Study with the several resources on Docsity
Earn points by helping other students or get them with a premium plan
Prepare for your exams
Study with the several resources on Docsity
Earn points to download
Earn points by helping other students or get them with a premium plan
Detailed information about MacroBID, a medication used to treat urinary tract infections. It covers indications, contraindications, warnings, adverse reactions, interactions, and dosage instructions. MacroBID is a nitrofurantoin product with unique properties that affect its dissolution and absorption.
Typology: Lecture notes
1 / 19
This page cannot be seen from the preview
Don't miss anything!
®
MacroBID ® Nitrofurantoin Capsules, USP
(nitrofurantoin monohydrate/macrocrystals)
THERAPEUTIC CLASSIFICATION Urinary Tract Antibacterial
Nitrofurantoin is reduced by bacterial flavoproteins to reactive intermediates which inactivate or alter bacterial ribosomal proteins and other macromolecules. As a result of such inactivations, the vital biochemical processes of protein synthesis, aerobic energy metabolism, DNA synthesis, RNA synthesis, and cell wall synthesis are inhibited. The broad-based nature of this mode of action may explain the lack of acquired bacterial resistance to nitrofurantoin, as the necessary multiple and simultaneous mutations of the target macromolecules would likely be lethal to the bacteria.
Each MacroBID capsule contains two forms of nitrofurantoin. Twenty-five percent is macrocrystalline nitrofurantoin, which has slower dissolution and absorption than nitrofurantoin monohydrate. The remaining 75% is nitrofurantoin monohydrate contained in a powder blend which, upon exposure to gastric and intestinal fluids, forms a gel matrix that releases nitrofurantoin over time.
Following a single 100 mg dose, the extent and rate of nitrofurantoin excretion in the urine are similar for 100 mg capsules of MacroBID and 50 or 100 mg capsules of Macrodantin (nitrofurantoin macrocrystals). Nitrofurantoin bioavailability can be increased by as much as 40% when MacroBID is administered with food. Approximately 20-25% of a single dose of MacroBID is recovered in the urine unchanged over 24 hours and drug concentrations inhibitory of bacterial growth are reached or exceeded in the urine. Plasma levels attained with MacroBID usually do not exceed 1 μg/mL and are not considered systemically therapeutic.
MacroBID is indicated for the treatment of acute uncomplicated urinary tract infections, e.g. cystitis, when due to susceptible strains of Escherichia coli , and Staphylococcus saprophyticus.
MacroBID is not indicated for the treatment of associated renal cortical or perinephric abscesses.
MacroBID is not indicated for therapy of any systemic infections or for use in prostatitis.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of MACROBID and other antibacterial drugs, MACROBID should be used only to treat 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
sign of hemolysis is an indication to discontinue the drug. Hemolysis ceases when the drug is withdrawn.
Pseudomonas is the organism most commonly implicated in superinfections in patients with nitrofurantoin preparations.
Carcinogenesis, Mutagenesis and Impairment of Fertility:
Nitrofurantoin presented evidence of carcinogenic activity in female B 6 C 3 F 1 mice as shown by increased incidences of tubular adenomas, benign mixed tumours, and granulosa cell tumours of the ovary. In male F344/N rats, there were increased incidences of uncommon kidney tubular cell neoplasms, osteosarcomas of the bone, and neoplasms of the subcutaneous tissue. In one study involving three subcutaneous injections of 75 mg/kg nitrofurantoin to pregnant female mice, lung papillary adenomas were observed in the F1 generation.
Nitrofurantoin was not carcinogenic when fed to female Holtzman rats for 44.5 weeks or to female Sprague-Dawley rats for 75 weeks. Two chronic rodent bioassays utilizing male and female Sprague-Dawley rats and two chronic bioassays in Swiss mice and BDF 1 mice revealed no evidence of carcinogenicity.
Nitrofurantoin has demonstrated mutagenic potential in a variety of laboratory assays conducted in vitro with mammalian and non-mammalian cells exposed to therapeutically attainable and higher concentrations. Point and possibly other types of mutations were observed in bacteria, yeast and fungi. Damage to DNA or inhibition of DNA synthesis were produced in human fibroblasts and lymphocytes, and Chinese hamster ovaries and lung fibroblasts.
In vivo tests on rodents utilizing a wide range of doses demonstrated similar potential. DNA damage to liver, lung, spleen and kidney were observed in rat (alkaline elution test), immature red blood cells (rat micronucleus test) and sperm (H-test in mouse). Some test results were negative such as the sex-linked recessive lethal assay in Drosophila where nitrofurantoin was administered by feeding or injection.
The significance of the carcinogenicity and mutagenicity findings relative to the therapeutic use of nitrofurantoin in humans is unknown. Because of the potential toxicity of nitrofurantoin when used for long-term therapy, the benefits of long-term therapy should be weighed against potential risks (See DOSAGE AND ADMINISTRATION section for prescribing information).
The administration of high doses of nitrofurantoin to rats causes temporary spermatogenic arrest, which is reversible on discontinuing the drug. Doses of 10 mg/kg/day or greater in healthy human males may, in certain unpredictable instances, produce slight to moderate spermatogenic arrest with a decrease in sperm count.
Susceptibility/Resistance:
Development of Drug Resistant Bacteria: Prescribing MACROBID in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.
Drug Interactions:
Antacids containing magnesium trisilicate, when administered concomitantly with nitrofurantoin, reduce both the rate and extent of absorption. The mechanism for this interaction probably is adsorption of drug onto the surface of magnesium trisilicate. Nitrofurantoin should not be given along with drugs which may produce impaired renal function. Uricosuric drugs, such as probenecid and sulfinpyrazone, may inhibit renal tubular secretion of nitrofurantoin. The resulting increase in serum levels may increase toxicity and the decreased urinary levels could lessen its efficacy as a urinary tract antibacterial.
Drug/Laboratory Test Interactions:
As a result of administration of nitrofurantoin, a false-positive reaction for glucose in the urine may occur. This has been observed with Benedict's and Fehling's solution but not with the glucose enzymatic test.
Antimicrobial Antagonism:
Antagonism has been demonstrated in vitro between nitrofurantoin and quinolone antimicrobials. Although the clinical significance of this finding is unknown, concomitant MacroBID and quinolone therapy should be approached with caution.
Pregnancy:
Several reproduction studies performed in rabbits and rats with low multiples of human doses and plasma levels revealed no evidence of general reproductive effects, impaired fertility or harm to the fetus. However, in one published study in which pregnant mice were administered 250 mg/kg subcutaneously on three days, growth retardation and a low incidence of malformations were observed. These effects were not observed at 100 mg/kg. In another controlled study in which cultured rat embryos were exposed for 26 hours to concentrations of 48 μg/mL all were malformed. None of those exposed to 60 μg/mL of nitrofurantoin survived.
The relevance of these findings to humans is uncertain. There are, however, no adequate well controlled studies in pregnant women. Though animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy unless clearly needed.
Labour and Delivery:
Nitrofurantoin should not be given to women during labour and delivery, or when the onset of labour is imminent (SEE CONTRAINDICATIONS).
Nursing Mothers:
Nitrofurantoin has been detected in trace amounts in breast milk. Caution should be exercised when nitrofurantoin is administered to a nursing woman, especially if the infant is known or suspected to have a glucose-6-phosphate dehydrogenase deficiency (SEE CONTRAINDICATIONS).
Hepatic:
Hepatic reactions, including hepatitis, cholestatic jaundice, chronic active hepatitis, and hepatic necrosis occur rarely (SEE WARNINGS). Neurologic:
Peripheral neuropathy, including optic neuritis (SEE WARNINGS).
Dizziness, drowsiness, amblyopia, asthenia, vertigo, and nystagmus also have been reported with the use of nitrofurantoin.
Benign intracranial hypertension has seldom been reported.
Confusion, depression, euphoria and psychotic reactions have been reported rarely.
Dermatologic:
Alopecia.
Exfoliative dermatitis and erythema multiforme (including Stevens-Johnson Syndrome) have been reported rarely.
Allergic Reactions:
Lupus-like syndrome associated with pulmonary reaction to nitrofurantoin has been reported. Also, angioedema; maculopapular, erythematous or eczematous eruptions; pruritis; urticaria; anaphylaxis; arthralgia; myalgia; drug fever; chills; and malaise have been reported.
Hematologic:
Glucose-6-phosphate dehydrogenase deficiency anemia (SEE WARNINGS), agranulocytosis, leukopenia, granulocytopenia, hemolytic anemia, thrombocytopenia, megaloblastic anemia, and eosinophilia have occurred. In most cases, these hematologic abnormalities resolved following cessation of therapy. Aplastic anemia has been reported rarely.
Miscellaneous:
As with other antimicrobial agents, superinfections with resistant organisms, e.g., Pseudomonas species or Candida species, may occur with the use of nitrofurantoin. Superinfections have been limited to the genitourinary tract.
Increased AST (SGOT), increased ALT (SGPT), decreased hemoglobin and increased serum phosphorus.
Nitrofurantoin may cause a rust yellow to brown discolouration of the urine. The clinical significance is unknown.
Occasional incidents of acute overdosage of nitrofurantoin have not resulted in any specific symptomatology other than vomiting. In case vomiting does not occur soon after an excessive dose, induction of emesis is recommended. There is no specific antidote for nitrofurantoin but a high fluid intake should be maintained to promote urinary excretion of the drug. It is dialyzable.
For management of a suspected drug overdose, contact your regional Poison Control Centre.
Adults and Children over 12 years:
One MacroBID 100 mg capsule twice a day for 7 days (maximum 200 mg/day).
MacroBID should be taken every 12 hours with food or milk to minimize gastric upset.
Therapy for acute urinary tract infections should be continued for 7 days or for at least 3 days after sterility of the urine is obtained. Continued infection indicates the need for re-evaluation.
Drug Substance
Proper Name
Nitrofurantoin Macrocrystals Nitrofurantoin Monohydrate
Chemical Name
1-[[(5-nitro-2-furanyl) 1-[[(5-nitro-2-furanyl) methylene]amino] -2,4 methylene]amino] -2, imidazolidinedione imidazolidinedione monohydrate
Structural Formula
O 2 N O CH N N NH
O O
O 2 N O CH N N NH
O O
.H 2 O
The in vitro antibacterial activity of nitrofurantoin against clinical isolates is given below.
Minimal Inhibitory Concentration (mcg/mL) Organism (# strains tested) MIC 50 MIC 90 Range Citrobacter freundii (97) 32 32 16 - > Enterobacter aerogenes (75) 64 128 32 - 128 Enterobacter cloacae (135) 64 128 4 - 128 Escherichia coli (1792) 16 32 8 - 128 Klebsiella oxytoca (52) 32 64 ≤16 - > Klebsiella pneumoniae (410) 64 128 32 - > Staphylococcus aureus (84) 16 32 16 - 32 Staphylococcus epidermidis (25) 16 16 8 - 32 Staphylococcus saprophyticus (25) 16 16 8 - 32 Enterococcus faecalis (598) 16 16 8 - 64
Nitrofurantoin is not active against most strains of Proteus or Serratia species. It has no activity against Pseudomonas species.
Nitrofurantoin is bactericidal in urine at levels equal to one or two times the MIC. Nitrofurantoin exhibits concentration dependent killing of bacteria.
Antagonism has been demonstrated in vitro between nitrofurantoin and quinolone antimicrobials. The clinical significance of this finding is unknown.
Development of resistance to nitrofurantoin has not been a significant problem since its introduction in 1953. Cross-resistance with antibiotics and sulfonamides has not been observed, and transferable resistance is, at most, a very rare phenomenon.
Susceptibility Tests - Quantitative methods that require measurement of zone diameters give the most precise estimates of antimicrobial susceptibility. One recommended procedure, (National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disc Susceptibility Tests, Approved Standard: M2-A4, Vol. 10, Number 7, 1990), uses a disc containing 300 mcg nitrofurantoin for testing susceptibility.
Reports from the laboratory should be interpreted according to the following criteria:
Susceptible organisms produce zones of 17 mm or greater indicating that the tested organism is likely to respond to therapy.
Organisms of intermediate susceptibility produce zones of 15 to 16 mm, indicating that the tested organism may or may not be susceptible.
Resistant organisms produce zones of 14 mm or less, indicating that other therapy should be selected.
Alternatively, a bacterial isolate may be considered susceptible if the MIC value for nitrofurantoin is not more than 32 mcg/mL. A MIC of 64 mcg/mL indicates intermediate
susceptibility. Organisms are considered resistant if the MIC is equal to or greater than 128 mcg/mL.
Dilution and diffusion susceptibility tests should give MICs and zone diameters within the ranges listed below for the following quality control organisms.
Organism MIC (mcg/mL) Zone Size Range (mm) E. coli (ATCC 25922) 4-16 20- S. aureus (ATCC 29213) 8-32 18- E. faecalis (ATCC 29212) 4-16 - -
Human:
Nitrofurantoin taken orally is rapidly absorbed from the gastrointestinal tract and appears to be widely distributed. Based upon urine recovery levels its bioavailability may be increased by as much as 40% when administered with food. In one study in which healthy male adults were provided a single 100 mg capsule of MacroBID with food the C (^) max, t (^) max, AUC and elimination t (^) 1/ were respectively 0.6 μg/mL, 5 hrs and 1.8 μg/mLxhrs and 0.8 hrs in plasma. In urine Cmax, t (^) max and elimination t (^) 1/2 were respectively 144 μg/mL, 5.1 hrs and 1.1 hrs. Plasma levels do not normally exceed 1 μg/mL following therapeutic administration of MacroBID to subjects with normal kidney function. Levels far exceeding those in plasma have been reported for human bile, seminal fluid and kidney. About 20-25% of a single dose of MacroBID is recovered in the urine and about 1.5% of urine contents are metabolized. Little is known about nitrofurantoin metabolism and the rate or extent of its excretion by other routes in humans.
Animal:
In Sprague-Dawley rats nitrofurantoin was rapidly and completely absorbed from the gastrointestinal tract and was widely distributed. Following administration of 0.5 mg/kg of a suspension by gavage it was excreted primarily in the feces (58%, all of which was metabolized) and urine (35%, three quarters of which was metabolized). A C (^) max of 0.05 μg/mL was attained at 0.5 hrs. Admixed to food in long term toxicity studies at average doses of 96 mg/kg/day plasma levels of 0.39 and 1.1 μg/mL were recorded in males and females respectively. The maximal plasma levels attained in rats appear low relative to those attained in humans.
Chronic Toxicity and Carcinogenicity Studies:
Nitrofurantoin was not considered carcinogenic when administered for 22 months to male and female Swiss mice at dietary doses up to 181 and 224 mg/kg/day respectively and in male and female BDF 1 mice at dietary doses (estimated from feed consumption of Swiss and B 6 C 3 F 1 mice historical controls) of up to 550 and 560 mg/kg/day respectively for 24 months. There was an increase in mortality in the high dosed males and changes in the urinary system and gonads (increase in ovarian cysts and testicular degeneration/atrophy) observed in Swiss mice. No
Montreal, Canada, Nov. 11-12, 1988, ed. Harrison, L.H., Royal Society of Medicine Services Ltd., London, 1990, P. 33-44.
MacroBID® Nitrofurantoin Capsules, USP
(nitrofurantoin monohydrate/macrocrystals)
Read this carefully before you start taking MacroBID and each time you get a refill. This leaflet is a summary and will not tell you everything about this drug. Talk to your healthcare professional about your medical condition and treatment and ask if there is any new information about MacroBID.
What is MacroBID used for?
MacroBID is used to treat infections of the urinary tract. Antibacterial drugs like MACROBID treat only bacterial infections. They do not treat viral infections.
How does MacroBID work? MacroBID is an antibiotic. It is activated when it is broken down by bacteria. After it is activated, MacroBID kills bacteria and prevents the growth of infections.
What are the ingredients in MacroBID? Medicinal ingredients: nitrofurantoin Non-medicinal ingredients: carbomer 934P, corn starch, compressible sugar, lactose, magnesium stearate, povidone, talc, hard gelatin capsule shell (D&C Yellow No. 10, edetate calcium disodium, edible gray ink, FD&C Blue No. 1, FD&C Red No. 40, gelatin, sodium lauryl sulfate, sodium propionate, and titanium dioxide).
MacroBID comes in the following dosage forms: MacroBID is available as a 100 mg capsule.
Do not use MacroBID if:
Do not give MacroBID to newborns or infants under one month of age.
To help avoid side effects and ensure proper use, talk to your healthcare professional before you take MacroBID. Talk about any health conditions or problems you may have, including if you:
Other warnings you should know about:
Tell your healthcare professional about all the medicines you take, including any drugs, vitamins, minerals, natural supplements or alternative medicines.
The following may interact with MacroBID:
Medicines:
You should not take MacroBID along with medicines that affect your kidneys
Laboratory tests:
How to take MacroBID:
Reporting Side Effects You can report any suspected side effects associated with the use of health products to Health Canada by:
Visiting the Web page on Adverse Reaction Reporting (http://www.hc-sc.gc.ca/dhp- mps/medeff/report-declaration/index-eng.php) for information on how to report online, by mail or by fax; or
Calling toll-free at 1-866-234-2345. NOTE: Contact your health professional if you need information about how to manage your side effects. The Canada Vigilance Program does not provide medical advice.
Storage: Store at room temperature (20ºC-25ºC). Keep out of reach and sight of children.
If you want more information about MacroBID: Talk to your healthcare professional Find the full Product Monograph that is prepared for healthcare professionals and includes this Patient Medication Information by visiting the Health Canada website (http://hc-sc.gc.ca/index-eng.php); the manufacturer’s website http://www.allergan.ca, or by calling 1-800-668-6424.
This leaflet was prepared by Allergan Pharma Co.
Last Revised: August 14, 2018
