levorphanol

lee-VOR-fa-nol

Commonly used brand name(s)

In the U.S.

• Levo-Dromoran

Available Dosage Forms:

• Tablet

Therapeutic Class: Analgesic

Chemical Class: Opioid

Uses For levorphanol

Levorphanol is used to relieve moderate to severe pain. It belongs to the group of medicines called narcotic analgesics (pain medicines). It acts on the central nervous system (CNS) to relieve pain.

When levorphanol is used for a long time, it may become habit-forming, causing mental or physical dependence. However, people who have continuing pain should not let the fear of dependence keep them from using narcotics to relieve their pain. Mental dependence (addiction) is not likely to occur when narcotics are used for this purpose. Physical dependence may lead to withdrawal side effects if treatment is stopped suddenly. However, severe withdrawal side effects can usually be prevented by gradually reducing the dose over a period of time before treatment is stopped completely.

levorphanol is available only with your doctor's prescription.

Before Using levorphanol

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

Allergies

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

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of levorphanol in the pediatric population. Safety and efficacy have not been established.

Geriatric

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

Pregnancy

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

Breast Feeding

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

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking levorphanol, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

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

• Naltrexone

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

• Adinazolam


• Alfentanil


• Alprazolam


• Amobarbital


• Anileridine


• Aprobarbital


• Bromazepam


• Brotizolam


• Buprenorphine


• Butabarbital


• Butalbital


• Butorphanol


• Carisoprodol


• Chloral Hydrate


• Chlordiazepoxide


• Chlorpromazine


• Chlorzoxazone


• Clobazam


• Clonazepam


• Clorazepate


• Codeine


• Dantrolene


• Dezocine


• Diazepam


• Estazolam


• Ethchlorvynol


• Fentanyl


• Flunitrazepam


• Fluphenazine


• Flurazepam


• Fospropofol


• Halazepam


• Hydrocodone


• Hydromorphone


• Ketazolam


• Levorphanol


• Lorazepam


• Lormetazepam


• Medazepam


• Meperidine


• Mephenesin


• Mephobarbital


• Meprobamate


• Metaxalone


• Methocarbamol


• Methohexital


• Midazolam


• Morphine


• Morphine Sulfate Liposome


• Nalbuphine


• Nitrazepam


• Nordazepam


• Opium


• Oxazepam


• Oxycodone


• Oxymorphone


• Pentazocine


• Pentobarbital


• Perphenazine


• Phenobarbital


• Prazepam


• Prochlorperazine


• Promazine


• Promethazine


• Propoxyphene


• Quazepam


• Remifentanil


• Secobarbital


• Sodium Oxybate


• Sufentanil


• Tapentadol


• Temazepam


• Thiethylperazine


• Thiopental


• Thioridazine


• Triazolam


• Trifluoperazine

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

• Risperidone

Interactions with Food/Tobacco/Alcohol

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

Other Medical Problems

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

• Addison's disease (adrenal gland problem) or


• Alcohol abuse, history of or


• Breathing or lung problems (e.g., chronic obstructive pulmonary disease [COPD], hypoxia) or


• Drug dependence, especially narcotic abuse or dependence, or history of or


• Enlarged prostate (BPH, prostatic hypertrophy) or


• Hypothyroidism (an underactive thyroid) or


• Infection, severe or


• Mental illness, history of or


• Problems with passing urine—Use with caution. May increase risk for more serious side effects.

• Brain tumor or


• Head injuries or


• Increased pressure in your head—Some of the side effects of levorphanol can cause serious problems in people who have these medical problems.

• Breathing problems (e.g., asthma), severe or


• Gallbladder surgery—Should not be used in patients with these conditions.

• Heart disease or


• Hypotension (low blood pressure) or


• Myocardial infarction (heart attack) or


• Respiratory depression (hypoventilation or slow breathing)—Use with caution. May make these conditions worse.

• Kidney disease or


• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

• Stomach or digestion problems—levorphanol may mask the diagnosis of these conditions.

Proper Use of levorphanol

Take levorphanol only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. This is especially important for elderly patients, who may be more sensitive to the effects of pain medicines. If too much of levorphanol is taken for a long time, it may become habit-forming (causing mental or physical dependence).

Dosing

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

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

• For oral dosage form (tablets):
  
  • For moderate to severe pain:
    
    • Adults—At first, 2 milligrams (mg) every 6 to 8 hours as needed. Your doctor may increase your dose as needed. However, the dose is usually not more than 6 to 12 mg per day.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

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

Storage

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

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

Precautions While Using levorphanol

It is very important that your doctor check your progress while you are using levorphanol. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it.

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

levorphanol may be habit-forming. If you feel that the medicine is not working as well, do not use more than your prescribed dose.

Dizziness, lightheadedness, or fainting may occur when you get up suddenly from a lying or sitting position. Getting up slowly may help lessen this problem. Also, lying down for a while may relieve dizziness or lightheadedness.

levorphanol may make you dizzy, drowsy, or lightheaded. Make sure you know how you react to levorphanol before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.

Do not change your dose or suddenly stop using levorphanol without first checking with your doctor. Your doctor may want you to gradually reduce the amount you are using before stopping it completely. This may help prevent worsening of your condition and reduce the possibility of withdrawal symptoms, such as abdominal or stomach cramps, anxiety, fever, nausea, runny nose, sweating, tremors, or trouble with sleeping.

Using levorphanol while you are pregnant may cause neonatal withdrawal syndrome in your newborn babies. Tell your doctor right away if your child has the following symptoms: abnormal sleep pattern, diarrhea, high-pitched cry, irritability, shakiness or tremor, weight loss, vomiting, or failure to gain weight.

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

levorphanol Side Effects

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

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

Incidence not known

• Agitation


• attempts at killing oneself


• bluish lips or skin


• blurred vision


• change in consciousness


• cold, clammy skin


• confusion


• decrease in the frequency of urination


• decrease in urine volume


• decreased urine output


• depression


• difficulty in passing urine (dribbling)


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


• extra heartbeats


• extremely shallow or slow breathing


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


• fast, weak pulse


• hostility


• lethargy


• lightheadedness


• loss of consciousness


• muscle twitching


• no blood pressure or pulse


• not breathing


• painful urination


• rapid weight gain


• seizures


• stopping of the heart


• stupor


• sweating


• swelling of the face, ankles, or hands


• unconsciousness


• unusual tiredness or weakness


• wheezing

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

Symptoms of overdose

• Chest pain or discomfort


• constricted, pinpoint, or small pupils (black part of the eye)


• decreased awareness or responsiveness


• difficult or troubled breathing


• difficulty with sleeping


• dilated neck veins


• disorientation


• drowsiness to profound coma


• extreme fatigue


• hallucination


• headache


• irregular, fast or slow, or shallow breathing


• no muscle tone or movement


• not breathing


• pale or blue lips, fingernails, or skin


• shortness of breath


• sleepiness or unusual drowsiness


• swelling of the face, fingers, feet, or lower legs


• weight gain

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

Incidence not known

• Abnormal dreams


• absence of or decrease in body movement


• acid or sour stomach


• belching


• change in personality


• changes in vision


• delusions


• dementia


• discouragement


• double vision


• dry mouth


• feeling sad or empty


• heartburn


• hives or welts


• increase in body movements


• indigestion


• irritability


• itching


• lack of appetite


• loss of interest or pleasure


• loss of memory


• nausea


• nervousness


• problems with memory


• redness of the skin


• seeing double


• skin rash


• stomach discomfort, upset, or pain


• sweating


• tiredness


• trouble concentrating


• trouble sleeping


• twitching, twisting, uncontrolled repetitive movements of the tongue, lips, face, arms, or legs


• upper abdominal or stomach pain


• vomiting

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

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

See also: levorphanol side effects (in more detail)

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

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

More levorphanol resources

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

• levorphanol Concise Consumer Information (Cerner Multum)


• Levorphanol Prescribing Information (FDA)


• Levorphanol MedFacts Consumer Leaflet (Wolters Kluwer)


• Levo-Dromoran Monograph (AHFS DI)


• Levo-Dromoran Prescribing Information (FDA)

Compare levorphanol with other medications

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Percamin

Percamin may be available in the countries listed below.

Ingredient matches for Percamin

Cinchocaine

Cinchocaine hydrochloride (a derivative of Cinchocaine) is reported as an ingredient of Percamin in the following countries:

• Japan

International Drug Name Search

Ceftriaxona MK

Ceftriaxona MK may be available in the countries listed below.

Ingredient matches for Ceftriaxona MK

Ceftriaxone

Ceftriaxone is reported as an ingredient of Ceftriaxona MK in the following countries:

• Belize


• Costa Rica


• Dominican Republic


• El Salvador


• Guatemala


• Honduras


• Nicaragua


• Panama

International Drug Name Search

Lithimole

Lithimole may be available in the countries listed below.

Ingredient matches for Lithimole

Timolol

Timolol maleate (a derivative of Timolol) is reported as an ingredient of Lithimole in the following countries:

• Bahrain


• Greece

International Drug Name Search

Lasix

Generic Name: furosemide

Dosage Form: tablet
Lasix®

(furosemide)

Tablets 20, 40, and 80 mg

Warning

Lasix® (furosemide) is a potent diuretic which, if given in excessive amounts, can lead to a profound diuresis with water and electrolyte depletion. Therefore, careful medical supervision is required and dose and dose schedule must be adjusted to the individual patient's needs. (See DOSAGE AND ADMINISTRATION.)

Lasix Description

Lasix® is a diuretic which is an anthranilic acid derivative. Lasix tablets for oral administration contain furosemide as the active ingredient and the following inactive ingredients: lactose monohydrate NF, magnesium stearate NF, starch NF, talc USP, and colloidal silicon dioxide NF. Chemically, it is 4-chloro-N-furfuryl-5-sulfamoylanthranilic acid. Lasix is available as white tablets for oral administration in dosage strengths of 20, 40 and 80 mg. Furosemide is a white to off-white odorless crystalline powder. It is practically insoluble in water, sparingly soluble in alcohol, freely soluble in dilute alkali solutions and insoluble in dilute acids.

The CAS Registry Number is 54-31-9.

The structural formula is as follows:

Lasix - Clinical Pharmacology

Investigations into the mode of action of Lasix have utilized micropuncture studies in rats, stop flow experiments in dogs and various clearance studies in both humans and experimental animals. It has been demonstrated that Lasix inhibits primarily the absorption of sodium and chloride not only in the proximal and distal tubules but also in the loop of Henle. The high degree of efficacy is largely due to the unique site of action. The action on the distal tubule is independent of any inhibitory effect on carbonic anhydrase and aldosterone.

Recent evidence suggests that furosemide glucuronide is the only or at least the major biotransformation product of furosemide in man. Furosemide is extensively bound to plasma proteins, mainly to albumin. Plasma concentrations ranging from 1 to 400 μg/mL are 91 to 99% bound in healthy individuals. The unbound fraction averages 2.3 to 4.1% at therapeutic concentrations.

The onset of diuresis following oral administration is within 1 hour. The peak effect occurs within the first or second hour. The duration of diuretic effect is 6 to 8 hours.

In fasted normal men, the mean bioavailability of furosemide from Lasix Tablets and Lasix Oral Solution is 64% and 60%, respectively, of that from an intravenous injection of the drug. Although furosemide is more rapidly absorbed from the oral solution (50 minutes) than from the tablet (87 minutes), peak plasma levels and area under the plasma concentration-time curves do not differ significantly. Peak plasma concentrations increase with increasing dose but times-to-peak do not differ among doses. The terminal half-life of furosemide is approximately 2 hours.

Significantly more furosemide is excreted in urine following the IV injection than after the tablet or oral solution. There are no significant differences between the two oral formulations in the amount of unchanged drug excreted in urine.

Geriatric Population

Furosemide binding to albumin may be reduced in elderly patients. Furosemide is predominantly excreted unchanged in the urine. The renal clearance of furosemide after intravenous administration in older healthy male subjects (60–70 years of age) is statistically significantly smaller than in younger healthy male subjects (20–35 years of age). The initial diuretic effect of furosemide in older subjects is decreased relative to younger subjects. (See PRECAUTIONS: Geriatric Use.)

Indications and Usage for Lasix

Edema

Lasix is indicated in adults and pediatric patients for the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and renal disease, including the nephrotic syndrome. Lasix is particularly useful when an agent with greater diuretic potential is desired.

Hypertension

Oral Lasix may be used in adults for the treatment of hypertension alone or in combination with other antihypertensive agents. Hypertensive patients who cannot be adequately controlled with thiazides will probably also not be adequately controlled with Lasix alone.

Contraindications

Lasix is contraindicated in patients with anuria and in patients with a history of hypersensitivity to furosemide.

Warnings

In patients with hepatic cirrhosis and ascites, Lasix therapy is best initiated in the hospital. In hepatic coma and in states of electrolyte depletion, therapy should not be instituted until the basic condition is improved. Sudden alterations of fluid and electrolyte balance in patients with cirrhosis may precipitate hepatic coma; therefore, strict observation is necessary during the period of diuresis. Supplemental potassium chloride and, if required, an aldosterone antagonist are helpful in preventing hypokalemia and metabolic alkalosis.

If increasing azotemia and oliguria occur during treatment of severe progressive renal disease, Lasix should be discontinued.

Cases of tinnitus and reversible or irreversible hearing impairment and deafness have been reported. Reports usually indicate that Lasix ototoxicity is associated with rapid injection, severe renal impairment, the use of higher than recommended doses, hypoproteinemia or concomitant therapy with aminoglycoside antibiotics, ethacrynic acid, or other ototoxic drugs. If the physician elects to use high dose parenteral therapy, controlled intravenous infusion is advisable (for adults, an infusion rate not exceeding 4 mg Lasix per minute has been used). (See PRECAUTIONS: Drug Interactions)

Precautions

General

Excessive diuresis may cause dehydration and blood volume reduction with circulatory collapse and possibly vascular thrombosis and embolism, particularly in elderly patients. As with any effective diuretic, electrolyte depletion may occur during Lasix therapy, especially in patients receiving higher doses and a restricted salt intake. Hypokalemia may develop with Lasix, especially with brisk diuresis, inadequate oral electrolyte intake, when cirrhosis is present, or during concomitant use of corticosteroids, ACTH, licorice in large amounts, or prolonged use of laxatives. Digitalis therapy may exaggerate metabolic effects of hypokalemia, especially myocardial effects.

All patients receiving Lasix therapy should be observed for these signs or symptoms of fluid or electrolyte imbalance (hyponatremia, hypochloremic alkalosis, hypokalemia, hypomagnesemia or hypocalcemia): dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, arrhythmia, or gastrointestinal disturbances such as nausea and vomiting. Increases in blood glucose and alterations in glucose tolerance tests (with abnormalities of the fasting and 2-hour postprandial sugar) have been observed, and rarely, precipitation of diabetes mellitus has been reported.

In patients with severe symptoms of urinary retention (because of bladder emptying disorders, prostatic hyperplasia, urethral narrowing), the administration of furosemide can cause acute urinary retention related to increased production and retention of urine. Thus, these patients require careful monitoring, especially during the initial stages of treatment.

In patients at high risk for radiocontrast nephropathy Lasix can lead to a higher incidence of deterioration in renal function after receiving radiocontrast compared to high-risk patients who received only intravenous hydration prior to receiving radiocontrast.

In patients with hypoproteinemia (e.g., associated with nephrotic syndrome) the effect of Lasix may be weakened and its ototoxicity potentiated.

Asymptomatic hyperuricemia can occur and gout may rarely be precipitated.

Patients allergic to sulfonamides may also be allergic to Lasix. The possibility exists of exacerbation or activation of systemic lupus erythematosus.

As with many other drugs, patients should be observed regularly for the possible occurrence of blood dyscrasias, liver or kidney damage, or other idiosyncratic reactions.

Information for Patients

Patients receiving Lasix should be advised that they may experience symptoms from excessive fluid and/or electrolyte losses. The postural hypotension that sometimes occurs can usually be managed by getting up slowly. Potassium supplements and/or dietary measures may be needed to control or avoid hypokalemia.

Patients with diabetes mellitus should be told that furosemide may increase blood glucose levels and thereby affect urine glucose tests. The skin of some patients may be more sensitive to the effects of sunlight while taking furosemide.

Hypertensive patients should avoid medications that may increase blood pressure, including over-the-counter products for appetite suppression and cold symptoms.

Laboratory Tests

Serum electrolytes (particularly potassium), CO2, creatinine and BUN should be determined frequently during the first few months of Lasix therapy and periodically thereafter. Serum and urine electrolyte determinations are particularly important when the patient is vomiting profusely or receiving parenteral fluids. Abnormalities should be corrected or the drug temporarily withdrawn. Other medications may also influence serum electrolytes.

Reversible elevations of BUN may occur and are associated with dehydration, which should be avoided, particularly in patients with renal insufficiency.

Urine and blood glucose should be checked periodically in diabetics receiving Lasix, even in those suspected of latent diabetes.

Lasix may lower serum levels of calcium (rarely cases of tetany have been reported) and magnesium. Accordingly, serum levels of these electrolytes should be determined periodically.

In premature infants Lasix may precipitate nephrocalcinosis/nephrolithiasis, therefore renal function must be monitored and renal ultrasonography performed. (See PRECAUTIONS: Pediatric Use)

Drug Interactions

Lasix may increase the ototoxic potential of aminoglycoside antibiotics, especially in the presence of impaired renal function. Except in life-threatening situations, avoid this combination.

Lasix should not be used concomitantly with ethacrynic acid because of the possibility of ototoxicity. Patients receiving high doses of salicylates concomitantly with Lasix, as in rheumatic disease, may experience salicylate toxicity at lower doses because of competitive renal excretory sites.

There is a risk of ototoxic effects if cisplatin and Lasix are given concomitantly. In addition, nephrotoxicity of nephrotoxic drugs such as cisplatin may be enhanced if Lasix is not given in lower doses and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment.

Lasix has a tendency to antagonize the skeletal muscle relaxing effect of tubocurarine and may potentiate the action of succinylcholine.

Lithium generally should not be given with diuretics because they reduce lithium's renal clearance and add a high risk of lithium toxicity.

Lasix combined with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers may lead to severe hypotension and deterioration in renal function, including renal failure. An interruption or reduction in the dosage of Lasix, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers may be necessary.

Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs.

Lasix may decrease arterial responsiveness to norepinephrine. However, norepinephrine may still be used effectively.

Simultaneous administration of sucralfate and Lasix tablets may reduce the natriuretic and antihypertensive effects of Lasix. Patients receiving both drugs should be observed closely to determine if the desired diuretic and/or antihypertensive effect of Lasix is achieved. The intake of Lasix and sucralfate should be separated by at least two hours.

In isolated cases, intravenous administration of Lasix within 24 hours of taking chloral hydrate may lead to flushing, sweating attacks, restlessness, nausea, increase in blood pressure and tachycardia. Use of Lasix concomitantly with chloral hydrate is, therefore, not recommended.

Phenytoin interferes directly with renal action of Lasix. There is evidence that treatment with phenytoin leads to decrease intestinal absorption of Lasix, and consequently to lower peak serum furosemide concentrations.

Methotrexate and other drugs that, like Lasix, undergo significant renal tubular secretion may reduce the effect of Lasix. Conversely, Lasix may decrease renal elimination of other drugs that undergo tubular secretion. High-dose treatment of both Lasix and these other drugs may result in elevated serum levels of these drugs and may potentiate their toxicity as well as the toxicity of Lasix.

Lasix can increase the risk of cephalosporin-induced nephrotoxicity even in the setting of minor or transient renal impairment.

Concomitant use of cyclosporine and Lasix is associated with increased risk of gouty arthritis secondary to Lasix-induced hyperurecemia and cyclosporine impairment of renal urate excretion.

One study in six subjects demonstrated that the combination of furosemide and acetylsalicylic acid temporarily reduced creatinine clearance in patients with chronic renal insufficiency. There are case reports of patients who developed increased BUN, serum creatinine and serum potassium levels, and weight gain when furosemide was used in conjunction with NSAIDs.

Literature reports indicate that coadministration of indomethacin may reduce the natriuretic and antihypertensive effects of Lasix (furosemide) in some patients by inhibiting prostaglandin synthesis. Indomethacin may also affect plasma renin levels, aldosterone excretion, and renin profile evaluation. Patients receiving both indomethacin and Lasix should be observed closely to determine if the desired diuretic and/or antihypertensive effect of Lasix is achieved.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Furosemide was tested for carcinogenicity by oral administration in one strain of mice and one strain of rats. A small but significantly increased incidence of mammary gland carcinomas occurred in female mice at a dose 17.5 times the maximum human dose of 600 mg. There were marginal increases in uncommon tumors in male rats at a dose of 15 mg/kg (slightly greater than the maximum human dose) but not at 30 mg/kg.

Furosemide was devoid of mutagenic activity in various strains of Salmonella typhimurium when tested in the presence or absence of an in vitro metabolic activation system, and questionably positive for gene mutation in mouse lymphoma cells in the presence of rat liver S9 at the highest dose tested. Furosemide did not induce sister chromatid exchange in human cells in vitro, but other studies on chromosomal aberrations in human cells in vitro gave conflicting results. In Chinese hamster cells it induced chromosomal damage but was questionably positive for sister chromatid exchange. Studies on the induction by furosemide of chromosomal aberrations in mice were inconclusive. The urine of rats treated with this drug did not induce gene conversion in Saccharomyces cerevisiae.

Lasix (furosemide) produced no impairment of fertility in male or female rats, at 100 mg/kg/day (the maximum effective diuretic dose in the rat and 8 times the maximal human dose of 600 mg/day).

Pregnancy

PREGNANCY CATEGORY C - Furosemide has been shown to cause unexplained maternal deaths and abortions in rabbits at 2, 4 and 8 times the maximal recommended human dose. There are no adequate and well-controlled studies in pregnant women. Lasix should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Treatment during pregnancy requires monitoring of fetal growth because of the potential for higher birth weights.

The effects of furosemide on embryonic and fetal development and on pregnant dams were studied in mice, rats and rabbits.

Furosemide caused unexplained maternal deaths and abortions in the rabbit at the lowest dose of 25 mg/kg (2 times the maximal recommended human dose of 600 mg/day). In another study, a dose of 50 mg/kg (4 times the maximal recommended human dose of 600 mg/day) also caused maternal deaths and abortions when administered to rabbits between Days 12 and 17 of gestation. In a third study, none of the pregnant rabbits survived a dose of 100 mg/kg. Data from the above studies indicate fetal lethality that can precede maternal deaths.

The results of the mouse study and one of the three rabbit studies also showed an increased incidence and severity of hydronephrosis (distention of the renal pelvis and, in some cases, of the ureters) in fetuses derived from the treated dams as compared with the incidence in fetuses from the control group.

Nursing Mothers

Because it appears in breast milk, caution should be exercised when Lasix is administered to a nursing mother.

Lasix may inhibit lactation.

Pediatric Use

In premature infants Lasix may precipitate nephrocalcinosis/nephrolithiasis.

Nephrocalcinosis/nephrolithiasis has also been observed in children under 4 years of age with no history of prematurity who have been treated chronically with Lasix. Monitor renal function, and renal ultrasonography should be considered, in pediatric patients receiving Lasix.

If Lasix is administered to premature infants during the first weeks of life, it may increase the risk of persistence of patent ductus arteriosus

Geriatric Use

Controlled clinical studies of Lasix did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for the elderly patient should be cautious, 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.

This drug is known to be substantially excreted by the kidney, and the risk of toxic 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 monitor renal function. (See PRECAUTIONS: General and DOSAGE AND ADMINISTRATION.)

Adverse Reactions

Adverse reactions are categorized below by organ system and listed by decreasing severity.

Gastrointestinal System Reactions

1. hepatic encephalopathy in patients with hepatocellular insufficiency


2. pancreatitis


3. jaundice (intrahepatic cholestatic jaundice)


4. increased liver enzymes


5. anorexia


6. oral and gastric irritation


7. cramping


8. diarrhea


9. constipation


10. nausea


11. vomiting

Systemic Hypersensitivity Reactions

1. Severe anaphylactic or anaphylactoid reactions (e.g. with shock)


2. systemic vasculitis


3. interstitial nephritis


4. necrotizing angiitis

Central Nervous System Reactions

1. tinnitus and hearing loss


2. paresthesias


3. vertigo


4. dizziness


5. headache


6. blurred vision


7. xanthopsia

Hematologic Reactions

1. aplastic anemia


2. thrombocytopenia


3. agranulocytosis


4. hemolytic anemia


5. leukopenia


6. anemia


7. eosinophilia

Dermatologic-Hypersensitivity Reactions

1. toxic epidermal necrolysis


2. Stevens-Johnson Syndrome


3. erythema multiforme


4. drug rash with eosinophilia and systemic symptoms


5. acute generalized exanthematous pustulosis


6. exfoliative dermatitis


7. bullous pemphigoid


8. purpura


9. photosensitivity


10. rash


11. pruritis


12. urticaria

Cardiovascular Reaction

1. Orthostatic hypotension may occur and be aggravated by alcohol, barbiturates or narcotics.


2. Increase in cholesterol and triglyceride serum levels

Other Reactions

1. hyperglycemia


2. glycosuria


3. hyperuricemia


4. muscle spasm


5. weakness


6. restlessness


7. urinary bladder spasm


8. thrombophlebitis


9. fever

Whenever adverse reactions are moderate or severe, Lasix dosage should be reduced or therapy withdrawn.

Overdosage

The principal signs and symptoms of overdose with Lasix are dehydration, blood volume reduction, hypotension, electrolyte imbalance, hypokalemia and hypochloremic alkalosis, and are extensions of its diuretic action.

The acute toxicity of Lasix has been determined in mice, rats and dogs. In all three, the oral LD50 exceeded 1000 mg/kg body weight, while the intravenous LD50 ranged from 300 to 680 mg/kg. The acute intragastric toxicity in neonatal rats is 7 to 10 times that of adult rats.

The concentration of Lasix in biological fluids associated with toxicity or death is not known.

Treatment of overdosage is supportive and consists of replacement of excessive fluid and electrolyte losses. Serum electrolytes, carbon dioxide level and blood pressure should be determined frequently. Adequate drainage must be assured in patients with urinary bladder outlet obstruction (such as prostatic hypertrophy).

Hemodialysis does not accelerate furosemide elimination.

Lasix Dosage and Administration

Edema

Therapy should be individualized according to patient response to gain maximal therapeutic response and to determine the minimal dose needed to maintain that response.

Adults

The usual initial dose of Lasix is 20 to 80 mg given as a single dose. Ordinarily a prompt diuresis ensues. If needed, the same dose can be administered 6 to 8 hours later or the dose may be increased. The dose may be raised by 20 or 40 mg and given not sooner than 6 to 8 hours after the previous dose until the desired diuretic effect has been obtained. The individually determined single dose should then be given once or twice daily (eg, at 8 am and 2 pm). The dose of Lasix may be carefully titrated up to 600 mg/day in patients with clinically severe edematous states.

Edema may be most efficiently and safely mobilized by giving Lasix on 2 to 4 consecutive days each week.

When doses exceeding 80 mg/day are given for prolonged periods, careful clinical observation and laboratory monitoring are particularly advisable. (See PRECAUTIONS: Laboratory Tests.)

Geriatric patients

In general, dose selection for the elderly patient should be cautious, usually starting at the low end of the dosing range (see PRECAUTIONS: Geriatric Use).

Pediatric patients

The usual initial dose of oral Lasix in pediatric patients is 2 mg/kg body weight, given as a single dose. If the diuretic response is not satisfactory after the initial dose, dosage may be increased by 1 or 2 mg/kg no sooner than 6 to 8 hours after the previous dose. Doses greater than 6 mg/kg body weight are not recommended. For maintenance therapy in pediatric patients, the dose should be adjusted to the minimum effective level.

Hypertension

Therapy should be individualized according to the patient's response to gain maximal therapeutic response and to determine the minimal dose needed to maintain the therapeutic response.

Adults

The usual initial dose of Lasix for hypertension is 80 mg, usually divided into 40 mg twice a day. Dosage should then be adjusted according to response. If response is not satisfactory, add other antihypertensive agents.

Changes in blood pressure must be carefully monitored when Lasix is used with other antihypertensive drugs, especially during initial therapy. To prevent excessive drop in blood pressure, the dosage of other agents should be reduced by at least 50 percent when Lasix is added to the regimen. As the blood pressure falls under the potentiating effect of Lasix, a further reduction in dosage or even discontinuation of other antihypertensive drugs may be necessary.

Geriatric patients

In general, dose selection and dose adjustment for the elderly patient should be cautious, usually starting at the low end of the dosing range (see PRECAUTIONS: Geriatric Use).

How is Lasix Supplied

Lasix (furosemide) Tablets 20 mg are supplied as white, oval, monogrammed tablets in Bottles of 100 (NDC 0039-0067-10), and 1000 (NDC 0039-0067-70). The 20 mg tablets are imprinted with "Lasix®" on one side.

Lasix Tablets 40 mg are supplied as white, round, monogrammed, scored tablets in Bottles of 100 (NDC 0039-0060-13), 500 (NDC 0039-0060-50), and 1000 (NDC 0039-0060-70). The 40 mg tablets are imprinted with "Lasix® 40" on one side.

Lasix Tablets 80 mg are supplied as white, round, monogrammed, facetted edge tablets in Bottles of 50 (NDC 0039-0066-05) and 500 (NDC 0039-0066-50). The 80 mg tablets are imprinted with "Lasix® 80" on one side.

Note: Dispense in well-closed, light-resistant containers. Exposure to light might cause a slight discoloration. Discolored tablets should not be dispensed.

Tested by USP Dissolution Test 2

Store at 25° C (77° F); excursions permitted to 15 – 30° C (59 – 86° F). [See USP Controlled Room Temperature.]

Revised August 2011

sanofi-aventis U.S. LLC

Bridgewater, NJ 08807

© 2011 sanofi-aventis U.S. LLC

PRINCIPAL DISPLAY PANEL - 20 mg Bottle Label

NDC 0039-0067-10

Lasix®

furosemide

Tablets

100 Tablets

20mg

sanofi aventis

PRINCIPAL DISPLAY PANEL - 40 mg Bottle Label

NDC 0039-0060-13

Lasix®

furosemide

Tablets

100 Tablets

40mg

sanofi aventis

PRINCIPAL DISPLAY PANEL - 80 mg Bottle Label

NDC 0039-0066-05

Lasix®

furosemide

Tablets

50 Tablets

80mg

sanofi aventis

Lasix  furosemide  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0039-0067 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength furosemide (furosemide) furosemide 20 mg

Inactive Ingredients Ingredient Name Strength lactose monohydrate   magnesium stearate   talc   silicon dioxide

Product Characteristics Color WHITE Score no score Shape OVAL (ellipsoidal) Size 8mm Flavor Imprint Code Lasix Contains

Packaging # NDC Package Description Multilevel Packaging 1 0039-0067-10 100 TABLET In 1 BOTTLE None 2 0039-0067-70 1000 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA016273	07/01/1966

Lasix  furosemide  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0039-0060 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength furosemide (furosemide) furosemide 40 mg

Inactive Ingredients Ingredient Name Strength lactose monohydrate   magnesium stearate   talc   silicon dioxide

Product Characteristics Color WHITE Score 2 pieces Shape ROUND Size 8mm Flavor Imprint Code Lasix;40 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0039-0060-13 100 TABLET In 1 BOTTLE None 2 0039-0060-50 500 TABLET In 1 BOTTLE None 3 0039-0060-70 1000 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA016273	07/01/1966

Lasix  furosemide  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0039-0066 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength furosemide (furosemide) furosemide 80 mg

Inactive Ingredients Ingredient Name Strength lactose monohydrate   magnesium stearate   talc   silicon dioxide

Product Characteristics Color WHITE Score 2 pieces Shape ROUND Size 10mm Flavor Imprint Code Lasix;80 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0039-0066-05 50 TABLET In 1 BOTTLE None 2 0039-0066-50 500 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA016273	07/01/1966

Labeler - Sanofi-Aventis U.S. LLC (824676584)

Establishment
Name	Address	ID/FEI	Operations
Sanofi-Aventis Canada Inc.		251046934	MANUFACTURE

Revised: 09/2011Sanofi-Aventis U.S. LLC

More Lasix resources

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

• Lasix Monograph (AHFS DI)


• Lasix Advanced Consumer (Micromedex) - Includes Dosage Information


• Lasix MedFacts Consumer Leaflet (Wolters Kluwer)


• Lasix Consumer Overview


• Furosemide Professional Patient Advice (Wolters Kluwer)


• Furosemide MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Lasix with other medications

• Ascites
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• Heart Failure
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• Hypercalcemia
• Nonobstructive Oliguria
• Oliguria
• Pulmonary Edema
• Renal Failure
• Renal Transplant

Lexiva

Dosage Form: tablet, film coated: oral suspension
FULL PRESCRIBING INFORMATION

Indications and Usage for Lexiva

Lexiva® is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection.

The following points should be considered when initiating therapy with Lexiva plus ritonavir in protease inhibitor-experienced patients:

• The protease inhibitor-experienced patient study was not large enough to reach a definitive conclusion that Lexiva plus ritonavir and lopinavir plus ritonavir are clinically equivalent [see Clinical Studies (14.2)].


• Once-daily administration of Lexiva plus ritonavir is not recommended for adult protease inhibitor-experienced patients or any pediatric patients.

Lexiva Dosage and Administration

Lexiva Tablets may be taken with or without food.

Adults should take Lexiva Oral Suspension without food. Pediatric patients should take Lexiva Oral Suspension with food [see Clinical Pharmacology (12.3)]. If emesis occurs within 30 minutes after dosing, re-dosing of Lexiva Oral Suspension should occur.

Higher-than-approved dose combinations of Lexiva plus ritonavir are not recommended due to an increased risk of transaminase elevations [see Overdosage (10)].

When Lexiva is used in combination with ritonavir, prescribers should consult the full prescribing information for ritonavir.

Adults

Therapy-Naive Adults

• Lexiva 1,400 mg twice daily (without ritonavir).


• Lexiva 1,400 mg once daily plus ritonavir 200 mg once daily.


• Lexiva 1,400 mg once daily plus ritonavir 100 mg once daily.

Dosing of Lexiva 1,400 mg once daily plus ritonavir 100 mg once daily is supported by pharmacokinetic data [see Clinical Pharmacology (12.3)].

• Lexiva 700 mg twice daily plus ritonavir 100 mg twice daily.


• Dosing of Lexiva 700 mg twice daily plus 100 mg ritonavir twice daily is supported by pharmacokinetic and safety data [see Clinical Pharmacology (12.3)].

Protease Inhibitor-Experienced Adults

• Lexiva 700 mg twice daily plus ritonavir 100 mg twice daily

Pediatric Patients (Aged 2 to 18 Years)

The recommended dosage of Lexiva in patients aged greater than or equal to 2 years should be calculated based on body weight (kg) and should not exceed the recommended adult dose. The data are insufficient to recommend: (1) once-daily dosing of Lexiva alone or in combination with ritonavir, and (2) any dosing of Lexiva in therapy-experienced patients aged 2 to 5 years.

Therapy-Naive Aged 2 to 5 Years

• Lexiva Oral Suspension 30 mg/kg twice daily, not to exceed the adult dose of Lexiva 1,400 mg twice daily.

Therapy-Naive Aged Greater Than or Equal to 6 Years

• Either Lexiva Oral Suspension 30 mg/kg twice daily not to exceed the adult dose of Lexiva 1,400 mg twice daily or Lexiva Oral Suspension 18 mg/kg plus ritonavir 3 mg/kg twice daily not to exceed the adult dose of Lexiva 700 mg plus ritonavir 100 mg twice daily.

Therapy-Experienced Aged Greater Than or Equal to 6 Years

• Lexiva Oral Suspension 18 mg/kg plus ritonavir 3 mg/kg administered twice daily not to exceed the adult dose of Lexiva 700 mg twice daily plus ritonavir 100 mg twice daily.

Other Dosing Considerations

• When administered without ritonavir, the adult regimen of Lexiva Tablets 1,400 mg twice daily may be used for pediatric patients weighing at least 47 kg.


• When administered in combination with ritonavir, Lexiva Tablets may be used for pediatric patients weighing at least 39 kg; ritonavir capsules may be used for pediatric patients weighing at least 33 kg.

Patients With Hepatic Impairment

See Clinical Pharmacology (12.3).Mild Hepatic Impairment (Child-Pugh Score Ranging From 5 to 6): Lexiva should be used with caution at a reduced dosage of 700 mg twice daily without ritonavir (therapy-naive) or 700 mg twice daily plus ritonavir 100 mg once daily (therapy-naive or protease inhibitor-experienced).

Moderate Hepatic Impairment (Child-Pugh Score Ranging From 7 to 9): Lexiva should be used with caution at a reduced dosage of 700 mg twice daily without ritonavir (therapy-naive), or 450 mg twice daily plus ritonavir 100 mg once daily (therapy-naive or protease inhibitor-experienced).

Severe Hepatic Impairment (Child-Pugh Score Ranging From 10 to 15): Lexiva should be used with caution at a reduced dosage of 350 mg twice daily without ritonavir (therapy-naive) or 300 mg twice daily plus ritonavir 100 mg once daily (therapy-naive or protease inhibitor-experienced).

Dosage Forms and Strengths

Lexiva Tablets, 700 mg, are pink, film-coated, capsule-shaped, biconvex tablets with “GX LL7” debossed on one face.

Lexiva Oral Suspension, 50 mg/mL, is a white to off-white suspension that has a characteristic grape-bubblegum-peppermint flavor.

Contraindications

Lexiva is contraindicated:

• in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome) to any of the components of this product or to amprenavir.


• when coadministered with drugs that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (Table 1).

Table 1. Drugs Contraindicated With Lexiva. (Information in the table applies to Lexiva with or without ritonavir, unless otherwise indicated.)

Drug Class/Drug Name	Clinical Comment
Alpha 1-adrenoreceptor antagonist: Alfuzosin	Potentially increased alfuzosin concentrations can result in hypotension.
Antiarrhythmics: Flecainide, propafenone	POTENTIAL for serious and/or life-threatening reactions such as cardiac arrhythmias secondary to increases in plasma concentrations of antiarrhythmics if Lexiva is co-prescribed with ritonavir.
Antimycobacterials: Rifampina	May lead to loss of virologic response and possible resistance to Lexiva or to the class of protease inhibitors.
Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine	POTENTIAL for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI motility agents: Cisapride	POTENTIAL for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal products: St. John’s wort (hypericum perforatum)	May lead to loss of virologic response and possible resistance to Lexiva or to the class of protease inhibitors.
HMG co-reductase inhibitors: Lovastatin, simvastatin	POTENTIAL for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: Pimozide	POTENTIAL for serious and/or life-threatening reactions such as cardiac arrhythmias.
Non-nucleoside reverse transcriptase inhibitor: Delavirdinea	May lead to loss of virologic response and possible resistance to delavirdine.
PDE5 inhibitor: Sildenafil (REVATIO®) (for treatment of pulmonary arterial hypertension)	A safe and effective dose has not been established when used with Lexiva. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope).
Sedative/hypnotics: Midazolam, triazolam	POTENTIAL for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.

a  See Clinical Pharmacology (12.3) Tables 10, 11, 12, or 13 for magnitude of interaction.

• when coadministered with ritonavir in patients receiving the antiarrhythmic agents flecainide and propafenone. If Lexiva is coadministered with ritonavir, reference should be made to the full prescribing information for ritonavir for additional contraindications.

Warnings and Precautions

Drug Interactions

See Table 1 for listings of drugs that are contraindicated due to potentially life-threatening adverse events, significant drug interactions, or due to loss of virologic activity [see Contraindications (4), Drug Interactions (7.2)]. See Table 6 for a listing of established and other potentially significant drug interactions [see Drug Interactions (7.3)].

Skin Reactions

Severe and life-threatening skin reactions, including 1 case of Stevens-Johnson syndrome among 700 patients treated with Lexiva in clinical studies. Treatment with Lexiva should be discontinued for severe or life-threatening rashes and for moderate rashes accompanied by systemic symptoms [see Adverse Reactions (6)].

Sulfa Allergy

Lexiva should be used with caution in patients with a known sulfonamide allergy. Fosamprenavir contains a sulfonamide moiety. The potential for cross-sensitivity between drugs in the sulfonamide class and fosamprenavir is unknown. In a clinical study of Lexiva used as the sole protease inhibitor, rash occurred in 2 of 10 patients (20%) with a history of sulfonamide allergy compared with 42 of 126 patients (33%) with no history of sulfonamide allergy. In 2 clinical studies of Lexiva plus low-dose ritonavir, rash occurred in 8 of 50 patients (16%) with a history of sulfonamide allergy compared with 50 of 412 patients (12%) with no history of sulfonamide allergy.

Hepatic Toxicity

Use of Lexiva with ritonavir at higher-than-recommended dosages may result in transaminase elevations and should not be used [see Dosage and Administration (2), Overdosage (10)]. Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for developing or worsening of transaminase elevations. Appropriate laboratory testing should be conducted prior to initiating therapy with Lexiva and patients should be monitored closely during treatment.

Diabetes/Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between protease inhibitor therapy and these events have not been established.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Lexiva. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance,” have been observed in patients receiving antiretroviral therapy, including Lexiva. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Lipid Elevations

Treatment with Lexiva plus ritonavir has resulted in increases in the concentration of triglycerides and cholesterol [see Adverse Reactions (6)]. Triglyceride and cholesterol testing should be performed prior to initiating therapy with Lexiva and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate [see Drug Interactions (7)].

Hemolytic Anemia

Acute hemolytic anemia has been reported in a patient treated with amprenavir.

Patients With Hemophilia

There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors. In some patients, additional factor VIII was required. In many of the reported cases, treatment with protease inhibitors was continued or restarted. A causal relationship between protease inhibitor therapy and these episodes has not been established.

Nephrolithiasis

Cases of nephrolithiasis were reported during postmarketing surveillance in HIV-infected patients receiving Lexiva.Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of therapy may be considered.

Resistance/Cross-Resistance

Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored, it is unknown what effect therapy with Lexiva will have on the activity of subsequently administered protease inhibitors. Lexiva has been studied in patients who have experienced treatment failure with protease inhibitors [see Clinical Studies (14.2)].

Adverse Reactions

• Severe or life-threatening skin reactions have been reported with the use of Lexiva [see Warnings and Precautions (5.2)].


• The most common moderate to severe adverse reactions in clinical studies of Lexiva were diarrhea, rash, nausea, vomiting, and headache.


• Treatment discontinuation due to adverse events occurred in 6.4% of patients receiving Lexiva and in 5.9% of patients receiving comparator treatments. The most common adverse reactions leading to discontinuation of Lexiva (incidence less than or equal to 1% of patients) included diarrhea, nausea, vomiting, AST increased, ALT increased, and rash.

Clinical Trials

Adults

  The data for the 3 active-controlled clinical trials described below reflect exposure of 700 HIV-1 infected patients to Lexiva Tablets, including 599 patients exposed to Lexiva for greater than 24 weeks, and 409 patients exposed for greater than 48 weeks. The population age ranged from 17 to 72 years. Of these patients, 26% were female, 51% Caucasian, 31% black, 16% American Hispanic, and 70% were antiretroviral-naive. Sixty-one percent received Lexiva 1,400 mg once daily plus ritonavir 200 mg once daily, 24% received Lexiva 1,400 mg twice daily, and 15% received Lexiva 700 mg twice daily plus ritonavir 100 mg twice daily.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Selected adverse reactions reported during the clinical efficacy studies of Lexiva are shown in Tables 2 and 3. Each table presents adverse reactions of moderate or severe intensity in patients treated with combination therapy for up to 48 weeks.

Table 2. Selected Moderate/Severe Clinical Adverse Reactions Reported in Greater Than or Equal to 2% of Antiretroviral-Naive Adult Patients

Adverse Reaction	APV30001a		APV30002a
	Lexiva 1,400 mg b.i.d. (n = 166)	Nelfinavir 1,250 mg b.i.d. (n = 83)	Lexiva 1,400 mg q.d./ Ritonavir 200 mg q.d. (n = 322)	Nelfinavir 1,250 mg b.i.d. (n = 327)
Gastrointestinal
Diarrhea	5%	18%	10%	18%
Nausea	7%	4%	7%	5%
Vomiting	2%	4%	6%	4%
Abdominal pain	1%	0%	2%	2%
Skin
Rash	8%	2%	3%	2%
General disorders
Fatigue	2%	1%	4%	2%
Nervous system
Headache	2%	4%	3%	3%

aAll patients also received abacavir and lamivudine twice daily.

Table 3. Selected Moderate/Severe Clinical Adverse Reactions Reported in Greater Than or Equal to 2% of Protease Inhibitor-Experienced Adult Patients (Study APV30003)

Adverse Reaction	Lexiva 700 mg b.i.d./ Ritonavir 100 mg b.i.d.a (n = 106)	Lopinavir 400 mg b.i.d./ Ritonavir 100 mg b.i.d.a (n = 103)
Gastrointestinal
Diarrhea	13%	11%
Nausea	3%	9%
Vomiting	3%	5%
Abdominal pain	<1%	2%
Skin
Rash	3%	0%
Nervous system
Headache	4%	2%

aAll patients also received 2 reverse transcriptase inhibitors.

Skin rash (without regard to causality) occurred in approximately 19% of patients treated with Lexiva in the pivotal efficacy studies. Rashes were usually maculopapular and of mild or moderate intensity, some with pruritus. Rash had a median onset of 11 days after initiation of Lexiva and had a median duration of 13 days. Skin rash led to discontinuation of Lexiva in less than 1% of patients. In some patients with mild or moderate rash, dosing with Lexiva was often continued without interruption; if interrupted, reintroduction of Lexiva generally did not result in rash recurrence.

The percentages of patients with Grade 3 or 4 laboratory abnormalities in the clinical efficacy studies of Lexiva are presented in Tables 4 and 5.

Table 4. Grade 3/4 Laboratory Abnormalities Reported in Greater Than or Equal to 2% of Antiretroviral-Naive Adult Patients in Studies APV30001 and APV30002

Laboratory Abnormality	APV30001a		APV30002a
	Lexiva 1,400 mg b.i.d. (n = 166)	Nelfinavir 1,250 mg b.i.d. (n = 83)	Lexiva 1,400 mg q.d./ Ritonavir 200 mg q.d. (n = 322)	Nelfinavir 1,250 mg b.i.d. (n = 327)
ALT (>5 x ULN)	6%	5%	8%	8%
AST (>5 x ULN)	6%	6%	6%	7%
Serum lipase (>2 x ULN)	8%	4%	6%	4%
Triglyceridesb (>750 mg/dL)	0%	1%	6%	2%
Neutrophil count, absolute (<750 cells/mm3)	3%	6%	3%	4%

aAll patients also received abacavir and lamivudine twice daily.

bFasting specimens.

ULN = Upper limit of normal.

The incidence of Grade 3 or 4 hyperglycemia in antiretroviral-naive patients who received Lexiva in the pivotal studies was less than 1%.

Table 5. Grade 3/4 Laboratory Abnormalities Reported in Greater Than or Equal to 2% of Protease Inhibitor-Experienced Adult Patients in Study APV30003

Laboratory Abnormality	Lexiva 700 mg b.i.d./ Ritonavir 100 mg b.i.d.a (n = 104)	Lopinavir 400 mg b.i.d./ Ritonavir 100 mg b.i.d.a (n = 103)
Triglyceridesb (>750 mg/dL)	11%c	6%c
Serum lipase (>2 x ULN)	5%	12%
ALT (>5 x ULN)	4%	4%
AST (>5 x ULN)	4%	2%
Glucose (>251 mg/dL)	2%c	2%c

aAll patients also received 2 reverse transcriptase inhibitors.

bFasting specimens.

cn = 100 for Lexiva plus ritonavir, n = 98 for lopinavir plus ritonavir.

ULN = Upper limit of normal.

Pediatric Patients: Lexiva with and without ritonavir was studied in 144 pediatric patients aged 2 to 18 years in 2 open-label studies. Safety information from 75 pediatric patients receiving Lexiva twice daily with or without ritonavir follows.

All adverse events regardless of causality, all drug-related adverse events, and all laboratory events occurred with similar frequency in pediatrics compared with adults, with the exception of vomiting. Vomiting, regardless of causality, occurred more frequently among pediatric patients receiving Lexiva twice daily with ritonavir ([30%] all aged between 2 and 18 years) and without ritonavir ([56%] all aged between 2 and 5 years) compared with adults receiving Lexiva twice daily with ritonavir (10%) and without ritonavir (16%). The median duration of drug-related vomiting episodes was 1 day (range: 1 to 62 days). Vomiting required temporary dose interruptions in 4 pediatric patients and was treatment-limiting in 1 pediatric patient, all of whom were receiving Lexiva twice daily with ritonavir.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following reactions have been identified during post-approval use of Lexiva. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Lexiva. 

Cardiac Disorders

Myocardial infarction.

Metabolism and Nutrition Disorders

Hypercholesterolemia.

Nervous System Disorders

Oral paresthesia.

Skin and Subcutaneous Tissue Disorders

Angioedema.

Urogenital

Nephrolithiasis.

Drug Interactions

See also Contraindications (4), Clinical Pharmacology (12.3).

If Lexiva is used in combination with ritonavir, see full prescribing information for ritonavir for additional information on drug interactions.

CYP Inhibitors and Inducers

Amprenavir, the active metabolite of fosamprenavir, is an inhibitor of cytochrome P450 3A4 metabolism and therefore should not be administered concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4. Data also suggest that amprenavir induces CYP3A4.

Amprenavir is metabolized by CYP3A4. Coadministration of Lexiva and drugs that induce CYP3A4, such as rifampin, may decrease amprenavir concentrations and reduce its therapeutic effect. Coadministration of Lexiva and drugs that inhibit CYP3A4 may increase amprenavir concentrations and increase the incidence of adverse effects.

The potential for drug interactions with Lexiva changes when Lexiva is coadministered with the potent CYP3A4 inhibitor ritonavir. The magnitude of CYP3A4-mediated drug interactions (effect on amprenavir or effect on coadministered drug) may change when Lexiva is coadministered with ritonavir. Because ritonavir is a CYP2D6 inhibitor, clinically significant interactions with drugs metabolized by CYP2D6 are possible when coadministered with Lexiva plus ritonavir.

There are other agents that may result in serious and/or life-threatening drug interactions [see Contraindications (4)].

Drugs That Should Not Be Coadministered With Lexiva

See Contraindications (4).

Established and Other Potentially Significant Drug Interactions

Table 6 provides a listing of established or potentially clinically significant drug interactions. Information in the table applies to Lexiva with or without ritonavir, unless otherwise indicated.

Table 6. Established and Other Potentially Significant Drug Interactions

Concomitant Drug Class: Drug Name	Effect on Concentration of Amprenavir or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: Efavirenza	Lexiva: ↓Amprenavir Lexiva/ritonavir: ↓Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with Lexiva/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with Lexiva plus ritonavir twice daily.
Non-nucleoside reverse transcriptase inhibitor: Nevirapinea	Lexiva: ↓Amprenavir ↑Nevirapine Lexiva/ritonavir: ↓Amprenavir ↑Nevirapine	Coadministration of nevirapine and Lexiva without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with Lexiva/ritonavir twice daily. The combination of nevirapine administered with Lexiva/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor: Atazanavira	Lexiva: Interaction has not been evaluated. Lexiva/ritonavir: ↓Atazanavir ↔Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Indinavira, nelfinavira	Lexiva: ↑Amprenavir Effect on indinavir and nelfinavir is not well established. Lexiva/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Lopinavir/ritonavira	↓Amprenavir ↓Lopinavir	An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor: Saquinavira	Lexiva: ↓Amprenavir Effect on saquinavir is not well established. Lexiva/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Raltegravira	Lexiva: ↓Amprenavir ↓Raltegravir Lexiva/ritonavir: ↓Amprenavir ↓Raltegravir	Appropriate doses of the combination with respect to safety and efficacy have not been established [see Clinical Pharmacology (12.3)].
Other Agents
Antiarrhythmics: Amiodarone, bepridil, lidocaine (systemic), and quinidine	↑Antiarrhythmics	Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant: Warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoina	Lexiva: ↓Amprenavir Lexiva/ritonavir: ↑Amprenavir ↓Phenytoin	Use with caution. Lexiva may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in Lexiva/ritonavir dose is recommended.
Antidepressant: Paroxetine, trazodone	↓Paroxetine ↑Trazodone	Coadministration of paroxetine with Lexiva/ritonavir significantly decreased plasma levels of paroxetine. Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Concomitant use of trazodone and Lexiva with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as Lexiva, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazolea, itraconazole	↑Ketoconazole ↑Itraconazole	Increase monitoring for adverse events. Lexiva: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. Lexiva/ritonavir: High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended.
Anti-gout: Colchicine	↑Colchicine	Patients with renal or hepatic impairment should not be given colchicine with Lexiva/ritonavir. Lexiva/ritonavirand coadministration of colchicine: Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Lexivaand coadministration of colchicine: Treatment of gout flares: 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day. Treatment of FMF: Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day).
Antimycobacterial: Rifabutina	↑Rifabutin and rifabutin metabolite	A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. Lexiva: A dosage reduction of rifabutin by at least half the recommended dose is required. Lexiva/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week).
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam	↑Benzodiazepines	Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine	↑Calcium channel blockers	Use with caution. Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓Amprenavir	Use with caution. Lexiva may be less effective due to decreased amprenavir plasma concentrations.
Endothelin receptor antagonists: Bosentan	↑Bosentan	Coadministration of bosentan in patients on Lexiva: In patients who have been receiving Lexiva for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of Lexiva in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of Lexiva. After at least 10 days following the initiation of Lexiva, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Histamine H2-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidinea	Lexiva: ↓Amprenavir Lexiva/ritonavir: Interaction not evaluated	Use with caution. Lexiva may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitors: Atorvastatina, rosuvastatin	↑Atorvastatin ↑Rosuvastatin	Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin or pravastatin.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin	↑Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents.
Inhaled beta agonist: Salmeterol	↑Salmeterol	Concurrent administration of salmeterol with Lexiva is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone	Lexiva: ↑Fluticasone Lexiva/ritonavir: ↑Fluticasone