Nimesuvar

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Ingredient matches for Nimesuvar

Nimesulide

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Rifampin Injection

Dosage Form: injection, powder, lyophilized, for solution
rifampin for injection, USP

Rx Only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of rifampin for injection, USP and other antibacterial drugs, rifampin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Rifampin Injection Description

Rifampin for injection, USP is a lyophilized powder that contains rifampin 600 mg, sodium formaldehyde sulfoxylate 10 mg, and sodium hydroxide to adjust pH.

Rifampin is a semisynthetic antibiotic derivative of rifamycin SV. Rifampin is a red-brown crystalline powder very slightly soluble in water at neutral pH, freely soluble in chloroform, soluble in ethyl acetate and in methanol. Its molecular weight is 822.95 and its chemical formula is C43H58N4O12.

The chemical name for rifampin is either:

3-[[(4-Methyl-1-piperazinyl)imino]methyl]rifamycin

or

5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,20,22–heptamethyl-8-[N-(4-methyl-1- piperazinyl)formimidoyl]-2,7-(epoxypentadeca[1,11,13]trienimino)naphtho[2,1-b]furan-1,11(2H)- dione 21-acetate.

Its structural formula is:

Rifampin Injection - Clinical Pharmacology

Intravenous Administration

After intravenous administration of a 300 or 600 mg dose of rifampin infused over 30 minutes to healthy male volunteers (n=12), mean peak plasma concentrations were 9.0 ± 3.0 and 17.5 ± 5.0 mcg/mL, respectively. Total body clearances after the 300 and 600 mg IV doses were 0.19 ± 0.06 and 0.14 ± 0.03 L/hr/kg, respectively. Volumes of distribution at steady state were 0.66 ± 0.14 and 0.64 ± 0.11 L/kg for the 300 and 600 mg IV doses, respectively. After intravenous administration of 300 or 600 mg doses, rifampin plasma concentrations in these volunteers remained detectable for 8 and 12 hours, respectively (see Table).

Plasma Concentrations (mean ± standard deviation, mcg/mL)

Rifampin Dosage IV	30 min	1 hr	2 hr	4 hr	8 hr	12 hr
300 mg	8.9±2.9	4.9±1.3	4±1.3	2.5±1	1.1±0.6	<0.4
600 mg	17.4±5.1	11.7±2.8	9.4±2.3	6.4±1.7	3.5±1.4	1.2±0.6

Plasma concentrations after the 600 mg dose, which were disproportionately higher (up to 30% greater than expected) than those found after the 300 mg dose, indicated that the elimination of larger doses was not as rapid.

After repeated once-a-day infusions (3 hr duration) of 600 mg in patients (n=5) for 7 days, concentrations of IV rifampin decreased from 5.81 ± 3.38 mcg/mL 8 hours after the infusion on day 1 to 2.6 ± 1.88 mcg/mL 8 hours after the infusion on day 7.

Rifampin is widely distributed throughout the body. It is present in effective concentrations in many organs and body fluids, including cerebrospinal fluid. Rifampin is about 80% protein bound. Most of the unbound fraction is not ionized and therefore diffuses freely into tissues.

Rifampin is rapidly eliminated in the bile and undergoes progressive enterohepatic circulation and deacetylation to the primary metabolite, 25-desacetyl-rifampin. This metabolite is microbiologically active. Less than 30% of the dose is excreted in the urine as rifampin or metabolites. Serum concentrations do not differ in patients with renal failure at a studied dose of 300 mg and consequently, no dosage adjustment is required.

Pediatrics

Intravenous Administration

In pediatric patients 0.25 to 12.8 years old (n=12), the mean peak serum concentration of rifampin at the end of a 30 minute infusion of approximately 300 mg/m2 was 25.9 ± 1.3 mcg/mL; individual peak concentrations 1 to 4 days after initiation of therapy ranged from 11.7 to 41.5 mcg/mL; individual peak concentrations 5 to 14 days after initiation of therapy were 13.6 to 37.4 mcg/mL. The individual serum half-life of rifampin changed from 1.04 to 3.81 hours early in therapy to 1.17 to 3.19 hours 5 to 14 days after therapy was initiated.

Mechanism of Action

Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible Mycobacterium tuberculosis organisms. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme.

Drug Resistance

Organisms resistant to rifampin are likely to be resistant to other rifamycins.

In the treatment of both tuberculosis and the meningococcal carrier state (see INDICATIONS AND USAGE), the small number of resistant cells present within large populations of susceptible cells can rapidly become predominant. In addition, resistance to rifampin has been determined to occur as single-step mutations of the DNA-dependent RNA polymerase. Since resistance can emerge rapidly, appropriate susceptibility tests should be performed in the event of persistent positive cultures.

Activity in vitro and in vivo

Rifampin has bactericidal activity in vitro against slow and intermittently growing M tuberculosis organisms.

Rifampin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

 

Aerobic Gram-Negative Microorganisms:

Neisseria meningitidis

 

"Other" Microorganisms:

Mycobacterium tuberculosis

The following in vitro data are available, but their clinical significance is unknown.

Rifampin exhibits in vitro activity against most strains of the following microorganisms; however, the safety and effectiveness of rifampin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.

 

Aerobic Gram-Positive Microorganisms:

Staphylococcus aureus (including Methicillin-Resistant S. aureus/MRSA)

Staphylococcus epidermidis

 

Aerobic Gram-Negative Microorganisms:

Haemophilus influenzae

 

"Other" Microorganisms:

Mycobacterium leprae

β-lactamase production should have no effect on rifampin activity.

Susceptibility Tests

Prior to initiation of therapy, appropriate specimens should be collected for identification of the infecting organism and in vitro susceptibility tests.

In vitro testing for Mycobacterium tuberculosis isolates:

Two standardized in vitro susceptibility methods are available for testing rifampin against M. tuberculosis organisms. The agar proportion method (CDC or NCCLS(1) M24-P) utilizes Middlebrook 7H10 medium impregnated with rifampin at a final concentration of 1.0 mcg/mL to determine drug resistance. After three weeks of incubation MIC99 values are calculated by comparing the quantity of organisms growing in the medium containing drug to the control cultures. Mycobacterial growth in the presence of drug, of at least 1% of the growth in the control culture, indicates resistance.

The radiometric broth method employs the BACTEC 460 machine to compare the growth index from untreated control cultures to cultures grown in the presence of 2 mcg/mL of rifampin. Strict adherence to the manufacturer's instructions for sample processing and data interpretation is required for this assay.

Susceptibility test results obtained by the two different methods can only be compared if the appropriate rifampin concentration is used for each test method as indicated above. Both procedures require the use of M. tuberculosis H37Rv ATCC 27294 as a control organism.

The clinical relevance of in vitro susceptibility test results for mycobacterial species other than M. tuberculosis using either the radiometric or the proportion method has not been determined.

In vitro testing for Neisseria meningitidis isolates:

Dilution Techniques

Quantitative methods that are used to determine minimum inhibitory concentrations provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized dilution method2,4 (broth, agar, or microdilution) or equivalent with rifampin powder. The MIC values obtained should be interpreted according to the following criteria for Neisseria meningitidis:

MIC (mcg/mL)	Interpretation
≤ 1	(S) Susceptible
2	(I) Intermediate
≥ 4	(R) Resistant

A report of "susceptible" indicates that the pathogen is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in the blood. A report of "intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where the maximum acceptable dose of drug can be used. This category also provides a buffer zone that prevents small-uncontrolled technical factors from causing major discrepancies in interpretation. A report of "resistant" indicates that usually achievable concentrations of the antimicrobial compound in the blood are unlikely to be inhibitory and that other therapy should be selected.

Measurement of MIC or minimum bactericidal concentrations (MBC) and achieved antimicrobial compound concentrations may be appropriate to guide therapy in some infections. (See CLINICAL PHARMACOLOGY section for further information on drug concentrations achieved in infected body sites and other pharmacokinetic properties of this antimicrobial drug product.)

Standardized susceptibility test procedures require the use of laboratory control microorganisms. The use of these microorganisms does not imply clinical efficacy (see INDICATIONS AND USAGE); they are used to control the technical aspects of the laboratory procedures. Standard rifampin powder should give the following MIC values:

Microorganism	MIC (mcg/mL)
Staphylococcus aureus	ATCC 29213	0.008 – 0.06
Enterococcus faecalis	ATCC 29212	1 – 4
Escherichia coli	ATCC 25922	8 – 32
Pseudomonas aeruginosa	ATCC 27853	32 – 64
Haemophilus influenzae	ATCC 49247	0.25 – 1

Diffusion Techniques

Quantitative methods that require measurement of zone diameters provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure3,4 that has been recommended for use with disks to test the susceptibility of microorganisms to rifampin uses the 5 mcg rifampin disk. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for rifampin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg rifampin disk should be interpreted according to the following criteria for Neisseria meningitidis:

Zone Diameter (mm)	Interpretation
≥ 20	(S) Susceptible
17–19	(I) Intermediate
≤ 16	(R) Resistant

Interpretation should be as stated above for results using dilution techniques.

As with standard dilution techniques, diffusion methods require the use of laboratory control microorganisms. The use of these microorganisms does not imply clinical efficacy (see INDICATIONS AND USAGE); they are used to control the technical aspects of the laboratory procedures. The 5 mcg rifampin disk should provide the following zone diameters in these quality control strains:

Microorganism		Zone Diameter (mm)
S. aureus	ATCC 25923	26 – 34
E. coli	ATCC 25922	8 – 10
H. influenzae	ATCC 49247	22 – 30

Indications and Usage for Rifampin Injection

In the treatment of both tuberculosis and the meningococcal carrier state, the small number of resistant cells present within large populations of susceptible cells can rapidly become the predominant type. Bacteriologic cultures should be obtained before the start of therapy to confirm the susceptibility of the organism to rifampin and they should be repeated throughout therapy to monitor the response to treatment. Since resistance can emerge rapidly, susceptibility tests should be performed in the event of persistent positive cultures during the course of treatment. If test results show resistance to rifampin and the patient is not responding to therapy, the drug regimen should be modified.

Tuberculosis

Rifampin is indicated in the treatment of all forms of tuberculosis.

A three-drug regimen consisting of rifampin, isoniazid, and pyrazinamide (e.g., RIFATER® manufactured by Sanofi Aventis) is recommended in the initial phase of short-course therapy which is usually continued for 2 months. The Advisory Council for the Elimination of Tuberculosis, the American Thoracic Society, and Centers for Disease Control and Prevention recommend that either streptomycin or ethambutol be added as a fourth drug in a regimen containing isoniazid (INH), rifampin, and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH resistance is very low. The need for a fourth drug should be reassessed when the results of susceptibility testing are known. If community rates of INH resistance are currently less than 4%, an initial treatment regimen with less than four drugs may be considered.

Following the initial phase, treatment should be continued with rifampin and isoniazid (e.g., RIFAMATE® manufactured by Sanofi Aventis) for at least 4 months. Treatment should be continued for longer if the patient is still sputum or culture positive, if resistant organisms are present, or if the patient is HIV positive.

Rifampin for injection is indicated for the initial treatment and retreatment of tuberculosis when the drug cannot be taken by mouth.

Meningococcal Carriers

Rifampin is indicated for the treatment of asymptomatic carriers of Neisseria meningitidis to eliminate meningococci from the nasopharynx. Rifampin is not indicated for the treatment of meningococcal infection because of the possibility of the rapid emergence of resistant organisms. (See WARNINGS.)

Rifampin should not be used indiscriminately, and therefore, diagnostic laboratory procedures, including serotyping and susceptibility testing, should be performed for establishment of the carrier state and the correct treatment. So that the usefulness of rifampin in the treatment of asymptomatic meningococcal carriers is preserved, the drug should be used only when the risk of meningococcal disease is high.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of rifampin and other antibacterial drugs, rifampin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Contraindications

Rifampin is contraindicated in patients with a history of hypersensitivity to rifampin or any of the components, or to any of the rifamycins. (See WARNINGS.)

Rifampin is contraindicated in patients who are also receiving ritonavir-boosted saquinavir due to an increased risk of severe hepatocellular toxicity. (See PRECAUTIONS, Drug Interactions.) Rifampin is contraindicated in patients who are also receiving atazanavir, darunavir, fosamprenavir, saquinavir, or tipranavir due to the potential of rifampin to substantially decrease plasma concentrations of these antiviral drugs, which may result in loss of antiviral efficacy and/or development of viral resistance.

Warnings

Rifampin has been shown to produce liver dysfunction. Fatalities associated with jaundice have occurred in patients with liver disease and in patients taking rifampin with other hepatotoxic agents. Patients with impaired liver function should be given rifampin only in cases of necessity and then with caution and under strict medical supervision. In these patients, careful monitoring of liver function, especially SGPT/ALT and SGOT/AST should be carried out prior to therapy and then every 2 to 4 weeks during therapy. If signs of hepatocellular damage occur, rifampin should be withdrawn.

In some cases, hyperbilirubinemia resulting from competition between rifampin and bilirubin for excretory pathways of the liver at the cell level can occur in the early days of treatment. An isolated report showing a moderate rise in bilirubin and/or transaminase level is not in itself an indication for interrupting treatment; rather, the decision should be made after repeating the tests, noting trends in the levels, and considering them in conjunction with the patient's clinical condition.

Rifampin has enzyme-inducing properties, including induction of delta amino levulinic acid synthetase. Isolated reports have associated porphyria exacerbation with rifampin administration. The possibility of rapid emergence of resistant meningococci restricts the use of rifampin to short-term treatment of the asymptomatic carrier state. Rifampin is not to be used for the treatment of meningococcal disease.

Precautions

General

Rifampin should be used with caution in patients with a history of diabetes mellitus, as diabetes management may be more difficult.

Prescribing rifampin 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.

For the treatment of tuberculosis, rifampin is usually administered on a daily basis. Doses of rifampin greater than 600 mg given once or twice weekly have resulted in a higher incidence of adverse reactions, including the "flu syndrome" (fever, chills and malaise), hematopoietic reactions (leukopenia, thrombocytopenia, or acute hemolytic anemia), cutaneous, gastrointestinal, and hepatic reactions, shortness of breath, shock, anaphylaxis, and renal failure. Recent studies indicate that regimens using twice-weekly doses of rifampin 600 mg plus isoniazid 15 mg/kg are much better tolerated.

Rifampin has enzyme induction properties that can enhance the metabolism of endogenous substrates including adrenal hormones, thyroid hormones, and vitamin D. Rifampin and isoniazid have been reported to alter vitamin D metabolism. In some cases, reduced levels of circulating 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D have been accompanied by reduced serum calcium and phosphate, and elevated parathyroid hormone.

Rifampin for Injection

For intravenous infusion only. Must not be administered by intramuscular or subcutaneous route. Avoid extravasation during injection: local irritation and inflammation due to extravascular infiltration of the infusion have been observed. If these occur, the infusion should be discontinued and restarted at another site.

Information for Patients

Patients should be counseled that antibacterial drugs including rifampin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When rifampin 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 rifampin or other antibacterial drugs in the future.

The patient should be told that rifampin may produce a reddish coloration of the urine, sweat, sputum, and tears, and the patient should be forewarned of this. Soft contact lenses may be permanently stained.

The patient should be advised that the reliability of oral or other systemic hormonal contraceptives may be affected; consideration should be given to using alternative contraceptive measures.

Patients should be instructed to notify their physicians promptly if they experience any of the following: fever, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, and pain or swelling of the joints.

Compliance with the full course of therapy must be emphasized, and the importance of not missing any doses must be stressed.

Laboratory Tests

Adults treated for tuberculosis with rifampin should have baseline measurements of hepatic enzymes, bilirubin, serum creatinine, a complete blood count, and a platelet count (or estimate). Baseline tests are unnecessary in pediatric patients unless a complicating condition is known or clinically suspected.

Patients should be seen at least monthly during therapy and should be specifically questioned concerning symptoms associated with adverse reactions. All patients with abnormalities should have follow-up, including laboratory testing, if necessary. Routine laboratory monitoring for toxicity in people with normal baseline measurements is generally not necessary.

Drug Interactions

Healthy subjects who received rifampin 600 mg once daily concomitantly with saquinavir 1000 mg/ritonavir 100 mg twice daily (ritonavir-boosted saquinavir) developed severe hepatocellular toxicity. Therefore, concomitant use of these medications is contraindicated. (See CONTRAINDICATIONS.)

ENZYME INDUCTION

Rifampin is known to induce certain cytochrome P-450 enzymes. Administration of rifampin with drugs that undergo biotransformation through these metabolic pathways may accelerate elimination of coadministered drugs. To maintain optimum therapeutic blood levels, dosages of drugs metabolized by these enzymes may require adjustment when starting or stopping concomitantly administered rifampin.

Rifampin has been reported to accelerate the metabolism of the following drugs: anticonvulsants (e.g., phenytoin), antiarrhythmics (e.g., disopyramide, mexiletine, quinidine, tocainide), oral anticoagulants, antifungals (e.g., fluconazole, itraconazole, ketoconazole), barbiturates, betablockers, calcium channel blockers (e.g., diltiazem, nifedipine, verapamil), chloramphenicol, clarithromycin, corticosteroids, cyclosporine, cardiac glycoside preparations, clofibrate, oral or other systemic hormonal contraceptives, dapsone, diazepam, doxycycline, fluoroquinolones (e.g., ciprofloxacin), haloperidol, oral hypoglycemic agents (sulfonylureas), levothyroxine, methadone, narcotic analgesics, nortriptyline, progestins, quinine, tacrolimus, theophylline tricyclic antidepressants (e.g., amitriptyline, nortriptyline) and zidovudine. It may be necessary to adjust the dosages of these drugs if they are given concurrently with rifampin.

Patients using oral or other systemic hormonal contraceptives should be advised to change to nonhormonal methods of birth control during rifampin therapy.

Rifampin has been observed to increase the requirements for anticoagulant drugs of the coumarin type. In patients receiving anticoagulants and rifampin concurrently, it is recommended that the prothrombin time be performed daily or as frequently as necessary to establish and maintain the required dose of anticoagulant.

Other Interactions

When the two drugs were taken concomitantly, decreased concentrations of atovaquone and increased concentrations of rifampin were observed.

Concurrent use of ketoconazole and rifampin has resulted in decreased serum concentrations of both drugs. Concurrent use of rifampin and enalapril has resulted in decreased concentrations of enalaprilat, the active metabolite of enalapril. Dosage adjustments should be made if indicated by the patient's clinical condition.

Concomitant antacid administration may reduce the absorption of rifampin. Daily doses of rifampin should be given at least 1 hour before the ingestion of antacids.

Probenecid and cotrimoxazole have been reported to increase the blood level of rifampin.

When rifampin is given concomitantly with either halothane or isoniazid, the potential for hepatotoxicity is increased. The concomitant use of rifampin and halothane should be avoided. Patients receiving both rifampin and isoniazid should be monitored close for hepatotoxicity.

Plasma concentrations of sulfapyridine may be reduced following the concomitant administration of sulfasalazine and rifampin. This finding may be the result of alteration in the colonic bacteria responsible for the reduction of sulfasalazine to sulfapyridine and mesalamine.

Drug/Laboratory Interactions

Cross-reactivity and false-positive urine screening tests for opiates have been reported in patients receiving rifampin when using the KIMS (Kinetic Interaction of Microparticles in Solution) method (e.g., Abuscreen OnLine opiates assay; Roche Diagnostic Systems). Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish rifampin from opiates.

Therapeutic levels of rifampin have been shown to inhibit standard microbiological assays for serum folate and vitamin B12. Thus, alternate assay methods should be considered. Transient abnormalities in liver function tests (e.g., elevation in serum bilirubin, alkaline phosphatase, and serum transaminases) and reduced biliary excretion of contrast media used for visualization of the gallbladder have also been observed. Therefore, these tests should be performed before the morning dose of rifampin.

Carcinogenesis, Mutagenesis, Impairment of Fertility

There are no known human data on long-term potential for carcinogenicity, mutagenicity, or impairment of fertility. A few cases of accelerated growth of lung carcinoma have been reported in man, but a causal relationship with the drug has not been established. An increase in the incidence of hepatomas in female mice (of a strain known to be particularly susceptible to the spontaneous development of hepatomas) was observed when rifampin was administered in doses 2 to 10 times the average daily human dose for 60 weeks, followed by an observation period of 46 weeks. No evidence of carcinogenicity was found in male mice of the same strain, mice of a different strain, or rats under similar experimental conditions.

Rifampin has been reported to possess immunosuppressive potential in rabbits, mice, rats, guinea pigs, human lymphocytes in vitro, and humans. Antitumor activity in vitro has also been shown with rifampin.

There was no evidence of mutagenicity in bacteria, Drosophila melanogaster, or mice. An increase in chromatid breaks was noted when whole blood cell cultures were treated with rifampin. Increased frequency of chromosomal aberrations was observed in vitro in lymphocytes obtained from patients treated with combinations of rifampin, isoniazid, and pyrazinamide and combinations of streptomycin, rifampin, isoniazid, and pyrazinamide.

Pregnancy

Teratogenic Effects

Category C

Rifampin has been shown to be teratogenic in rodents given oral doses of rifampin 15 to 25 times the human dose. Although rifampin has been reported to cross the placental barrier and appear in cord blood, the effect of rifampin, alone or in combination with other antituberculosis drugs, on the human fetus is not known. Neonates of rifampin-treated mothers should be carefully observed for any evidence of adverse effects. Isolated cases of fetal malformations have been reported; however, there are no adequate and well-controlled studies in pregnant women. Rifampin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Rifampin in oral doses of 150 to 250 mg/kg produced teratogenic effects in mice and rats. Malformations were primarily cleft palate in the mouse and spina bifida in the rat. The incidence of these anomalies was dose-dependent. When rifampin was given to pregnant rabbits in doses up to 20 times the usual daily human dose, imperfect osteogenesis and embryotoxicity were reported.

Pregnancy–Non-Teratogenic Effects

When administered during the last few weeks of pregnancy, rifampin can cause post-natal hemorrhages in the mother and infant for which treatment with vitamin K may be indicated.

Nursing Mothers

Because of the potential for tumorigenicity shown for rifampin in animal studies, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

See CLINICAL PHARMACOLOGY– Pediatrics; see also DOSAGE AND ADMINISTRATION.

Geriatric Use

Clinical studies of rifampin 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. Caution should therefore be observed in using rifampin in elderly patients. (See WARNINGS).

Adverse Reactions

Gastrointestinal

Heartburn, epigastric distress, anorexia, nausea, vomiting, jaundice, flatulence, cramps, and diarrhea have been noted in some patients. Although Clostridium difficile has been shown in vitro to be sensitive to rifampin, pseudomembranous colitis has been reported with the use of rifampin (and other broad spectrum antibiotics). Therefore, it is important to consider this diagnosis in patients who develop diarrhea in association with antibiotic use.

Hepatic

Transient abnormalities in liver function tests (e.g., elevations in serum bilirubin, BSP, alkaline phosphatase, serum transaminases) have been observed. Rarely, hepatitis or a shock-like syndrome with hepatic involvement and abnormal liver function tests has been reported.

Hematologic

Thrombocytopenia has occurred primarily with high dose intermittent therapy, but has also been noted after resumption of interrupted treatment. It rarely occurs during well supervised daily therapy. This effect is reversible if the drug is discontinued as soon as purpura occurs. Cerebral hemorrhage and fatalities have been reported when rifampin administration has been continued or resumed after the appearance of purpura.

Rare reports of disseminated intravascular coagulation have been observed.

Leukopenia, hemolytic anemia, and decreased hemoglobin have been observed.

Agranulocytosis has been reported very rarely.

Central Nervous System

Headache, fever, drowsiness, fatigue, ataxia, dizziness, inability to concentrate, mental confusion, behavioral changes, muscular weakness pains in extremities, and generalized numbness have been observed.

Psychoses have been rarely reported.

Rare reports of disseminated intravascular coagulation have been observed.

Ocular

Visual disturbances have been observed.

Endocrine

Menstrual disturbances have been observed.

Rare reports of adrenal insufficiency in patients with compromised adrenal function have been observed.

Renal

Elevations in BUN and serum uric acid have been reported. Rarely, hemolysis, hemoglobinuria, hematuria, interstitial nephritis, acute tubular necrosis, renal insufficiency, and acute renal failure have been noted. These are generally considered to be hypersensitivity reactions. They usually occur during intermittent therapy or when treatment is resumed following intentional or accidental interruption of a daily dosage regimen, and are reversible when rifampin is discontinued and appropriate therapy instituted.

Dermatologic

Cutaneous reactions are mild and self-limiting and do not appear to be hypersensitivity reactions. Typically, they consist of flushing and itching with or without a rash. More serious cutaneous reactions which may be due to hypersensitivity occur but are uncommon.

Hypersensitivity Reactions

Occasionally, pruritus, urticaria, rash, pemphigoid reaction, erythema multiforme including Stevens-Johnson Syndrome, toxic epidermal necrolysis, vasculitis, eosinophilia, sore mouth, sore tongue, and conjunctivitis have been observed.

Anaphylaxis has been reported rarely.

Miscellaneous

Edema of the face and extremities has been reported. Other reactions reported to have occurred with intermittent dosage regimens include "flu syndrome" (such as episodes of fever, chills, headache, dizziness, and bone pain), shortness of breath, wheezing, decrease in blood pressure and shock. The "flu syndrome" may also appear if rifampin is taken irregularly by the patient or if daily administration is resumed after a drug free interval.

Overdosage

Signs and Symptoms

Nausea, vomiting, abdominal pain, pruritus, headache, and increasing lethargy will probably occur within a short time after ingestion; unconsciousness may occur when there is severe hepatic disease. Transient increases in liver enzymes and/or bilirubin may occur. Brownish-red or orange discoloration of the skin, urine, sweat, saliva, tears, and feces will occur, and its intensity is proportional to the amount ingested.

Liver enlargement, possibly with tenderness, can develop within a few hours after severe overdosage; bilirubin levels may increase and jaundice may develop rapidly. Hepatic involvement may be more marked in patients with prior impairment of hepatic function. Other physical findings remain essentially normal. A direct effect upon the hematopoietic system, electrolyte levels, or acid-base balance is unlikely.

Facial or periorbital edema has also been reported in pediatric patients. Hypotension, sinus tachycardia, ventricular arrhythmias, seizures and cardiac arrest were reported in some fatal cases.

Acute Toxicity

The LD50 of rifampin is approximately 885 mg/kg in the mouse, 1720 mg/kg in the rat, and 2120 mg/kg in the rabbit.

The minimum acute lethal or toxic dose is not well established. However, nonfatal acute overdoses in adults have been reported with doses ranging from 9 to 12 gm rifampin. Fatal acute overdoses in adults have been reported with doses ranging from 14 to 60 gm. Alcohol or a history of alcohol abuse was involved in some of the fatal and nonfatal reports. Nonfatal overdoses in pediatric patients ages 1 to 4 years old of 100 mg/kg for one to two doses has been reported.

Treatment

Intensive support measures should be instituted and individual symptoms treated as they arise. The airway should be secured and adequate respiratory exchange established. Since nausea and vomiting are likely to be present, gastric lavage within the first 2 to 3 hours after ingestion is probably preferable to induction of emesis. Following evacuation of the gastric contents, the instillation of activated charcoal slurry into the stomach may help absorb any remaining drug from the gastrointestinal tract. Antiemetic medication may be required to control severe nausea and vomiting.

Active diuresis (with measured intake and output) will help promote excretion of the drug.

For severe cases, extracorporeal hemodialysis may be required. If this is not available, peritoneal dialysis can be used along with forced diuresis.

Rifampin Injection Dosage and Administration

Rifampin can be administered by IV infusion (see INDICATIONS AND USAGE).

See CLINICAL PHARMACOLOGY for dosing information in patients with renal failure.

Tuberculosis

Adults: 10 mg/kg, in a single daily administration, not to exceed 600 mg/day, IV

Pediatric Patients: 10–20 mg/kg, not to exceed 600 mg/day, IV

Rifampin is indicated in the treatment of all forms of tuberculosis. A three-drug regimen consisting of rifampin, isoniazid, and pyrazinamide (e.g., RIFATER® manufactured by Sanofi Aventis) is recommended in the initial phase of short-course therapy which is usually continued for 2 months. The Advisory Council for the Elimination of Tuberculosis, the American Thoracic Society, and the Centers for Disease Control and Prevention recommend that either streptomycin or ethambutol be added as a fourth drug in a regimen containing isoniazid (INH), rifampin and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH resistance is very low. The need for a fourth drug should be reassessed when the results of susceptibility testing are known. If community rates of INH resistance are currently less than 4%, an initial treatment regimen with less than four drugs may be considered.

Following the initial phase, treatment should be continued with rifampin and isoniazid (e.g., RIFAMATE® manufactured by Sanofi Aventis) for at least 4 months. Treatment should be continued for longer if the patient is still sputum or culture positive, if resistant organisms are present, or if the patient is HIV positive.

Preparation of Solution for IV Infusion

Reconstitute the lyophilized powder by transferring 10 mL of sterile water for injection to a vial containing 600 mg of rifampin for injection. Swirl vial gently to completely dissolve the antibiotic. The reconstituted solution contains 60 mg rifampin per mL and is stable at room temperature for 24 hours. Prior to administration, withdraw from the reconstituted solution a volume equivalent to the amount of rifampin calculated to be administered and add to 500 mL of infusion medium. Mix well and infuse at a rate allowing for complete infusion within 3 hours. Alternatively, the amount of rifampin calculated to be administered may be added to 100 mL of infusion medium and infused in 30 minutes.

Dilutions in dextrose 5% for injection (D5W) are stable at room temperature for up to 4 hours and should be prepared and used within this time. Precipitation of rifampin from the infusion solution may occur beyond this time. Dilutions in normal saline are stable at room temperature for up to 24 hours and should be prepared and used within this time. Other infusion solutions are not recommended.

Incompatibilities

Physical incompatibility (precipitate) was observed with undiluted (5 mg/mL) and diluted (1 mg/mL in normal saline) diltiazem hydrochloride and rifampin (6 mg/mL in normal saline) during simulated Y-site administration.

Meningococcal Carriers

Adults: For adults, it is recommended that 600 mg rifampin be administered twice daily for two days.

Pediatric Patients: Pediatric patients 1 month of age or older: 10 mg/kg (not to exceed 600 mg per dose) every 12 hours for two days.

Pediatric patients under 1 month of age: 5 mg/kg every 12 hours for two days.

How is Rifampin Injection Supplied

Rifampin for injection, USP is available in glass vials containing 600 mg rifampin (NDC 0069-0112-01).

Storage

Store at 20° to 25°C (68° to 77°F)[see USP Controlled Room Temperature]. Avoid excessive heat (temperatures above 40°C or 104°F). Protect from light.

References

1. Clinical Laboratory Standards Institute, Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard CLSI Document M24-A, Vol. 23, No. 18, CLSI, Villanova, PA, 2003.


2. Clinical Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically -- Eighth Edition. Approved Standard CLSI Document M7- A8, Vol. 29, No. 2, CLSI, Villanova, PA, January 2009.


3. Clinical Laboratory Standards Institute. Performance Standards for Antimicrobial Disk Susceptibility Tests -- Tenth Edition. Approved Standard CLSI Document M2-A10, Vol. 29, No. 1, CLSI, Villanova, PA, January 2009.


4. Clinical Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Twentieth Informational Supplement, CLSI Document M100-S20, Vol. 30, No. 1, CLSI, Villanova, PA, January 2010.

1015331

February 2011

PRINCIPAL DISPLAY PANEL - 600 mg Vial Carton

600 mg

NDC 0069-0112-01

Rx only

1 Vial

rifampin for

injection, USP

600 mg/vial

Sterile

For IV Infusion Only

Pfizer Injectables

RIFAMPIN  rifampin  injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0069-0112 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Rifampin (Rifampin) Rifampin 600 mg  in 10 mL

Inactive Ingredients Ingredient Name Strength Sodium Formaldehyde Sulfoxylate 10 mg  in 10 mL Sodium Hydroxide

Product Characteristics Color RED (Red-Brown) Score      Shape Size Flavor Imprint Code Contains

Packaging #

Indo

Indo may be available in the countries listed below.

Ingredient matches for Indo

Indometacin

Indometacin is reported as an ingredient of Indo in the following countries:

• Singapore

International Drug Name Search

Nystacid

Nystacid may be available in the countries listed below.

Ingredient matches for Nystacid

Nystatin

Nystatin is reported as an ingredient of Nystacid in the following countries:

• South Africa

International Drug Name Search

Darvocet A500

propoxyphene napsylate and acetaminophen

Dosage Form: tablet, film coated
Darvocet A500® (PROPOXYPHENE NAPSYLATE AND ACETAMINOPHEN TABLETS, USP) 100 mg/500 mg

CIV

Rx only

WARNINGS

• There have been numerous cases of accidental and intentional overdose with propoxyphene products either alone or in combination with other CNS depressants, including alcohol. Fatalities within the first hour of overdosage are not uncommon. Many of the propoxyphene-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation/attempts and/or concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Do not prescribe propoxyphene for patients who are suicidal or have a history of suicidal ideation.


• The metabolism of propoxyphene may be altered by strong CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) leading to enhanced propoxyphene plasma levels. Patients receiving propoxyphene and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted (see CLINICAL PHARMACOLOGY – Drug Interactions, and WARNINGS, PRECAUTIONS and DOSAGE AND ADMINISTRATION for further information).

DESCRIPTION

Darvocet A500 contains propoxyphene napsylate and acetaminophen.

Propoxyphene Napsylate, USP is an odorless, white crystalline powder with a bitter taste. It is very slightly soluble in water and soluble in methanol, ethanol, chloroform, and acetone. Chemically, it is (α S, 1 R)-α-[ 2-(Dimethylamino)-1-methylethyl ] -α-phenylphenethyl propionate compound with 2-naphthalenesulfonic acid (1:1) monohydrate, which can be represented by the accompanying structural formula. Its molecular weight is 565.72.

Propoxyphene napsylate differs from propoxyphene hydrochloride in that it allows more stable liquid dosage forms and tablet formulations. Because of differences in molecular weight, a dose of 100 mg (176.8 μmol) of propoxyphene napsylate is required to supply an amount of propoxyphene equivalent to that present in 65 mg (172.9 μmol) of propoxyphene hydrochloride.

Acetaminophen, 4'-hydroxyacetanilide, is a non-opiate, non-salicylate analgesic and antipyretic which occurs as a white, odorless, crystalline powder, possessing a slightly bitter taste. The molecular formula for acetaminophen is C8H9NO2 and the molecular weight is 151.17. It may be represented by the following structural formula:

Each tablet of Darvocet A500® contains 100 mg (176.8 μmol) propoxyphene napsylate and 500 mg (3307.8 μmol) acetaminophen.

Each tablet also contains anhydrous lactose, colloidal silicon dioxide, crospovidone, magnesium stearate (powder), microcrystalline cellulose, povidone, pregelatinized corn starch, and stearic acid (powder). Film coating composed of: carnauba wax, hypromellose 2910 6cP, polyethylene glycol, purified water, sodium citrate, titanium dioxide, FD&C Red No. 40 Aluminum Lake, and FD&C Yellow No. 6 Aluminum Lake.

CLINICAL PHARMACOLOGY

Pharmacology

Propoxyphene is a centrally acting opiate analgesic. In vitro studies demonstrated propoxyphene and the metabolite norpropoxyphene inhibit sodium channels (local anesthetic effect) with norpropoxyphene being approximately 2-fold more potent than propoxyphene and propoxyphene approximately 10-fold more potent than lidocaine. Propoxyphene and norpropoxyphene inhibit the voltage-gated potassium current carried by cardiac rapidly activating delayed rectifier (hERG) channels with approximately equal potency. It is unclear if the effects on ion channels occur within therapeutic dose range.

Acetaminophen is a non-opiate, non-salicylate analgesic and antipyretic. The site and mechanism for the analgesic effect of acetaminophen has not been determined. The antipyretic effect of acetaminophen is mediated through activity in the hypothalamic heat-regulating centers. Acetaminophen inhibits prostaglandin synthetase. Therapeutic doses of acetaminophen have negligible effects on the cardiovascular or respiratory systems; however, toxic doses may cause circulatory failure and rapid, shallow breathing.

Pharmacokinetics

Absorption

Peak plasma concentrations of propoxyphene are reached in 2 to 2.5 h. After a 65-mg oral dose of propoxyphene hydrochloride, peak plasma levels of 0.05 to 0.1 μg/mL for propoxyphene and 0.1 to 0.2 μg/mL for norpropoxyphene (major metabolite) are achieved. Repeated doses of propoxyphene at 6 h intervals lead to increasing plasma concentrations, with a plateau after the ninth dose at 48 h. Propoxyphene has a half-life of 6 to 12 h, whereas that of norpropoxyphene is 30 to 36 h.

Acetaminophen is absorbed from the gastrointestinal tract and has a plasma half-life of 1.25 to 3 h, which may be increased by liver damage and following overdosage.

Distribution

Propoxyphene is about 80% bound to proteins and has a large volume of distribution, 16 L/kg.

Acetaminophen is relatively uniformly distributed throughout most body fluids. Binding of the drug to plasma proteins is variable; only 20% to 50% may be bound at the concentrations encountered during acute intoxication.

Metabolism

Propoxyphene undergoes extensive first-pass metabolism by intestinal and hepatic enzymes. The major route of metabolism is cytochrome CYP3A4 mediated N-demethylation to norpropoxyphene, which is excreted by the kidneys. Ring hydroxylation and glucuronide formation are minor metabolic pathways.

Acetaminophen is extensively metabolized in the liver. Less than 5% of acetaminophen dose is excreted unchanged in the kidney. About 85% of an acetaminophen dose is metabolized by conjugation, mainly glucuronidation via UDP-glucuronosyltransferase (mainly UGT1A6) and to a lesser extent sulfation via sulfotransferase (mainly SLT1A1 and SLT1A3). The glucuronide and sulfate conjugates are non-toxic and are largely excreted in the urine and bile. About 8-10% of an acetaminophen dose is oxidized by cytochrome CYP2E1 to form the toxic reactive intermediate, N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is further metabolized via glutathione (GSH) conjugation, yielding non-toxic thiol metabolites including cysteine, mercapturate, methylthioacetaminophen, and methanesulfinylacetaminophen that are excreted in the urine. Acetaminophen is also oxidized at a low percentage by cytochrome CYP2A6 to form inert catechols (e.g., methoxyacetaminophen).

Excretion

In 48 h, approximately 20% to 25% of the administered dose of propoxyphene is excreted via the urine, most of which is free or conjugated norpropoxyphene. The renal clearance rate of propoxyphene is 2.6 L/min.

Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Approximately 85% of an oral dose appears in the urine within 24 hours of administration, most as the glucuronide conjugate, with small amounts of other conjugates and unchanged drug.

SPECIAL POPULATIONS

Geriatric Patients

After oral administration of propoxyphene in elderly patients (70-78 years), much longer half-lives of propoxyphene and norpropoxyphene have been reported (propropoxyphene 13 to 35 h, norpropoxyphene 22 to 41 h). In addition, the AUC was an average of 3-fold higher and the Cmax was an average of 2.5-fold higher in the elderly when compared to a younger (20-28 years) population. Longer dosage intervals may be considered in the elderly because the metabolism of propoxyphene may be reduced in this patient population. After multiple oral doses of propoxyphene in elderly patients (70-78 years), the Cmax of the metabolite (norpropoxyphene) was increased 5-fold.

Pediatric Patients

Neither propoxyphene alone nor in combination with acetaminophen has been studied in pediatric patients.

Hepatic Impairment

No formal pharmacokinetic study of either propoxyphene alone or in combination with acetaminophen has been conducted in patients with mild, moderate or severe hepatic impairment.

After oral administration of propoxyphene in patients with cirrhosis, plasma concentrations of propoxyphene were considerably higher and norpropoxyphene concentrations were much lower than in control patients. This is presumably because of a decreased first-pass metabolism of orally administered propoxyphene in these patients. The AUC ratio of norpropoxyphene: propoxyphene was significantly lower in patients with cirrhosis (0.5 to 0.9) than in controls (2.5 to 4).

Compared to healthy subjects, acetaminophen had a lower total clearance and longer half-life in patients with liver disease. Decreased metabolite formation clearance (8-42%) was observed in subjects with liver disease compared to healthy subjects after both single and multiple-doses (at steady state). In addition, there is an increase in the amount of acetaminophen excreted unchanged in the urine (4.7% vs. 2.5%) in patients with liver disease compared to healthy subjects after repeat doses, suggesting that more acetaminophen was excreted by renal elimination in the liver disease state.

Renal Impairment

No formal pharmacokinetic study of either propoxyphene alone or in combination with acetaminophen has been conducted in patients with mild, moderate or severe renal impairment.

After oral administration of propoxyphene in anephric patients, the AUC and Cmax values were an average of 76% and 88% greater, respectively. Dialysis removes only insignificant amounts (8%) of administered dose of propoxyphene.

Drug Interactions

The metabolism of propoxyphene may be altered by strong CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) leading to enhanced propoxyphene plasma levels. On the other hand, strong CYP3A4 inducers such as rifampin may lead to enhanced metabolite (norpropoxyphene) levels.

Propoxyphene is also thought to possess CYP3A4 and CYP2D6 enzyme inhibiting properties. Coadministration with a drug that is a substrate of CYP3A4 or CYP2D6, may result in higher plasma concentrations and increased pharmacologic or adverse effects of that drug.

CLINICAL STUDIES

The efficacy of propoxyphene in combination with acetaminophen was studied in seven single-dose, randomized, double-blind, placebo-controlled trials in patients with mild to severe postpartum pain. One of the studies demonstrated that both propoxyphene and acetaminophen in the combination contributed to a greater reduction in pain than acetaminophen and propoxyphene alone and that propoxyphene was superior to placebo.

There is insufficient information available to assess efficacy of propoxyphene in combination with acetaminophen in patients with chronic pain.

INDICATION

Darvocet A500 is indicated for the relief of mild to moderate pain.

CONTRAINDICATIONS

Darvocet A500 is contraindicated in patients with known hypersensitivity to propoxyphene or acetaminophen.

Darvocet A500 is contraindicated in patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment) and patients with acute or severe asthma or hypercarbia.

Darvocet A500 is contraindicated in any patient who has or is suspected of having paralytic ileus.

WARNINGS

Risk of Overdose

There have been numerous cases of accidental and intentional overdose with propoxyphene products either alone or in combination with other CNS depressants, including alcohol. Fatalities within the first hour of overdosage are not uncommon. Many of the propoxyphene-related deaths have occurred in patients with previous histories of emotional disturbances or suicidal ideation/attempts and/or concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs. Do not prescribe propoxyphene for patients who are suicidal or have a history of suicidal ideation.

Respiratory Depression

Respiratory depression is the chief hazard from all opioid agonist preparations. Respiratory depression occurs most frequently in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration. Darvocet A500 should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of Darvocet A500 may decrease respiratory drive to the point of apnea. In these patients alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose.

Hypotensive Effect

Darvocet A500, like all opioid analgesics, may cause severe hypotension in an individual whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents which compromise vasomotor tone. Darvocet A500 may produce orthostatic hypotension in ambulatory patients. Darvocet A500, like all opioid analgesics, should be administered with caution to patients in circulatory shock, since vasodilatation produced by the drug may further reduce cardiac output and blood pressure.

Head Injury and Increased Intracranial Pressure

The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries.

Drug Interactions

The concomitant use of propoxyphene and CNS depressants, including alcohol, can result in potentially serious adverse events including death. Because of its added depressant effects, propoxyphene should be prescribed with caution for those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS-depressant drugs.

Usage in Ambulatory Patients

Propoxyphene may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly.

Use with Other Acetaminophen-Containing Agents

Due to the potential for acetaminophen hepatotoxicity at doses higher than the recommended dose, Darvocet A500 should not be used concomitantly with other acetaminophen-containing products.

Use with Alcohol

Hepatotoxicity and severe hepatic failure occurred in chronic alcoholics following therapeutic doses of acetaminophen. Patients should be cautioned about the concomitant use of propoxyphene products and alcohol because of potentially serious CNS-additive effects of these agents that can lead to death.

PRECAUTIONS

Tolerance and Physical Dependence

Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy.

The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including: irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION: Cessation of Therapy).

If Darvocet A500 is abruptly discontinued in a physically dependent patient, an abstinence syndrome may occur (see DRUG ABUSE AND DEPENDENCE). If signs and symptoms of withdrawal occur, patients should be treated by reinstitution of opioid therapy followed by gradual tapered dose reduction of Darvocet A500 combined with symptomatic support (see DOSAGE AND ADMINISTRATION: Cessation of Therapy).

Use in Pancreatic/Biliary Tract Disease

Darvocet A500 may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like Darvocet A500 may cause increases in the serum amylase level.

Hepatic or Renal Impairment

Insufficient information exists to make appropriate dosing recommendations regarding the use of either propoxyphene alone or in combination with acetaminophen in patients with hepatic or renal impairment as a function of degree of impairment. Higher plasma concentrations and/or delayed elimination may occur in case of impaired hepatic function and/or impaired renal function (see CLINICAL PHARMACOLOGY). If the drug is used in these patients, it should be used with caution because of the hepatic metabolism of propoxyphene and acetaminophen and renal excretion of their metabolites.

Information for Patients/Caregivers

1. Patients should be advised to report pain and adverse experiences occurring during therapy. Individualization of dosage is essential to make optimal use of this medication.


2. Patients should be advised not to adjust the dose of Darvocet A500 without consulting the prescribing professional.


3. Patients should be advised that Darvocet A500 may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating heavy machinery).


4. Patients should not combine Darvocet A500 with central nervous system depressants (e.g., sleep aids, tranquilizers) except by the orders of the prescribing physician, because additive effects may occur.


5. Patients should be instructed not to consume alcoholic beverages, including prescription and over-the-counter medications that contain alcohol, while using Darvocet A500 because of risk of serious adverse events including death.


6. Women of childbearing potential who become, or are planning to become, pregnant should be advised to consult their physician regarding the effects of analgesics and other drug use during pregnancy on themselves and their unborn child.


7. Patients should be advised that Darvocet A500 is a potential drug of abuse. They should protect it from theft, and it should never be given to anyone other than the individual for whom it was prescribed.


8. Patients should be advised that if they have been receiving treatment with Darvocet A500 for more than a few weeks and cessation of therapy is indicated, it may be appropriate to taper the Darvocet A500 dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. Their physician can provide a dose schedule to accomplish a gradual discontinuation of the medication.


9. Instruct patients not to consume any other medication that contains acetaminophen, including acetaminophen-based over-the-counter medications, while taking Darvocet A500.

Drug Interactions with Propoxyphene

Propoxyphene is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur when propoxyphene is administered concurrently with agents that affect CYP3A4 activity.

The metabolism of propoxyphene may be altered by strong CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) leading to enhanced propoxyphene plasma levels. Coadministration with agents that induce CYP3A4 activity may reduce the efficacy of propoxyphene. Strong CYP3A4 inducers such as rifampin may lead to enhanced metabolite (norpropoxyphene) levels.

Propoxyphene is also thought to possess CYP3A4 and CYP2D6 enzyme inhibiting properties and coadministration with drugs that rely on either of these enzymes for metabolism may result in increased pharmacologic or adverse effects of that drug. Severe neurologic signs, including coma, have occurred with concurrent use of carbamazepine (metabolized by CYP3A4).

Increased risk of bleeding has been observed with warfarin-like agents when given along with propoxyphene; however, the mechanistic basis of this interaction is unknown.

CNS Depressants

Patients receiving narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with Darvocet A500 may exhibit an additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with the usual dosage of Darvocet A500. When such combined therapy is contemplated, the dose of one or both agents should be reduced.

Mixed Agonist/Antagonist Opioid Analgesics

Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol and buprenorphine) should be administered with caution to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic such as Darvocet A500. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of Darvocet A500 and/or may precipitate withdrawal symptoms in these patients.

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs have been reported to intensify the effects of at least one opioid drug causing anxiety, confusion and significant depression of respiration or coma. The use of Darvocet A500 is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

Drug Interactions with Acetaminophen

Alcohol: Hepatotoxicity has occurred in chronic alcoholics following various dose levels (moderate to excessive) of acetaminophen.

Anticholinergics: The onset of acetaminophen effect may be delayed or decreased slightly, but the ultimate pharmacological effect is not significantly affected by anticholinergics.

Oral Contraceptives: Increase in glucuronidation resulting in increased plasma clearance and a decreased half-life of acetaminophen.

Beta Blockers (Propranolol): Propranolol appears to inhibit the enzyme systems responsible for the glucuronidation and oxidation of acetaminophen. Therefore, the pharmacologic effects of acetaminophen may be increased.

Loop Diuretics: The effects of the loop diuretic may be decreased because acetaminophen may decrease renal prostaglandin excretion and decrease plasma renin activity.

Lamotrigine: Serum lamotrigine concentrations may be reduced, producing a decrease in therapeutic effects.

Probenecid: Probenecid may increase the therapeutic effectiveness of acetaminophen slightly.

Zidovudine: The pharmacologic effects of zidovudine may be decreased because of enhanced nonhepatic or renal clearance of zidovudine.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The mutagenic and carcinogenic potential of propoxyphene and acetaminophen alone and in combination have not been evaluated.

In animal studies there was no effect of propoxyphene on mating behavior, fertility, duration of gestation, or parturition when rats were fed propoxyphene as a component of their daily diet at estimated daily propoxyphene intake up to 8-fold greater than the maximum human equivalent dose (HED) based on body surface area comparison. At this highest dose, fetal weight and survival on postnatal day 4 was reduced. Acetaminophen has not been studied in animals for effects on fertility and the effects on human fertility are unknown.

Pregnancy

Risk summary

Pregnancy category C.

There are no adequate and well-controlled studies of propoxyphene with acetaminophen in pregnant women. While there are limited data in the published literature, adequate animal reproduction studies have not been conducted with propoxyphene or acetaminophen. Therefore, it is not known whether propoxyphene or acetaminophen can affect reproduction or cause fetal harm when administered to a pregnant woman. Propoxyphene with acetaminophen should be given to a pregnant woman only if clearly needed.

Clinical considerations

Acetaminophen, propoxyphene and its major metabolite, norpropoxyphene, cross the human placenta. Neonates whose mothers have taken opiates chronically may exhibit respiratory depression or withdrawal symptoms.

Data

In published animal reproduction studies, no teratogenic effects occurred in offspring born to pregnant rats or rabbits that received propoxyphene during organogenesis. Pregnant animals received propoxyphene doses approximately 10-fold (rats) and 4-fold (rabbits) the maximum recommended human dose (based on mg/m2 body surface area comparison).

Nursing Mothers

Propoxyphene, norpropoxyphene (major metabolite), and acetaminophen are excreted in human milk. Published studies of nursing mothers using propoxyphene detected no adverse effects in nursing infants. Based on a study of six mother-infant pairs, an exclusively breastfed infant receives approximately 2% of the maternal weight-adjusted dose. Norpropoxyphene is renally excreted and renal clearance is lower in neonates than in adults. Therefore, it is possible that prolonged maternal propoxyphene use could result in norpropoxyphene accumulation in a breastfed infant. Watch breastfeeding infants for signs of sedation including poor feeding, somnolence, or respiratory depression. Caution should be exercised when Darvocet A500 is administered to a nursing woman.

Pediatric Patients

Safety and effectiveness in pediatric patients have not been established.

Elderly Patients

Clinical studies of propoxyphene napsylate combined with acetaminophen did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, postmarketing reports suggest that patients over the age of 65 may be more susceptible to CNS-related side effects. Therefore, dose selection for an 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. Decreased total daily dosage should be considered (see DOSAGE AND ADMINISTRATION).

Adverse Reactions

During clinical trials, the most frequently reported adverse reactions were dizziness, sedation, nausea, and vomiting. Other adverse reactions include constipation, abdominal pain, skin rashes, lightheadedness, headache, weakness, euphoria, dysphoria, hallucinations, and minor visual disturbances.

The most frequently reported postmarketing adverse events have included completed suicide, accidental and intentional overdose, drug dependence, cardiac arrest, coma, drug ineffective, drug toxicity, nausea, respiratory arrest, cardio-respiratory arrest, death, vomiting, dizziness, convulsion, confusional state, and diarrhea.

Additional adverse experiences reported through postmarketing surveillance include:

Cardiac disorders: arrhythmia, bradycardia, cardiac/respiratory arrest, congestive arrest, congestive heart failure (CHF), tachycardia, myocardial infarction (MI)

Eye disorder: eye swelling, vision blurred

General disorder and administration site conditions: drug ineffective, drug interaction, drug tolerance, influenza type illness, drug withdrawal syndrome

Gastrointestinal disorder: gastrointestinal bleed, acute pancreatitis

Hepatobiliary disorder: hepatic steatosis, hepatomegaly, hepatocellular injury

Immune system disorder: hypersensitivity

Injury poisoning and procedural complications: drug toxicity, hip fracture, multiple drug overdose, narcotic overdose

Investigations: blood pressure decreased, heart rate elevated/abnormal

Metabolism and nutrition disorder: metabolic acidosis

Nervous system disorder: ataxia, coma, dizziness, somnolence, syncope

Psychiatric: abnormal behavior, confusional state, hallucinations, mental status change

Respiratory, thoracic, and mediastinal disorders: respiratory depression, dyspnoea

Skin and subcutaneous tissue disorder: rash, itch

Liver dysfunction has been reported in association with both active components of Darvocet A500. Propoxyphene therapy has been associated with abnormal liver function tests and, more rarely, with instances of reversible jaundice (including cholestatic jaundice). Hepatic necrosis may result from acute overdose of acetaminophen (see OVERDOSAGE). In chronic ethanol abusers, this has been reported rarely with short-term use of acetaminophen dosages of 2.5 to 10 g/day. Fatalities have occurred.

There have also been postmarketing reports of renal papillary necrosis associated with chronic acetaminophen use, particularly when the dosage is greater than recommended and when combined with aspirin. Subacute painful myopathy has been reported following chronic propoxyphene overdosage.

DRUG ABUSE AND DEPENDENCE

Controlled Substance

Darvocet A500 is a Schedule IV narcotic under the U.S. Controlled Substances Act. Darvocet A500 can produce drug dependence of the morphine type, and therefore, has the potential for being abused. Psychic dependence, physical dependence and tolerance may develop upon repeated administration. Darvocet A500 should be prescribed and administered with the same degree of caution appropriate to the use of other narcotic-containing medications.

Abuse

Since Darvocet A500 is a mu-opioid agonist, it may be subject to misuse, abuse, and addiction. Addiction to opioids prescribed for pain management has not been estimated. However, requests for opioids from opioid-addicted patients occur. As such, physicians should take appropriate care in prescribing Darvocet A500.

Dependence

Opioid analgesics may cause psychological and physical dependence. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug after long term administration. Also, symptoms of withdrawal may be precipitated through the administration of drugs with mu-opioid antagonist activity, e.g., naloxone or mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine, dezocine) (see OVERDOSAGE). Physical dependence usually does not occur to a clinically significant degree, until after several weeks of continued opioid usage. Tolerance, in which increasingly larger doses are required to produce the same degree of analgesia, is initially manifested by a shortened duration of an analgesic effect and subsequently, by decreases in the intensity of analgesia.

In chronic pain patients, and in opioid-tolerant cancer patients, the administration of Darvocet A500 should be guided by the degree of tolerance manifested and the doses needed to adequately relieve pain.

The severity of the Darvocet A500 abstinence syndrome may depend on the degree of physical dependence. Withdrawal is characterized by rhinitis, myalgia, abdominal cramping, and occasional diarrhea. Most observable symptoms disappear in 5 to 14 days without treatment; however, there may be a phase of secondary or chronic abstinence which may last for 2 to 6 months characterized by insomnia, irritability, and muscular aches. The patient may be detoxified by gradual reduction of the dose. Gastrointestinal disturbances or dehydration should be treated with supportive care.

OVERDOSAGE

Darvocet A500 is a combination product containing propoxyphene and acetaminophen. Overdose of Darvocet A500 may present with the signs and symptoms of propoxyphene overdose, acetaminophen overdose or both. Fatalities within the first hour of overdosage are not uncommon.

In all cases of suspected overdosage, call your regional Poison Control Center to obtain the most up-to-date information about the treatment of overdose. This recommendation is made because, in general, information regarding the treatment of overdosage may change more rapidly than do package inserts.

Initial consideration should be given to the management of the CNS effects of propoxyphene overdosage. Resuscitative measures should be initiated promptly.

Propoxyphene Overdosage

Symptoms of Propoxyphene Overdosage

The manifestations of acute overdosage with propoxyphene are those of opioid overdosage. The patient is usually somnolent but may be stuporous or comatose and convulsing. Respiratory depression is characteristic. The ventilatory rate and/or tidal volume is decreased, which results in cyanosis and hypoxia. Pupils, initially pinpoint, may become dilated as hypoxia increases. Cheyne-Stokes respiration and apnea may occur. Blood pressure and heart rate are usually normal initially, but blood pressure falls and cardiac performance deteriorates, which ultimately results in pulmonary edema and circulatory collapse, unless the respiratory depression is corrected and adequate ventilation is restored promptly. Cardiac arrhythmias and conduction delay may be present. A combined respiratory-metabolic acidosis occurs owing to retained CO2 (hypercapnia) and to lactic acid formed during anaerobic glycolysis. Acidosis may be severe if large amounts of salicylates have also been ingested. Death may occur.

Treatment of Propoxyphene Overdosage

Attention should be directed first to establishing a patent airway and to restoring ventilation. Mechanically assisted ventilation, with or without oxygen, may be required, and positive pressure respiration may be desirable if pulmonary edema is present. The opioid antagonist naloxone will markedly reduce the degree of respiratory depression and should be administered promptly, preferably intravenously. The duration of action of the antagonist may be brief. If no response is observed after 10 mg of naloxone have been administered, the diagnosis of propoxyphene toxicity should be questioned.

In addition to the use of an opioid antagonist, the patient may require careful titration with an anticonvulsant to control convulsions. Activated charcoal can adsorb a significant amount of ingested propoxyphene. Dialysis is of little value in poisoning due to propoxyphene. Efforts should be made to determine whether other agents, such as alcohol, barbiturates, tranquilizers, or other CNS depressants, were also ingested, since these increase CNS depression as well as cause specific toxic effects or death.

Acetaminophen Overdosage

Symptoms of Acetaminophen Overdosage

Overdose of acetaminophen may cause dose-dependent potentially fatal hepatic toxicity. Early symptoms within 24 hours after the overdose may include anorexia, nausea, vomiting, diaphoresis, general malaise and abdominal pain. The patient may then present no symptoms, but evidence of liver dysfunction may become apparent up to 72 hours after ingestion, with elevated serum transaminase and lactic dehydrogenase levels, an increase in serum bilirubin concentrations, and a prolonged prothrombin time. Death from hepatic failure may result 3 to 7 days after overdosage.

Because clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion, liver function studies should be obtained initially and repeated at 24-hour intervals.

Acute renal failure may accompany the hepatic dysfunction and has been noted in patients who do not exhibit signs of fulminant hepatic failure. Typically, renal impairment is more apparent 6 to 9 days after ingestion of the overdose.

Treatment of Acetaminophen Overdosage

In all cases of suspected overdose, immediately call the Rocky Mountain Poison Center's toll-free number (800-525-6115) for assistance in diagnosis and for directions in the use of N-acetylcysteine as an antidote.

Patients' estimates of the quantity of a drug ingested are notoriously unreliable. Therefore, if an acetaminophen overdose is suspected, a serum acetaminophen assay should be obtained as early as possible, but no sooner than 4 hours following ingestion. The antidote, N-acetylcysteine, should be administered as early as possible, and within 16 hours of the overdose ingestion for optimal results.

DOSAGE AND ADMINISTRATION

Darvocet A500 is intended for the management of mild to moderate pain. The dose should be individually adjusted according to severity of pain, patient response and patient size.

Darvocet A500 (100 mg propoxyphene napsylate and 500 mg acetaminophen)

The usual dosage is one tablet every 4 hours orally as needed for pain. The maximum dose of Darvocet A500 is 6 tablets per day. Do not exceed the maximum daily dose.

Patients receiving propoxyphene and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted.

Consideration should be given to a reduced total daily dosage in elderly patients and in patients with hepatic or renal impairment.

Cessation of Therapy

For patients who used Darvocet A500 on a regular basis for a period of time, when therapy with Darvocet A500 is no longer needed for the treatment of their pain, it may be useful to gradually discontinue the Darvocet A500 over time to prevent the development of an opioid abstinence syndrome (narcotic withdrawal). In general, therapy can be decreased by 25% to 50% per day with careful monitoring for signs and symptoms of withdrawal (see DRUG ABUSE AND DEPENDENCE for description of the signs and symptoms of withdrawal). If the patient develops these signs or symptoms, the dose should be raised to the previous level and titrated down more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both.

HOW SUPPLIED

Darvocet A500® Tablets, USP 100 mg/500 mg are available as dark orange, film coated, oval shaped tablets debossed “A500” on both sides.

Bottles of 100 Tablets NDC# 66479-513-10

Storage: Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Inform patients of the availability of a Medication Guide for Darvocet A500 that accompanies each prescription dispensed. Instruct patients to read the Darvocet A500 Medication Guide prior to using Darvocet A500.

Darvocet A500 is a registered trademark of Xanodyne Pharmaceuticals, Inc.

© 2009 Xanodyne Pharmaceuticals, Inc.

Marketed by:

Xanodyne Pharamaceuticals, Inc.

Newport, KY    41071

PI-513-A    Rev. 11/2009

MEDICATION GUIDE

Darvocet A500 [dar-vo-cet A 500]

(C-IV)

(propoxyphene napsylate and acetaminophen)

tablets

Read this Medication Guide before you start taking Darvocet A500 and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.

What is the most important information I should know about Darvocet A500?

Darvocet A500 and other medicines that contain propoxyphene can cause serious side effects, including:

Overdoses by accident or on purpose (intentional overdose). Overdoses with Darvocet A500 may happen when it is taken by itself, or with alcohol or other medicines that can also decrease your breathing and make you very sleepy.

• Death can happen within 1 hour of taking an overdose of Darvocet A500.
  
  Many of the deaths that happen in people who take Darvocet A500 happen in those who:
  
  • have emotional problems
  
  
  • have thoughts of suicide or attempted suicide, or
  
  
  • also take antidepressants, sedatives, tranquilizers, muscle relaxants, or other medicines that affect your breathing and make you very sleepy. You should not use any of these medicines with Darvocet A500 without talking to your doctor.
  
  


• Before taking Darvocet A500 tell your doctor if you:
  
  • have a lung problem, such as COPD or cor pulmonale
  
  
  • have liver or kidney problems
  
  
  • have problems with your pancreas or gallbladder
  
  
  • have a history of head injury
  
  
  • are over age 65
  
  
  • have a history of drug or alcohol abuse or addiction
  
  

Take Darvocet A500 exactly as prescribed. Do not change your dose or stop taking Darvocet A500 without first talking to your doctor.

• Do not take more than 6 tablets in one day.


• Before taking Darvocet A500, tell your doctor about all the medicines you take. Darvocet A500 and many other medicines may interact with each other and may cause serious side effects. Certain medicines can affect how your liver breaks down other medicines. See “What should I tell my doctor before taking Darvocet A500?”


• Do not drink grapefruit juice or eat grapefruit while you are taking Darvocet A500. Grapefruit juice may interact with Darvocet A500.


• Do not drink alcohol while using Darvocet A500. Using alcohol with Darvocet A500 may increase your risk of having dangerous side effects.

What is Darvocet A500?

• Darvocet A500 is a prescription medicine that contains two medicines: propoxyphene and acetaminophen. Darvocet A500 is used to relieve mild to moderate pain.

Darvocet A500 is a federally controlled substance (C-IV) because it is a strong opioid pain medicine that can be abused by people who abuse prescription medicines or street drugs.

Prevent theft, misuse or abuse. Keep Darvocet A500 in a safe place to protect it from being stolen. Darvocet A500 can be a target for people who misuse or abuse prescription medicines or street drugs.

Never give Darvocet A500 to anyone else, even if they have the same symptoms that you have. It may harm them or even cause death. Selling or giving away this medicine is against the law.

It is not known if Darvocet A500 is safe and effective in children under age 18.

Who should not take Darvocet A500?

Do not take Darvocet A500 if you:

• are allergic to propoxyphene or acetaminophen. Ask your doctor if you are not sure. See the end of this Medication Guide for a list of the ingredients in Darvocet A500.


• are having an asthma attack or have severe asthma, trouble breathing, or lung problems.


• have a bowel blockage called paralytic ileus.

What should I tell my doctor before taking Darvocet A500?

Before taking Darvocet A500, tell your doctor:

• if you have any of the conditions listed in the section “What is the most important information I should know about Darvocet A500?”


• if you are allergic to propoxyphene or acetaminophen


• if you plan to have surgery with general anesthesia


• if you are pregnant or plan to become pregnant.


• if you take Darvocet A500 regularly before your baby is born, your newborn baby may have withdrawal symptoms because their body has become used to the medicine. Symptoms of withdrawal in a newborn baby may include:
  
  • irritability
  
  
  • crying more than usual
  
  
  • shaking (tremors)
  
  
  • jitteriness
  
  
  • breathing faster than normal
  
  
  • diarrhea or more stools than normal
  
  
  • vomiting
  
  
  • fever
  
  


• if you take Darvocet A500 right before your baby is born, your baby could have breathing problems.


• if you are breast-feeding or plan to breast-feed. Some Darvocet A500 passes into breast milk.


• Tell your doctor about all the medicines you take, including prescription, and non-prescription medicines, vitamins, and herbal supplements. Darvocet A500 interacts with many medicines and may lead to serious side effects. The doses of certain medicines may need to be changed.


• Especially tell your doctor if you take:

See “What is the most important information I should know about Darvocet A500?”

• certain medicines that can affect how your liver breaks down other medicines.


• a monoamine oxidase inhibitor (MAOI) medicine


• other medicines that make you sleepy, such as: other medicines for pain, including other opioid medicines, anti-depressant medicines, sleeping pills, anti-anxiety medicines, muscle relaxants, anti-nausea medicines, or tranquilizers


• an anticholinergic medicine


• a water pill (diuretic)


• a medicine for high blood pressure or irregular heart beat


• birth control pills taken by mouth


• lamotrigine (Lamictal, Lamictal CD, Lamictal XR, Lamictal ODT)


• probenecid (Probalan)


• a blood-thinner medicine. You may have an increased