg/dL respectively compared to decreases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 6.1 mg/dL, 4.3 mg/dL, and 10.7 mg/dL for placebo-treated patients. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated patients and placebo-treated patients. Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline, where lipid dysregulation was defined as patients diagnosed with dyslipidemia or related adverse reactions, patients treated with lipid lowering agents, or patients with high baseline lipid levels.

In long-term studies (at least 48 weeks), patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.6 mg/dL, 2.5 mg/dL, and 18.7 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 0.16 mg/dL. In an analysis of patients who completed 12 months of therapy, the mean nonfasting total cholesterol did not increase further after approximately 4 to 6 months.

The proportion of patients who had changes (at least once) in total cholesterol, LDL cholesterol or triglycerides from normal or borderline to high, or changes in HDL cholesterol from normal or borderline to low, was greater in long-term studies (at least 48 weeks) as compared with short-term studies. Table 4 shows categorical changes in fasting lipids values.

Table 4: Changes in Fasting Lipids Values from Adult Olanzapine Monotherapy Studies

* Not Applicable
			Up to 12 weeks exposure		At least 48 weeks exposure
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	N	Patients	N	Patients
Fasting Triglycerides	Increase by ≥ 50 mg/dL	Olanzapine	745	39.6%	487	61.4%
		Placebo	402	26.1%	NA*	NA*
	Normal to High (< 150 mg/dL to ≥ 200 mg/dL	Olanzapine	457	9.2%	293	32.4%
		Placebo	251	4.4%	NA*	NA*
	Borderline to High (≥ 150 mg/dL and < 200 mg/dL to ≥ 200 mg/dL)	Olanzapine	135	39.3%	75	70.7%
		Placebo	65	20%	NA*	NA*
Fasting Total Cholesterol	Increase by ≥ 40 mg/dL	Olanzapine	745	21.6%	489	32.9%
		Placebo	402	9.5%	NA*	NA*
	Normal to High (< 200 mg/dL to ≥ 240 mg/dL	Olanzapine	392	2.8%	283	14.8%
		Placebo	207	2.4%	NA*	NA*
	Borderline to High (≥ 200 mg/dL and < 240 mg/dL to ≥ 240 mg/dL)	Olanzapine	222	23%	125	55.2%
		Placebo	112	12.5%	NA*	NA*
Fasting LDL Cholesterol	Increase by ≥ 30 mg/dL	Olanzapine	536	23.7%	483	39.8%
		Placebo	304	14.1%	NA*	NA*
	Normal to High (< 100 mg/dL to ≥ 160 mg/dL	Olanzapine	154	0%	123	7.3%
		Placebo	82	1.2%	NA*	NA*
	Borderline to High (≥ 100 mg/dL and < 160 mg/dL to ≥ 160 mg/dL)	Olanzapine	302	10.6%	284	31%
		Placebo	173	8.1%	NA*	NA*

In phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), over a median exposure of 9.2 months, the mean increase in triglycerides in patients taking olanzapine was 40.5 mg/dL. In phase 1 of CATIE, the mean increase in total cholesterol was 9.4 mg/dL.

Olanzapine Monotherapy in Adolescents

The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescents, including those with schizophrenia (6 weeks) or bipolar I disorder (manic or mixed episodes) (3 weeks), olanzapine-treated adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 12.9 mg/dL, 6.5 mg/dL, and 28.4 mg/dL, respectively, compared to increases from baseline in mean fasting total cholesterol and LDL cholesterol of 1.3 mg/dL and 1.0 mg/dL, and a decrease in triglycerides of 1.1 mg/dL for placebo-treated adolescents. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated adolescents and placebo-treated adolescents.

In long-term studies (at least 24 weeks), adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.5 mg/dL, 5.4 mg/dL, and 20.5 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 4.5 mg/dL. Table 5 shows categorical changes in fasting lipids values in adolescents.

Table 5: Changes in Fasting Lipids Values from Adolescent Olanzapine Monotherapy Studies

			Up to 6 weeks exposure		At least 24 weeks exposure
Laboratory Analyte	Category Change (at least once) from Baseline	Treatment Arm	N	Patients	N	Patients
Fasting Triglycerides	Increase by ≥ 50 mg/dL	Olanzapine	138	37.0%	122	45.9%
		Placebo	66	15.2%	NAa	NAa
	Normal to High (< 90 mg/dL to > 130 mg/dL)	Olanzapine	67	26.9%	66	36.4%
		Placebo	28	10.7%	NAa	NAa
	Borderline to High (≥ 90 mg/dL and ≤ 130 mg/dL to > 130 mg/dL)	Olanzapine	37	59.5%	31	64.5%
		Placebo	17	35.3%	NAa	NAa
Fasting Total Cholesterol	In

Doxa XL

Doxa XL may be available in the countries listed below.

Ingredient matches for Doxa XL

Doxazosin

Doxazosin mesilate (a derivative of Doxazosin) is reported as an ingredient of Doxa XL in the following countries:

• Czech Republic

International Drug Name Search

Sastid

In the US, Sastid (salicylic acid/sulfur topical) is a member of the drug class miscellaneous topical agents and is used to treat Acne and Dandruff.

US matches:

• SAStid Soap


• SAStid Topical


• Sastid Soap Topical

Ingredient matches for Sastid

Clotrimazole

Clotrimazole is reported as an ingredient of Sastid in the following countries:

• Singapore

Salicylic Acid

Salicylic Acid is reported as an ingredient of Sastid in the following countries:

• Chile

International Drug Name Search

Maprotilin-Teva

Maprotilin-Teva may be available in the countries listed below.

Ingredient matches for Maprotilin-Teva

Maprotiline

Maprotiline hydrochloride (a derivative of Maprotiline) is reported as an ingredient of Maprotilin-Teva in the following countries:

• Germany

International Drug Name Search

Verapamilo La Santé

Verapamilo La Santé may be available in the countries listed below.

Ingredient matches for Verapamilo La Santé

Verapamil

Verapamil is reported as an ingredient of Verapamilo La Santé in the following countries:

• Colombia

International Drug Name Search

Simvafour

Simvafour may be available in the countries listed below.

Ingredient matches for Simvafour

Simvastatin

Simvastatin is reported as an ingredient of Simvafour in the following countries:

• Belgium

International Drug Name Search