POLYMYXIN B (Polymyxin B Sulfate) Injection, Powder, Lyophilized, For Solution [Alvogen Inc.]

WARNING

CAUTION: WHEN THIS DRUG IS GIVEN INTRAMUSCULARLY AND/OR INTRATHECALLY, IT SHOULD BE GIVEN ONLY TO HOSPITALIZED PATIENTS, SO AS TO PROVIDE CONSTANT SUPERVISION BY A PHYSICIAN.

RENAL FUNCTION SHOULD BE CAREFULLY DETERMINED AND PATIENTS WITH RENAL DAMAGE AND NITROGEN RETENTION SHOULD HAVE REDUCED DOSAGE. PATIENTS WITH NEPHROTOXICITY DUE TO POLYMYXIN B SULFATE USUALLY SHOW ALBUMINURIA, CELLULAR CASTS, AND AZOTEMIA. DIMINISHING URINE OUTPUT AND A RISING BUN ARE INDICATIONS FOR DISCONTINUING THERAPY WITH THIS DRUG.

NEUROTOXIC REACTIONS MAY BE MANIFESTED BY IRRITABILITY, WEAKNESS, DROWSINESS, ATAXIA, PERIORAL PARESTHESIA, NUMBNESS OF THE EXTREMITIES, AND BLURRING OF VISION. THESE ARE USUALLY ASSOCIATED WITH HIGH SERUM LEVELS FOUND IN PATIENTS WITH IMPAIRED RENAL FUNCTION AND/OR NEPHROTOXICITY.

THE CONCURRENT OR SEQUENTIAL USE OF OTHER NEUROTOXIC AND/OR NEPHROTOXIC DRUGS WITH POLYMYXIN B SULFATE, PARTICULARLY BACITRACIN, STREPTOMYCIN, NEOMYCIN, KANAMYCIN, GENTAMICIN, TOBRAMYCIN, AMIKACIN, CEPHALORIDINE, PAROMOMYCIN, VIOMYCIN, AND COLISTIN SHOULD BE AVOIDED.

THE NEUROTOXICITY OF POLYMYXIN B SULFATE CAN RESULT IN RESPIRATORY PARALYSIS FROM NEUROMUSCULAR BLOCKADE, ESPECIALLY WHEN THE DRUG IS GIVEN SOON AFTER ANESTHESIA AND/OR MUSCLE RELAXANTS.

USAGE IN PREGNANCY: THE SAFETY OF THIS DRUG IN HUMAN PREGNANCY HAS NOT BEEN ESTABLISHED.

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POLYMYXIN B (Polymyxin B Sulfate) Injection, Powder, Lyophilized, For Solution [Alvogen Inc.]

SERTRALINE Tablet, Film Coated [Exelan Pharmaceuticals, Inc.]

Sertraline Tablets, USP
(SIR-trah-leen)

What is the most important information I should know about sertraline tablets?

Sertraline tablets and other antidepressant medicines may cause serious side effects. Call your healthcare provider right away if you have any of the following symptoms, or call 911 if there is an emergency.

1. Suicidal thoughts or actions:

• Sertraline tablets and other antidepressant medicines may increase suicidal thoughts or actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed.
• Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions.
• Watch for these changes and call your healthcare provider right away if you notice new or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.
  • Pay particular attention to such changes when sertraline tablets are started or when the dose is changed.
  • Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.

Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you:

o attempts to commit suicide              o acting on dangerous impulses

o acting aggressive or violent             o thoughts about suicide or dying

o new or worse depression                 o new or worse anxiety or panic attacks

o feeling agitated, restless,
angry or irritable                                 o trouble sleeping

o an increase in activity or
talking more than what is
normal for you                                    o other unusual changes in behavior or mood

2. Serotonin Syndrome. This condition can be life-threatening and symptoms may include:

• agitation, hallucinations, coma, or other changes in mental status     • nausea, vomiting, or diarrhea

• racing heartbeat, high or low blood pressure                                      • sweating or fever

• coordination problems or muscle twitching (overactive reflexes)     • muscle rigidity

3. Increased chance of bleeding: Sertraline tablets and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin®, Jantoven®), a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin.

4. Manic episodes. Symptoms may include:

• greatly increased energy          • severe trouble sleeping          • excessive happiness or irritability

• racing thoughts                        • reckless behavior

• unusually grand ideas                                                               • talking more or faster than usual

5. Seizures or convulsions.

6. Glaucoma (angle-closure glaucoma). Many antidepressant medicines including sertraline tablets may cause a certain type of eye problem called angle-closure glaucoma. Call your healthcare provider if you have eye pain, changes in your vision, or swelling or redness in or around the eye. Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

7. Changes in appetite or weight. Children and adolescents should have height and weight monitored during treatment.

8. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:

• Headache          • weakness or feeling unsteady           • confusion, problems concentrating or thinking, memory problems

Do not stop sertraline tablets without first talking to your healthcare provider. Stopping sertraline tablets too quickly may cause serious symptoms including:

• anxiety, irritability, high or low mood, feeling restless or changes in sleep habits
• headache, sweating, nausea, dizziness
• electric shock-like sensations, shaking, confusion

What are sertraline tablets?

Sertraline tablets are a prescription medicine used to treat:

• Major Depressive Disorder (MDD)            • Obsessive Compulsive Disorder (OCD)

• Panic Disorder                                             • Posttraumatic Stress Disorder (PTSD)

• Social Anxiety Disorder                              • Premenstrual Dysphoric Disorder (PMDD)

It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider.
Sertraline tablets are safe and effective in treating children with OCD age 6 to 17 years.
It is not known if sertraline tablets are safe and effective for use in children under 6 years of age with OCD or children with other behavior health conditions.
Talk to your healthcare provider if you do not think that your condition is getting better with sertraline tablets treatment.

Who should not take sertraline tablets?

Do not take sertraline tablets if you:

• take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
• have taken an MAOI within 2 weeks of stopping sertraline tablets unless directed to do so by your healthcare provider.
• have stopped taking an MAOI in the last 2 weeks unless directed to do so by your healthcare provider.
• take any other medicines that contain sertraline (such as sertraline HCl or sertraline hydrochloride.
• take the antipsychotic medicine pimozide (Orap®) because this can cause serious heart problems.
• are allergic to sertraline or any of the ingredients in sertraline tablets. See the end of this Medication Guide for a complete list of ingredients in sertraline tablets.

People who take sertraline tablets close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms:

o high fever                                      o uncontrolled muscle spasms                             o stiff muscles

o rapid changes in heart rate
or blood pressure                             o confusion                                                           o loss of consciousness (pass out)

What should I tell my healthcare provider before taking sertraline tablets?

Before starting sertraline tablets, tell your healthcare provider:

• if you have:

o liver problems                           o kidney problems                                            o a history of a stroke

o heart problems                          o or have had seizures or convulsions              o high blood pressure

o bipolar disorder or mania         o low sodium levels in your blood                    o or have had bleeding problems

• are pregnant or plan to become pregnant. Your baby may have withdrawal symptoms after birth or may be at increased risk for a serious lung problem at birth. Talk to your healthcare provider about the benefits and risks of taking sertraline tablets during pregnancy.
• are breastfeeding or plan to breastfeed. A small amount of sertraline may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking sertraline tablets.

Tell your healthcare provider about all the medicines that you take, including prescription and over-the- counter medicines, vitamins, and herbal supplements.

Sertraline tablets and some medicines may interact with each other, may not work as well, or may cause serious side effects.

Your healthcare provider or pharmacist can tell you if it is safe to take sertraline tablets with your other medicines. Do not start or stop any medicine while taking sertraline tablets without talking to your healthcare provider first.

How should I take sertraline tablets?

• Take sertraline tablets exactly as prescribed. Your healthcare provider may need to change the dose of sertraline until it is the right dose for you.
• Sertraline tablets may be taken with or without food.
• If you miss a dose of sertraline, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of sertraline at the same time.

If you take too many sertraline tablets, call your healthcare provider or poison control center right away, or go to the nearest hospital emergency room right away.

What should I avoid while taking sertraline tablets?

Sertraline tablets can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how sertraline tablets affects you. Do not drink alcohol while you take sertraline tablets.

What are the possible side effects of sertraline tablets?

Sertraline tablets may cause serious side effects, including:

• See “What is the most important information I should know about sertraline tablets?”

The most common side effects in adults who take sertraline tablets include:

• nausea, loss of appetite, diarrhea, or indigestion              • change in sleep habits including increased sleepiness or insomnia

• increased sweating                                                            • sexual problems including decreased libido and ejaculation failure

• tremor or shaking                                                              • feeling tired or fatigued

• agitation                                                                             • anxiety

The most common side effects in children and adolescents who take sertraline tablets include abnormal increase in muscle movement or agitation, nose bleeds, urinary incontinence, aggressive reaction, possible slowed growth rate, and weight change. Your child’s height and weight should be monitored during treatment with sertraline tablets.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of sertraline tablets. For more information, ask your healthcare provider or pharmacist.

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

How should I store sertraline tablets?

• Store sertraline tablets at room temperature, 68 °F to 77°F (20°C to 25°C).
• Keep sertraline tablets bottle closed tightly.

Keep sertraline tablets and all medicines out of the reach of children.

General information about the safe and effective use of sertraline tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use sertraline tablets for a condition for which it was not prescribed. Do not give sertraline tablets to other people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about sertraline tablets. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about sertraline tablets that is written for healthcare professionals.

For more information about sertraline tablets call Exelan Pharmaceuticals, Inc. at 1-855-295-7455 or visit www.exelanpharma.com

What are the ingredients in sertraline tablets?

Active ingredient: sertraline hydrochloride, USP

Inactive ingredients: dibasic calcium phosphate dihydrate, hydroxypropyl cellulose, microcrystalline cellulose, magnesium stearate, opadry green (titanium dioxide, hypromellose 3cP, hypromellose 6cP, Macrogol/Peg 400, polysorbate 80, D&C Yellow #10 Aluminum Lake, and FD&C Blue # 2/Indigo Carmine Aluminum Lake for 25 mg tablet), opadry light blue (hypromellose 3cP, hypromellose 6cP, titanium dioxide, Macrogol/Peg 400, FD&C Blue #2/ Indigo Carmine Aluminum Lake and polysorbate 80 for 50 mg tablet), opadry yellow (hypromellose 3cP, hypromellose 6cP, titanium dioxide, Macrogol/Peg 400, polysorbate 80, Iron Oxide Yellow, Iron Oxide Red for 100 mg tablet) and sodium starch glycolate.

Disclaimer: Other brands listed are the registered trademarks of their respective owner and are not trademarks of Exelan.

This Medication Guide has been approved by the U.S. Food and Drug Administration

Manufactured for:
Exelan Pharmaceuticals, Inc.           
Lawrenceville, GA 30046

Manufactured by:
InvaGen Pharmaceuticals, Inc.
Hauppauge, NY 11788

or

Ascent Pharmaceuticals, Inc.
Central Islip, NY 11722

Revised: 08/2017

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SERTRALINE Tablet, Film Coated [Exelan Pharmaceuticals, Inc.]

Rules Update: Company Rep rule changes

Today, I'm making the following changes to the rules on Company Reps:

• Clarified that company reps are required to follow the company rep rules (section 15 in the rules) regardless of whether they have a "Rep for _____" title or not.
• Clarified that it is not up to the rep themselves whether they are considered a rep or not. If they meet the criteria (Any individual who owns or is employed by any company which sells adult diapers or ABDL products) they are considered a rep.
• Note: reps who are here in a purely personal capacity don't have to have a "Rep for _____" title, but they DO still have to email me, and they ARE still subject to all the rules for company reps.
• Clarified that company reps may create one thread to announce the launch of entirely new products of their own design, but all other marketing/promotion threads require my approval before they can be posted. Such approval must be requested at least a week in advance, via forum PM, is not guaranteed, and, when obtained, must be clearly displayed in any resulting thread. This rule is so that other moderators don't assume the thread wasn't approved before it was posted.
• This also means that we may, from time to time, approve company reps creating marketing/announcement/giveaway/sale threads, IF we think that this is in the best interest of our community - but they have to convince us of that before they can post them. We're very unlikely to approve things like a 10% off sale thread, but a 50% off sale thread, we might. The thread has to has serious value to our community for us to approve it. Remember, ADISC is run as a not-for-profit, not a business. We survive on donations. We are not here to make money. We are not interested in selling any form of advertising on our site. That means if you approach us and offer money in any form in exchange for permission to advertise here, the answer will be no. Don't offer us money. Instead, explain to us how the thread you want to create enriches our community. How it gives them a rare opportunity. That is the only method that is going to be able to secure permission to post marketing/announcement/giveaway/promotion threads here.
• Clarified that company reps may not talk about their company or its products without disclosing that they work there. Almost all company reps here on ADISC are clearly marked as "Rep for companyname" in their title, and so already meet this requirement. This is being added to explicitly prevent employees of ABDL companies from posting about their company, or its products, while pretending to be just a customer.

Rules Update: Company Rep rule changes

Rules Update: Company Rep rule changes

Today, I'm making the following changes to the rules on Company Reps:

• Clarified that company reps are required to follow the company rep rules (section 15 in the rules) regardless of whether they have a "Rep for _____" title or not.
• Clarified that it is not up to the rep themselves whether they are considered a rep or not. If they meet the criteria (Any individual who owns or is employed by any company which sells adult diapers or ABDL products) they are considered a rep.
• Note: reps who are here in a purely personal capacity don't have to have a "Rep for _____" title, but they DO still have to email me, and they ARE still subject to all the rules for company reps.
• Clarified that company reps may create one thread to announce the launch of entirely new products of their own design, but all other marketing/promotion threads require my approval before they can be posted. Such approval must be requested at least a week in advance, via forum PM, is not guaranteed, and, when obtained, must be clearly displayed in any resulting thread. This rule is so that other moderators don't assume the thread wasn't approved before it was posted.
• This also means that we may, from time to time, approve company reps creating marketing/announcement/giveaway/sale threads, IF we think that this is in the best interest of our community - but they have to convince us of that before they can post them. We're very unlikely to approve things like a 10% off sale thread, but a 50% off sale thread, we might. The thread has to has serious value to our community for us to approve it. Remember, ADISC is run as a not-for-profit, not a business. We survive on donations. We are not here to make money. We are not interested in selling any form of advertising on our site. That means if you approach us and offer money in any form in exchange for permission to advertise here, the answer will be no. Don't offer us money. Instead, explain to us how the thread you want to create enriches our community. How it gives them a rare opportunity. That is the only method that is going to be able to secure permission to post marketing/announcement/giveaway/promotion threads here.
• Clarified that company reps may not talk about their company or its products without disclosing that they work there. Almost all company reps here on ADISC are clearly marked as "Rep for companyname" in their title, and so already meet this requirement. This is being added to explicitly prevent employees of ABDL companies from posting about their company, or its products, while pretending to be just a customer.

Rules Update: Company Rep rule changes

VANCOMYCIN HYDROCHLORIDE Injection, Powder, Lyophilized, For Solution [Athenex Pharmaceutical Division, LLC.]

Clinically significant serum concentrations have been reported in some patients being treated for active C. difficile-induced pseudomembranous colitis after multiple oral doses of vancomycin.

Prolonged use of vancomycin hydrochloride for injection may result in the overgrowth of nonsusceptible microorganisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken. In rare instances, there have been reports of pseudomembranous colitis due to C. difficile developing in patients who received intravenous vancomycin hydrochloride for injection.

Serial tests of auditory function may be helpful in order to minimize the risk of ototoxicity.

Reversible neutropenia has been reported in patients receiving vancomycin hydrochloride for injection (see ADVERSE REACTIONS). Patients who will undergo prolonged therapy with vancomycin hydrochloride for injection or those who are receiving concomitant drugs which may cause neutropenia should have periodic monitoring of the leukocyte count.

Vancomycin hydrochloride for injection is irritating to tissue and must be given by a secure IV route of administration. Pain, tenderness, and necrosis occur with intramuscular (IM) injection of vancomycin hydrochloride for injection, or with inadvertent extravasation. Thrombophlebitis may occur, the frequency and severity of which can be minimized by administering the drug slowly as a dilute solution (2.5 to 5 g/L) and by rotation of venous access sites.

There have been reports that the frequency of infusion-related events (including hypotension, flushing, erythema, urticaria, and pruritus) increases with the concomitant administration of anesthetic agents. Infusion-related events may be minimized by the administration of vancomycin as a 60-minute infusion prior to anesthetic induction. The safety and efficacy of vancomycin administered by the intrathecal (intralumbar or intraventricular) route or by the intraperitoneal route have not been established by adequate and well controlled trials.

Reports have revealed that administration of sterile vancomycin by the intraperitoneal route during continuous ambulatory peritoneal dialysis (CAPD) has resulted in a syndrome of chemical peritonitis. To date, this syndrome has ranged from cloudy dialysate alone to a cloudy dialysate accompanied by variable degrees of abdominal pain and fever. This syndrome appears to be short-lived after discontinuation of intraperitoneal vancomycin.

Prescribing vancomycin hydrochloride for injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Drug Interactions

Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing (see Pediatric Use, PRECAUTIONS) and anaphylactoid reactions (see ADVERSE REACTIONS).

Monitor renal function in patients receiving vancomycin and concurrent and/or sequential systemic or topical use of other potentially, neurotoxic and/or nephrotoxic drugs, such as amphotericin B, aminoglycosides, bacitracin, polymyxin B, colistin, viomycin, or cisplatin.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Although no long-term studies in animals have been performed to evaluate carcinogenic potential, no mutagenic potential of vancomycin hydrochloride for injection was found in standard laboratory tests. No definitive fertility studies have been performed.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Animal reproduction studies have not been conducted with vancomycin. It is not known whether vancomycin can affect reproduction capacity. In a controlled clinical study, the potential ototoxic and nephrotoxic effects of vancomycin on infants were evaluated when the drug was administered to pregnant women for serious staphylococcal infections complicating intravenous drug abuse. Vancomycin was found in cord blood. No sensorineural hearing loss or nephrotoxicity attributable to vancomycin was noted. One infant whose mother received vancomycin in the third trimester experienced conductive hearing loss that was not attributed to the administration of vancomycin. Because the number of patients treated in this study was limited and vancomycin was administered only in the second and third trimesters, it is not known whether vancomycin causes fetal harm. Vancomycin should be given to a pregnant woman only if clearly needed.

Nursing Mothers

Vancomycin hydrochloride for injection is excreted in human milk. Caution should be exercised when vancomycin hydrochloride for injection is administered to a nursing woman. Because of the potential for adverse events, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

In pediatric patients, it may be appropriate to confirm desired vancomycin serum concentrations. Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing in pediatric patients (see PRECAUTIONS).

Geriatric Use

The natural decrement of glomerular filtration with increasing age may lead to elevated vancomycin serum concentrations if dosage is not adjusted. Vancomycin dosage schedules should be adjusted in elderly patients (see DOSAGE AND ADMINISTRATION).

Information for Patients

Patients should be counseled that antibacterial drugs including vancomycin hydrochloride for injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When vancomycin hydrochloride for injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Vancomycin Hydrochloride for Injection, USP or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

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VANCOMYCIN HYDROCHLORIDE Injection, Powder, Lyophilized, For Solution [Athenex Pharmaceutical Division, LLC.]

HYDROCODONE BITARTRATE AND ACETAMINOPHEN Solution [Preferred Pharmaceuticals Inc.]

Risks of Driving and Operating Machinery

Hydrocodone Bitartrate and Acetaminophen Oral Solution may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Hydrocodone Bitartrate and Acetaminophen Oral Solution and know how they will react to the medication [see PRECAUTIONS; Information for Patients/Caregivers].

Information for Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Medication Errors

Instruct patients how to measure and take the correct dose of Hydrocodone Bitartrate and Acetaminophen Oral Solution and to always use a calibrated measuring device when administering Hydrocodone Bitartrate and Acetaminophen Oral Solution to ensure the dose is measured and administered accurately [see WARNINGS].

If the prescribed concentration is changed, instruct patients on how to correctly measure the new dose to avoid errors which could result in accidental overdose and death.

Addiction, Abuse, and Misuse

Inform patients that the use of Hydrocodone Bitartrate and Acetaminophen Oral Solution, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see WARNINGS].  Instruct patients not to share Hydrocodone Bitartrate and Acetaminophen Oral Solution with others and to take steps to protect Hydrocodone Bitartrate and Acetaminophen Oral Solution from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Hydrocodone Bitartrate and Acetaminophen Oral Solution or when the dosage is increased, and that it can occur even at recommended dosages [see WARNINGS].  Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see WARNINGS].  Instruct patients to take steps to store securely and to dispose of unused Hydrocodone Bitartrate and Acetaminophen Oral Solution by flushing down the toilet.

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if Hydrocodone Bitartrate and Acetaminophen Oral Solution is used with benzodiazepines and other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see WARNINGS, PRECAUTIONS; Drug Interactions] .

Serotonin Syndrome

Inform patients that Hydrocodone Bitartrate and Acetaminophen Oral Solution could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs.  Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop.  Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see PRECAUTIONS; Drug Interactions].

Monoamine Oxidase Inhibitor (MAOI) Interaction

Inform patients to avoid taking Hydrocodone Bitartrate and Acetaminophen Oral Solution while using any drugs that inhibit monoamine oxidase.  Patients should not start MAOIs while taking Hydrocodone Bitartrate and Acetaminophen Oral Solution [see PRECAUTIONS; Drug Interactions].

Adrenal Insufficiency

Inform patients that Hydrocodone Bitartrate and Acetaminophen Oral Solution opioids could cause adrenal insufficiency, a potentially life-threatening condition.  Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.  Advise patients to seek medical attention if they experience a constellation of these symptoms [see WARNINGS].

Important Administration Instructions

Instruct patients how to properly measure and take Hydrocodone Bitartrate and Acetaminophen Oral Solution [see DOSAGE AND ADMINISTRATION, WARNINGS].

•

Advise patients to always use the enclosed calibrated oral syringe/dosing cup when administering Hydrocodone Bitartrate and Acetaminophen Oral Solution to ensure the dose is measured and administered accurately [see WARNINGS].

•

Advise patients never to use household teaspoons or tablespoons to measure Hydrocodone Bitartrate and Acetaminophen Oral Solution.

•

Advise patients not to adjust the dose of Hydrocodone Bitartrate and Acetaminophen Oral Solution without consulting with a physician or other healthcare professional.

•

If patients have been receiving treatment with Hydrocodone Bitartrate and Acetaminophen Oral Solution for more than a few weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the dose as abrupt discontinuation of the medication could precipitate withdrawal symptoms.  Provide a dose schedule to accomplish a gradual discontinuation of the medication [see DOSAGE AND ADMINISTRATION].

Maximum Daily Dose of Acetaminophen

Inform patients to not take more than 4,000 milligrams of acetaminophen per day.  Advise patients to call their prescriber if they take more than the recommended dose.

Hypotension

Inform patients that Hydrocodone Bitartrate and Acetaminophen Oral Solution may cause orthostatic hypotension and syncope.  Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see WARNINGS].

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in Hydrocodone Bitartrate and Acetaminophen Oral Solution.  Advise patients how to recognize such a reaction and when to seek medical attention [see CONTRAINDICATIONS, ADVERSE REACTIONS] .

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of Hydrocodone Bitartrate and Acetaminophen Oral Solution during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see WARNINGS, PRECAUTIONS; Pregnancy].

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that Hydrocodone Bitartrate and Acetaminophen Oral Solution can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see PRECAUTIONS; Pregnancy].

Lactation

Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness.  Instruct nursing mothers to seek immediate medical care if they notice these signs [see PRECAUTIONS; Nursing Mothers].

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS] .

Driving or Operating Heavy Machinery

Inform patients that Hydrocodone Bitartrate and Acetaminophen Oral Solution may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see WARNINGS].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY].

Disposal of Unused Hydrocodone Bitartrate and Acetaminophen Oral Solution

Advise patients to dispose of unused Hydrocodone Bitartrate and Acetaminophen Oral Solution by flushing unused Hydrocodone Bitartrate and Acetaminophen Oral Solution down the toilet.

Laboratory Tests

In patients with severe hepatic or renal disease, effects of therapy should be followed with serial liver and/or renal function tests.

Drug Interactions

Inhibitors of CYP3A4 and CYP2D6

The concomitant use of Hydrocodone Bitartrate and Acetaminophen Oral Solution and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), and protease inhibitors (e.g., ritonavir), can increase the plasma concentration of hydrocodone from Hydrocodone Bitartrate and Acetaminophen Oral Solution, resulting in increased or prolonged opioid effects.  These effects could be more pronounced with concomitant use of Hydrocodone Bitartrate and Acetaminophen Oral Solution and both CYP3A4 and CYP2D6 inhibitors, particularly when an inhibitor is added after a stable dose of Hydrocodone Bitartrate and Acetaminophen Oral Solution is achieved [see WARNINGS].

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, hydrocodone plasma concentration will decrease [see CLINICAL PHARMACOLOGY], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to Hydrocodone Bitartrate and Acetaminophen Oral Solution.

If concomitant use is necessary, consider dosage reduction of Hydrocodone Bitartrate and Acetaminophen Oral Solution until stable drug effects are achieved.  Follow patients for respiratory depression and sedation at frequent intervals.  If a CYP3A4 inhibitor is discontinued, consider increasing the Hydrocodone Bitartrate and Acetaminophen Oral Solution dosage until stable drug effects are achieved. Follow patients for signs or symptoms of opioid withdrawal.

Inducers of CYP3A4

The concomitant use of Hydrocodone Bitartrate and Acetaminophen Oral Solution and CYP3A4 inducers, such as rifampin, carbamazepine, and phenytoin, can decrease the plasma concentration of hydrocodone [see CLINICAL PHARMACOLOGY], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to Hydrocodone Bitartrate and Acetaminophen Oral Solution [see WARNINGS].

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [see CLINICAL PHARMACOLOGY], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

If concomitant use is necessary, consider increasing the Hydrocodone Bitartrate and Acetaminophen Oral Solution dosage until stable drug effects are achieved [see DOSAGE AND ADMINISTRATION].  Follow for signs of opioid withdrawal.  If a CYP3A4 inducer is discontinued, consider Hydrocodone Bitartrate and Acetaminophen Oral Solution dosage reduction and monitor for signs of respiratory depression.

Benzodiazepines and Other CNS Depressants

Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants such as benzodiazepines and other sedative hypnotics, anxiolytics, and tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required.  Follow patients closely for signs of respiratory depression and sedation [see WARNINGS].

Serotonergic Drugs

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome. [see PRECAUTIONS; Information for Patients].

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.  Discontinue Hydrocodone Bitartrate and Acetaminophen Oral Solution if serotonin syndrome is suspected.

Monoamine Oxidase Inhibitors (MAOIs)

The concomitant use of opioids and MAOIs, such as phenelzine, tranylcypromine, or linezolid, may manifest as serotonin syndrome, or opioid toxicity (e.g., respiratory depression, coma) [see WARNINGS].

The use of Hydrocodone Bitartrate and Acetaminophen Oral Solution is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

The concomitant use of opioids with other opioid analgesics, such as butorphanol, nalbuphine, pentazocine, may reduce the analgesic effect of Hydrocodone Bitartrate and Acetaminophen Oral Solution and/or precipitate withdrawal symptoms.

Advise patient to avoid concomitant use of these drugs.

Muscle Relaxants

Hydrocodone Bitartrate and Acetaminophen Oral Solution may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

If concomitant use is warranted, follow patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Hydrocodone Bitartrate and Acetaminophen Oral Solution and/or the muscle relaxant as necessary.

Diuretics

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

If concomitant use is warranted, monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs

The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

If concomitant use is warranted, follow patients for signs of urinary retention or reduced gastric motility when Hydrocodone Bitartrate and Acetaminophen Oral Solution are used concomitantly with anticholinergic drugs.

Drug/Laboratory Test Interactions

Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleactic acid.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies to evaluate the carcinogenic potential of the combination of Hydrocodone Bitartrate and Acetaminophen Oral Solution have not been conducted.

Long-term studies in mice and rats have been completed by the National Toxicology Program to evaluate the carcinogenic potential of acetaminophen.  In 2-year feeding studies, F344/N rats and B6C3F1 mice were fed a diet containing acetaminophen up to 6000 ppm.  Female rats demonstrated equivocal evidence of carcinogenic activity based on increased incidences of mononuclear cell leukemia at 0.8 times the maximum human daily dose (MHDD) of 4 grams/day, based on a body surface area comparison. In contrast, there was no evidence of carcinogenic activity in male rats that received up to 0.7 times or mice at up to 1.2-1.4 times the MHDD, based on a body surface area comparison.

Mutagenesis

In the published literature, acetaminophen has been reported to be clastogenic when administered at 1500 mg/kg/day to the rat model (3.6-times the MHDD, based on a body surface area comparison). In contrast, no clastogenicity was noted at a dose of 750 mg/kg/day (1.8-times the MHDD, based on a body surface area comparison), suggesting a threshold effect.

Impairment of Fertility

In studies conducted by the National Toxicology Program, fertility assessments with acetaminophen have been completed in Swiss CD-1 mice via a continuous breeding study.  There were no effects on fertility parameters in mice consuming up to 1.7 times the MHDD of acetaminophen, based on a body surface area comparison.  Although there was no effect on sperm motility or sperm density in the epididymis, there was a significant increase in the percentage of abnormal sperm in mice consuming 1.78 times the MHDD (based on a body surface comparison) and there was a reduction in the number of mating pairs producing a fifth litter at this dose, suggesting the potential for cumulative toxicity with chronic administration of acetaminophen near the upper limit of daily dosing.

Published studies in rodents report that oral acetaminophen treatment of male animals at doses that are 1.2 times the MHDD and greater (based on a body surface comparison) result in decreased testicular weights, reduced spermatogenesis, reduced fertility, and reduced implantation sites in females given the same doses.  These effects appear to increase with the duration of treatment. The clinical significance of these findings is not known.

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see ADVERSE REACTIONS].

Teratogenic Effects

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Hydrocodone Bitartrate and Acetaminophen Oral Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Fetal/Neonatal Adverse Reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight.  The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.  Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see WARNINGS].

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates.  An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Hydrocodone Bitartrate and Acetaminophen Oral Solution is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate.  Opioid analgesics, including Hydrocodone Bitartrate and Acetaminophen Oral Solution, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions.  However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Nursing Mothers

Hydrocodone is present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Hydrocodone Bitartrate and Acetaminophen Oral Solution and any potential adverse effects on the breastfed infant from Hydrocodone Bitartrate and Acetaminophen Oral Solution or from the underlying maternal condition.

Infants exposed to Hydrocodone Bitartrate and Acetaminophen Oral Solution through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Pediatric Use

The safety and effectiveness of Hydrocodone Bitartrate and Acetaminophen Oral Solution in the pediatric population below the age of two years have not been established. Use of Hydrocodone Bitartrate and Acetaminophen Oral Solution in the pediatric patients over the age of 2 years is supported by evidence from adequate and well controlled studies of hydrocodone and acetaminophen combination products in adults, along with additional data which support the development of metabolic pathways in children two years of age and over [see DOSAGE AND ADMINISTRATION] for pediatric dosage information.

Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to Hydrocodone Bitartrate and Acetaminophen Oral Solution. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Hydrocodone Bitartrate and Acetaminophen Oral Solution slowly in geriatric patients and follow closely for signs of central nervous system and respiratory depression [see WARNINGS].

Hydrocodone and acetaminophen are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to follow renal function.

Hepatic Impairment

Patients with hepatic impairment may have higher plasma hydrocodone concentrations than those with normal function. Use a low initial dose of Hydrocodone Bitartrate and Acetaminophen Oral Solution in patients with hepatic impairment and follow closely for adverse events such as respiratory depression and sedation.

Renal Impairment

Patients with renal impairment may have higher plasma hydrocodone concentrations than those with normal function. Use a low initial dose Hydrocodone Bitartrate and Acetaminophen Oral Solution in patients with renal impairment and follow closely for adverse events such as respiratory depression and sedation.

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HYDROCODONE BITARTRATE AND ACETAMINOPHEN Solution [Preferred Pharmaceuticals Inc.]

GOJO E2 SANITIZING LTN SP (Triclosan) Liquid [GOJO Industries, Inc.]

Water (Aqua), Coconut Acid, Sodium Sulfate, Oleic Acid, Ethanolamine, Cocamide MEA, Coco-Betaine, Propylene Glycol, Retinyl Palmitate, Tetrasodium EDTA, Tocopheryl Acetate, Zea Mays (Corn) Oil, Hydroxypropyl Methylcellulose, Methylchloroisothiazolinone, Methylisothiazolinone

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GOJO E2 SANITIZING LTN SP (Triclosan) Liquid [GOJO Industries, Inc.]

O SKIN ACNE MODERATE (Benzoyl Peroxide) Cream [O SKIN CARE LLC]

DO NOT USE THIS PRODUCT IF YOU HAVE VERY SENSITIVE SKIN OR IF YOU ARE SENSITIVE TO BENZOYL PEROXIDE. THIS PRODUCT MAY CAUSE IRRITATION.

ASK A PHYSICIAN OR PHARMACIST BEFORE USE IF YOU ARE USING OTHER TOPICAL ACNE MEDICATIONS AT THE SAME TIME OR IMMEDIATELY FOLLOWING USE OF THIS PRODUCT. THIS MAY INCREASE DRYNESS OR IRRITATION OF THE SKIN. IF THIS OCCURS, ONLY ONE MEDICATION SHOULD BE USED UNLESS DIRECTED BY A PHYSICIAN. AVOID UNNECESSARY SUN EXPOSURE. USE A SUNSCREEN WHILE USING THIS PRODUCT AND FOR A WEEK AFTERWARDS.

STOP USE AND ASK A PHYSICIAN IF SKIN IRRITATION OCCURS, AND BECOMES SEVERE.

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O SKIN ACNE MODERATE (Benzoyl Peroxide) Cream [O SKIN CARE LLC]

DOXAZOSIN Tablet [Cardinal Health]

Read this leaflet:

•

before you start taking doxazosin tablets.

•

each time you get a new prescription.

You and your doctor should discuss this treatment and your BPH symptoms before you start taking doxazosin tablets and at your regular checkups. This leaflet does NOT take the place of discussions with your doctor.

Doxazosin tablets are used to treat both benign prostatic hyperplasia (BPH) and high blood pressure (hypertension). This leaflet describes doxazosin tablets as treatment for BPH (although you may be taking doxazosin tablets for both your BPH and high blood pressure).

WHAT IS BPH: BPH is an enlargement of the prostate gland. This gland surrounds the tube that drains the urine from the bladder. The symptoms of BPH can be caused by a tensing of the enlarged muscle in the prostate gland which blocks the passage of urine. This can lead to such symptoms as:

•

a weak or start-and-stop stream when urinating

•

a feeling that the bladder is not completely emptied after urination

•

a delay or difficulty in the beginning of urination

•

a need to urinate often during the day and especially at night

•

a feeling that you must urinate immediately.

TREATMENT OPTIONS FOR BPH: The four main treatment options for BPH are:

•

If you are not bothered by your symptoms, you and your doctor may decide on a program of "watchful waiting". It is not an active treatment like taking medication or surgery but involves having regular checkups to see if your condition is getting worse or causing problems.

•

Treatment with doxazosin tablets or other similar drugs. Doxazosin tablets is the medication your doctor has prescribed for you. See "What Doxazosin Tablets Do", below.

•

Treatment with the medication class of 5-alpha reductase inhibitors (e.g., finasteride). It can cause the prostate to shrink. It may take 6 months or more for the full benefit of finasteride to be seen.

•

Various surgical procedures. Your doctor can describe these procedures to you. The best procedure for you depends on your BPH symptoms and medical condition.

WHAT DOXAZOSIN TABLETS DO: Doxazosin tablets work on a specific type of muscle found in the prostate, causing it to relax. This in turn decreases the pressure within the prostate, thus improving the flow of urine and your symptoms.

•

Doxazosin tablets help relieve the symptoms of BPH (weak stream, start-and-stop stream, a feeling that your bladder is not completely empty, delay in beginning of urination, need to urinate often during the day and especially at night, and feeling that you must urinate immediately). It does not change the size of the prostate. The prostate may continue to grow; however, a larger prostate is not necessarily related to more symptoms or to worse symptoms. Doxazosin tablets can decrease your symptoms and improve urinary flow, without decreasing the size of the prostate.

•

If doxazosin tablets are helping you, you should notice an effect within 1 to 2 weeks after you start your medication. Doxazosin tablets have been studied in over 900 patients for up to 2 years and the drug has been shown to continue to work during long-term treatment. Even though you take doxazosin tablets and it may help you, doxazosin tablets may not prevent the need for surgery in the future.

•

Doxazosin tablets do not affect PSA levels. PSA is the abbreviation for Prostate Specific Antigen. Your doctor may have done a blood test called PSA. You may want to ask your doctor more about this if you have had a PSA test done.

OTHER IMPORTANT FACTS:

•

You should see an improvement of your symptoms within 1 to 2 weeks. In addition to your other regular checkups you will need to continue seeing your doctor regularly to check your progress regarding your BPH and to monitor your blood pressure.

•

Doxazosin tablets are not a treatment for prostate cancer. Your doctor has prescribed doxazosin tablets for your BPH and not for prostate cancer; however, a man can have BPH and prostate cancer at the same time. Doctors usually recommend that men be checked for prostate cancer once a year when they turn 50 (or 40 if a family member has had prostate cancer). A higher incidence of prostate cancer has been noted in men of African-American descent. These checks should continue even if you are taking doxazosin tablets.

HOW TO TAKE DOXAZOSIN TABLETS AND WHAT YOU SHOULD KNOW WHILE TAKING DOXAZOSIN TABLETS FOR BPH: Doxazosin Tablets Can Cause a Sudden Drop in Blood Pressure After the VERY FIRST DOSE. You may feel dizzy, faint or "light-headed", especially after you stand up from a lying or sitting position. This is more likely to occur after you've taken the first few doses or if you increase your dose, but can occur at any time while you are taking the drug. It can also occur if you stop taking the drug and then restart treatment. If you feel very dizzy, faint or "light-headed" you should contact your doctor. Your doctor will discuss with you how often you need to visit and how often your blood pressure should be checked.

Your blood pressure should be checked when you start taking doxazosin tablets even if you do not have high blood pressure (hypertension). Your doctor will discuss with you the details of how blood pressure is measured.

Blood Pressure Measurement: Whatever equipment is used, it is usual for your blood pressure to be measured in the following way: measure your blood pressure after lying quietly on your back for 5 minutes. Then, after standing for 2 minutes measure your blood pressure again. Your doctor will discuss with you what other times during the day your blood pressure should be taken, such as 2 to 6 hours after a dose, before bedtime or after waking up in the morning. Note that moderate to high-intensity exercise can, over a period of time, lower your average blood pressure.

You can take doxazosin tablets either in the morning or at bedtime and it will be equally effective. If you take doxazosin tablets at bedtime but need to get up from bed to go to the bathroom, get up slowly and cautiously until you are sure how the medication affects you. It is important to get up slowly from a chair or bed at any time until you learn how you react to doxazosin tablets. You should not drive or do any hazardous tasks until you are used to the effects of the medication. If you begin to feel dizzy, sit or lie down until you feel better.

•

You will start with a 1 mg dose of doxazosin tablets once daily. Then the once daily dose will be increased as your body gets used to the effects of the medication. Follow your doctor's instructions about how to take doxazosin tablets. You must take it every day at the dose prescribed. Talk with your doctor if you don't take it for a few days for some reason; you may then need to restart the medication at a 1 mg dose, increase your dose gradually and again be cautious about possible dizziness. Do not share doxazosin tablets with anyone else; it was prescribed only for you.

•

Other side effects you could have while taking doxazosin tablets, in addition to lowering of the blood pressure, include dizziness, fatigue (tiredness), swelling of the feet and shortness of breath. Most side effects are mild. However, you should discuss any unexpected effects you notice with your doctor.

•

WARNING: Extremely rarely, doxazosin tablets and similar medications have caused painful erection of the penis, sustained for hours and unrelieved by sexual intercourse or masturbation. This condition is serious, and if untreated it can be followed by permanent inability to have an erection. If you have a prolonged abnormal erection, call your doctor or go to an emergency room as soon as possible.

•

Tell your surgeon if you take or have taken doxazosin tablets if you plan to have surgery for cataracts (clouding of the eye). During cataract surgery, a condition called Intraoperative Floppy Iris Syndrome (IFIS) can happen if you take or have taken doxazosin tablets.

•

If you use doxazosin tablets with an oral erectile dysfunction medicine (phosphodiesterase-5 (PDE-5) inhibitor), it can cause a sudden drop in your blood pressure and you can become dizzy or faint. Talk with your healthcare provider before using PDE-5 inhibitors.

•

Keep doxazosin tablets and all medicines out of the reach of children.

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

FOR MORE INFORMATION ABOUT DOXAZOSIN TABLETS AND BPH TALK WITH YOUR DOCTOR, NURSE, PHARMACIST OR OTHER HEALTH CARE PROVIDER.

For more information, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

Manufactured by:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Distributed by:
Mylan Institutional Inc.
Rockford, IL 61103 U.S.A.

Repackaged By:

Cardinal Health

Zanesville, OH 43701

L32992290116

L35229010817

L32992370414

S-12118
8/14

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DOXAZOSIN Tablet [Cardinal Health]

HANSKIN NONTOURING GRADATION PACT L21 FAIR EDGE COVER BALM (Octinoxate, Octisalate, Titanium Dioxide) Powder [Celltrion Skincure Co.,Ltd.]

Inactive ingredients: Water, Phenyl Trimethicone, Isoeicosane, Euphorbia Cerifera (Candelilla) Wax, Talc, Glycerin, Propylene Glycol, Dimethicone, Niacinamide, Diisopropyl Adipate, Lauryl PEG-8 Dimethicone, Bismuth Oxychloride, Ceresin, Silica, C30-45 Alkyl Methicone, Sorbitan Sesquioleate, Myristyl Myristate, Dimethicone/PEG-10/15 Crosspolymer, C30-45 Olefin, Ethylhexyl Hydroxystearate, Octyldodecanol, Phenoxyethanol, Isododecane, Propanediol, Fragrance, Ethylhexylglycerin, Bis-Hydroxyethoxypropyl Dimethicone/IPDI Copolymer Ethylcarbamate, Triethoxycaprylylsilane, Echium Plantagineum Seed Oil, Adenosine, Xanthan Gum, Trimethylsiloxysilicate, Dimethiconol, Dipropylene Glycol, Viscum Album (Mistletoe) Leaf Extract, Centella Asiatica Extract, Portulaca Oleracea Extract, Helianthus Annuus (Sunflower) Seed Oil Unsaponifiables, Cardiospermum Halicacabum Flower/Leaf/Vine Extract, Sodium Citrate, Sodium Hyaluronate, Hydrogenated Polyisobutene, Tocopherol, Sodium Starch Octenylsuccinate, Calcium Pantothenate, Maltodextrin, Ceramide NP, Ascorbic Acid Polypeptide, Sodium Ascorbyl Phosphate, Butylene Glycol, Tocopheryl Acetate, Pyridoxine HCL, Caprylyl Glycol, Pentylene Glycol, Soluble Collagen, Acetyl Hexapeptide-8, Anemarrhena Asphodeloides Root Extract, Triethanolamine, Iron Oxides(CI 77492), Iron Oxides(CI 77499), Iron Oxide(CI 77491)

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METAXALONE Tablet [Dr. Reddys Laboratories Limited]

Mechanism of Action:

The mechanism of action of metaxalone in humans has not been established, but may be due to general central nervous system depression. Metaxalone has no direct action on the contractile mechanism of striated muscle, the motor end plate or the nerve fiber.

Pharmacokinetics:

The pharmacokinetics of metaxalone have been evaluated in healthy adult volunteers after single dose administration of metaxalone under fasted and fed conditions at doses ranging from 400 mg to 800 mg.

Absorption

Peak plasma concentrations of metaxalone occur approximately 3 hours after a 400 mg oral dose under fasted conditions. Thereafter, metaxalone concentrations decline log-linearly with a terminal half-life of 9.0 ± 4.8 hours. Doubling the dose of metaxalone from 400 mg to 800 mg results in a roughly proportional increase in metaxalone exposure as indicated by peak plasma concentrations (Cmax) and area under the curve (AUC). Dose proportionality at doses above 800 mg has not been studied. The absolute bioavailability of metaxalone is not known.

The single-dose pharmacokinetic parameters of metaxalone in two groups of healthy volunteers are shown in Table 1.

Food Effects

A randomized, two-way, crossover study was conducted in 42 healthy volunteers (31 males, 11 females) administered one 400 mg metaxalone tablet under fasted conditions and following a standard high-fat breakfast. Subjects ranged in age from 18 to 48 years (mean age = 23.5 ± 5.7 years). Compared to fasted conditions, the presence of a high fat meal at the time of drug administration increased Cmax by 177.5% and increased AUC (AUC0-t, AUC∞) by 123.5% and 115.4%, respectively. Time-to-peak concentration (Tmax) was also delayed (4.3 h versus 3.3 h) and terminal half-life was decreased (2.4 h versus 9.0 h) under fed conditions compared to fasted.

In a second food effect study of similar design, two 400 mg metaxalone tablets (800 mg) were administered to healthy volunteers (N=59, 37 males, 22 females), ranging in age from 18 to 50 years (mean age = 25.6± 8.7 years). Compared to fasted conditions, the presence of a high fat meal at the time of drug administration increased Cmax by 193.6% and increased AUC (AUC0-t, AUC∞) by 146.4% and 142.2%, respectively. Time-to-peak concentration (Tmax) was also delayed (4.9 h versus 3.0 h) and terminal half-life was decreased (4.2 h versus 8.0 h) under fed conditions compared to fasted conditions. Similar food effect results were observed in the above study when one metaxalone 800 mg tablet was administered in place of two metaxalone 400 mg tablets. The increase in metaxalone exposure coinciding with a reduction in half-life may be attributed to more complete absorption of metaxalone in the presence of a high fat meal (Figure 1).

Distribution, Metabolism, and Excretion

Although plasma protein binding and absolute bioavailability of metaxalone are not known, the apparent volume of distribution (V/F ~ 800 L) and lipophilicity (log P = 2.42) of metaxalone suggest that the drug is extensively distributed in the tissues. Metaxalone is metabolized by the liver and excreted in the urine as unidentified metabolites. Hepatic Cytochrome P450 enzymes play a role in the metabolism of metaxalone. Specifically, CYP1A2, CYP2D6, CYP2E1, and CYP3A4 and, to a lesser extent, CYP2C8, CYP2C9, and CYP2C19 appear to metabolize metaxalone.

Metaxalone does not significantly inhibit major CYP enzymes such as CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Metaxalone does not significantly induce major CYP enzymes such as CYP1A2, CYP2B6, and CYP3A4 in vitro.

Pharmacokinetics in Special Populations

Age:

The effects of age on the pharmacokinetics of metaxalone were determined following single administration of two 400 mg tablets (800 mg) under fasted and fed conditions. The results were analyzed separately, as well as in combination with the results from three other studies. Using the combined data, the results indicate that the pharmacokinetics of metaxalone are significantly more affected by age under fasted conditions than under fed conditions, with bioavailability under fasted conditions increasing with age. 

The bioavailability of metaxalone under fasted and fed conditions in three groups of healthy volunteers of varying age is shown in Table 2.

Gender:

The effect of gender on the pharmacokinetics of metaxalone was assessed in an open label study, in which 48 healthy adult volunteers (24 males, 24 females) were administered two metaxalone 400 mg tablets (800 mg) under fasted conditions. The bioavailability of metaxalone was significantly higher in females compared to males as evidenced by Cmax (2,115 ng/mL versus 1,335 ng/mL) and AUC∞ (17,884 ng·h/mL versus 10,328 ng·h/mL). The mean half-life was 11.1 hours in females and 7.6 hours in males. The apparent volume of distribution of metaxalone was approximately 22% higher in males than in females, but not significantly different when adjusted for body weight. Similar findings were also seen when the previously described combined dataset was used in the analysis.

Hepatic/Renal Insufficiency:

The impact of hepatic and renal disease on the pharmacokinetics of metaxalone has not been determined. In the absence of such information, metaxalone should be used with caution in patients with hepatic and/or renal impairment.

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METAXALONE Tablet [Dr. Reddys Laboratories Limited]

LEGATRIN PM (Acetaminophen, Diphenhydramine Hci) Tablet [Church Dwight Co., Inc.]

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LEGATRIN PM (Acetaminophen, Diphenhydramine Hci) Tablet [Church Dwight Co., Inc.]

BUPROPION HYDROCHLORIDE Tablet, Extended Release [REMEDYREPACK INC.]

12.1 Mechanism of Action

The mechanism of action of bupropion is unknown, as is the case with other antidepressants. However, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine and does not inhibit monoamine oxidase or the reuptake of serotonin.

12.3 Pharmacokinetics

Bupropion is a racemic mixture. The pharmacologic activity and pharmacokinetics of the individual enantiomers have not been studied.

Following chronic dosing, the mean steady-state plasma concentration of bupropion was reached within 8 days. The mean elimination half-life (±SD) of bupropion is 21 (±9) hours.

In a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion).

Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites.

Absorption
Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion.

Distribution
In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that of bupropion.

Metabolism
Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance, because the plasma concentrations of the metabolites are as high or higher than those of bupropion.

At steady state, peak plasma concentration of hydroxybupropion occurred approximately 7 hours after administration of bupropion hydrochloride extended-release tablets (XL), and it was approximately 7 times the peak level of the parent drug. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours, and its AUC at steady state is about 13 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of hydroxybupropion. However, the elimination half-lives of erythrohydrobupropion and threohydrobupropion are longer, approximately 33 (±10) and 37 (±13) hours, respectively, and steady-state AUCs were 1.4 and 7 times that of bupropion, respectively.

Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg/day.

Elimination
Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. Only 0.5% of the oral dose was excreted as unchanged bupropion.

Population Subgroups
Factors or conditions altering metabolic capacity (e.g., liver disease, congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may be expected to influence the degree and extent of accumulation of the active metabolites of bupropion. The elimination of the major metabolites of bupropion may be affected by reduced renal or hepatic function, because they are moderately polar compounds and are likely to undergo further metabolism or conjugation in the liver prior to urinary excretion.

Renal Impairment
There is limited information on the pharmacokinetics of bupropion in patients with renal impairment. An inter-trial comparison between normal subjects and subjects with end-stage renal failure demonstrated that the parent drug C max and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for subjects with end-stage renal failure. A second study, comparing normal subjects and subjects with moderate-to-severe renal impairment (GFR 30.9 ± 10.8 mL/min) showed that after a single 150 mg dose of sustained-release bupropion, exposure to bupropion was approximately 2-fold higher in subjects with impaired renal function, while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys. The elimination of the major metabolites of bupropion may be reduced by impaired renal function. Bupropion hydrochloride extended-release tablets (XL) should be used with caution in patients with renal impairment, and a reduced frequency and/or dose should be considered [see Dosage and Administration ( 2.7) and Use in Specific Populations ( 8.6)].

Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of bupropion was characterized in 2 single-dose trials, one in subjects with alcoholic liver disease and one in subjects with mild to severe cirrhosis. The first trial demonstrated that the half-life of hydroxybupropion was significantly longer in 8 subjects with alcoholic liver disease than in 8 healthy volunteers (32±14 hours versus 21±5 hours, respectively). Although not statistically significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be greater (by 53% to 57%) in patients with alcoholic liver disease. The differences in half-life for bupropion and the other metabolites in the 2 groups were minimal.

The second trial demonstrated no statistically significant differences in the pharmacokinetics of bupropion and its active metabolites in 9 subjects with mild to moderate hepatic cirrhosis compared to 8 healthy volunteers. However, more variability was observed in some of the pharmacokinetic parameters for bupropion (AUC, C max, and T max) and its active metabolites (t 1/2) in subjects with mild to moderate hepatic cirrhosis. In addition, in patients with severe hepatic cirrhosis, the bupropion C max and AUC were substantially increased (mean difference:  by approximately 70% and 3-fold, respectively) and more variable when compared to values in healthy volunteers; the mean bupropion half-life was also longer (29 hours in subjects with severe hepatic cirrhosis vs. 19 hours in healthy subjects). For the metabolite hydroxybupropion, the mean C max was approximately 69% lower. For the combined amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, the mean C max was approximately 31% lower. The mean AUC increased by about 1½-fold for hydroxybupropion and about 2½-fold for threo/erythrohydrobupropion. The median T max was observed 19 hours later for hydroxybupropion and 31 hours later for threo/erythrohydrobupropion. The mean half-lives for hydroxybupropion and  threo/erythrohydrobupropion were increased 5- and 2-fold, respectively, in patients with severe hepatic cirrhosis compared to healthy volunteers [see Dosage and Administration ( 2.6) and Use in Specific Populations ( 8.7)].

Left Ventricular Dysfunction
During a chronic dosing study with bupropion in 14 depressed patients with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray), there was no apparent effect on the pharmacokinetics of bupropion or its metabolites, compared to healthy volunteers.

Age
The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady-state bupropion concentrations from several depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that in younger subjects. These data suggest that there is no prominent effect of age on bupropion concentration; however, another single- and multiple-dose pharmacokinetic study suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites [see Use in Specific Populations ( 8.5)].

Gender
A single-dose study involving 12 healthy male and 12 healthy female volunteers revealed no sex-related differences in the pharmacokinetic parameters of bupropion. In addition, pooled analysis of bupropion pharmacokinetic data from 90 healthy male and 90 healthy female volunteers revealed no sex-related differences in the peak plasma concentrations of bupropion. The mean systemic exposure (AUC) was approximately 13% higher in male volunteers compared to female volunteers.

Smokers
The effects of cigarette smoking on the pharmacokinetics of bupropion hydrochloride were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single 150 mg dose of bupropion, there was no statistically significant difference in C max, half-life, T max, AUC, or clearance of bupropion or its active metabolites between smokers and nonsmokers.

Drug Interactions
Potential for Other Drugs to Affect Bupropion Hydrochloride Extended-Release Tablets (XL)
I n vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion hydrochloride extended-release tablets (XL) and drugs that are inhibitors or inducers of CYP2B6. In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion.

Inhibitors of CYP2B6
Ticlopidine and Clopidogrel: In a study in healthy male volunteers, clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily increased exposures (C max and AUC) of bupropion by 40% and 60% for clopidogrel, by 38% and 85% for ticlopidine, respectively. The exposures of hydroxybupropion were decreased.

Prasugrel: In healthy subjects, prasugrel increased bupropion C max and AUC values by 14% and 18%, respectively, and decreased C max and AUC values of hydroxybupropion by 32% and 24%, respectively.

Cimetidine: Following oral administration of bupropion 300 mg with and without cimetidine 800 mg in 24 healthy young male volunteers, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and C max, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.

Citalopram: Citalopram did not affect the pharmacokinetics of bupropion and its three metabolites.

Inducers of CYP2B6
Ritonavir and Lopinavir: In a healthy volunteer study, ritonavir 100 mg twice daily reduced the AUC and C max of bupropion by 22% and 21%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the threohydrobupropion decreased by 38%, and the erythrohydrobupropion decreased by 48%. In a second healthy volunteer study, ritonavir 600 mg twice daily decreased the AUC and C max of bupropion by 66% and 62%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 78%, the threohydrobupropion decreased by 50%, and the erythrohydrobupropion decreased by 68%.

In another healthy volunteer study, lopinavir 400 mg/ritonavir 100 mg twice daily decreased bupropion AUC and C max by 57%. The AUC and C max of hydroxybupropion metabolite were decreased by 50% and 31%, respectively.

Efavirenz: In a study of healthy volunteers, efavirenz 600 mg once daily for 2 weeks reduced the AUC and C max of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged, whereas C max of hydroxybupropion was increased by 50%.

Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion.

Potential for Bupropion Hydrochloride Extended-Release Tablets (XL) to Affect Other Drugs
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In a study of 8 healthy male volunteers, following a 14-day administration of bupropion 100 mg three times per day, there was no evidence of induction of its own metabolism. Nevertheless, there may be the potential for clinically important alterations of blood levels of coadministered drugs.

Drugs Metabolized by CYP2D6
In vitro, bupropion and hydroxybupropion are CYP2D6 inhibitors. In a clinical study of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of CYP2D6, bupropion given as 150 mg twice daily followed by a single dose of 50 mg desipramine increased the C max, AUC, and T½ of desipramine by an average of approximately 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied.

Citalopram: Although citalopram is not primarily metabolized by CYP2D6, in one study bupropion increased the C max and AUC of citalopram by 30% and 40%, respectively.

Lamotrigine: Multiple oral doses of bupropion had no statistically significant effects on the single-dose pharmacokinetics of lamotrigine in 12 healthy volunteers.

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BUPROPION HYDROCHLORIDE Tablet, Extended Release [REMEDYREPACK INC.]