Overdose
Occasional incidents of acute overdosage of Macrodantin
have not resulted in any specific symptoms other than vomiting. Induction of
emesis is recommended. There is no specific antidote, but a high fluid intake
should be maintained to promote urinary excretion of the drug. It is
dialyzable.
Contraindications
Anuria, oliguria, or
significant impairment of renal function (creatinine clearance under 60 mL per
minute or clinically significant elevated serum creatinine) are
contraindications. Treatment of this type of patient carries an increased risk
of toxicity because of impaired excretion of the drug.
Because of the possibility of
hemolytic anemia due to immature erythrocyte enzyme systems(glutathione
instability), the drug is contraindicated in pregnant patients at term (38-42
weeks' gestation), during labor and delivery, or when the onset of labor is
imminent. For the same reason, the drug is contraindicated in neonates under
one month of age.
Macrodantin is contraindicated
in patients with a previous history of cholestatic jaundice/ hepatic
dysfunction associated with nitrofurantoin.
Macrodantin is also
contraindicated in those patients with known hypersensitivity to
nitrofurantoin.
Undesirable effects
Respiratory
CHRONIC, SUBACUTE, OR ACUTE PULMONARY HYPERSENSITIVITY
REACTIONS MAY OCCUR.
CHRONIC PULMONARY REACTIONS OCCUR GENERALLY IN PATIENTS W
HO HAVE RECEIVED CONTINUOUS TREATMENT FOR SIX MONTHS OR LONGER. MALAISE,
DYSPNEA ON EXERTION, COUGH, AND ALTERED PULMONARY FUNCTION ARE COMMON
MANIFESTATIONS WHICH CAN OCCUR INSIDIOUSLY. RADIOLOGIC AND HISTOLOGIC FINDINGS
OF DIFFUSE INTERSTITIAL PNEUMONITIS OR FIBROSIS, OR BOTH, ARE ALSO COMMON
MANIFESTATIONS OF THE CHRONIC PULMONARY REACTION. FEVER IS RARELY PROMINENT.
THE SEVERITY OF CHRONIC PULMONARY REACTIONS AND THEIR
DEGREE OF RESOLUTION APPEAR TO BE RELATED TO THE DURATION OF THERAPY AFTER THE
FIRST CLINICAL SIGNS APPEAR. PULMONARY FUNCTION MAY BE IMPAIRED PERMANENTLY,
EVEN AFTER CESSATION OF THERAPY. THE RISK IS GREATER WHEN CHRONIC PULMONARY
REACTIONS ARE NOT RECOGNIZED EARLY.
In subacute pulmonary reactions, fever and eosinophilia
occur less often than in the acute form. Upon cessation of therapy, recovery
may require several months. If the symptoms are not recognized as being
drug-related and nitrofurantoin therapy is not stopped, the symptoms may become
more severe.
Acute pulmonary reactions are commonly manifested by
fever, chills, cough, chest pain, dyspnea, pulmonary infiltration with
consolidation or pleural effusion on x-ray, and eosinophilia. Acute reactions
usually occur within the first week of treatment and are reversible with
cessation of therapy. Resolution often is dramatic (see WARNINGS).
Changes in EKG (e.g., non-specific ST/T wave changes,
bundle branch block) have been reported in association with pulmonary
reactions.
Cyanosis has been reported rarely.
Hepatic: Hepatic reactions, including hepatitis,
cholestatic jaundice, chronic active hepatitis, and hepatic necrosis, occur
rarely (see WARNINGS).
Neurologic: Peripheral neuropathy, which may
become severe or irreversible, has occurred. Fatalities have been reported.
Conditions such as renal impairment (creatinine clearance under 60 mL per
minute or clinically significant elevated serum creatinine), anemia, diabetes
mellitus, electrolyte imbalance, vitamin B deficiency, and debilitating
diseases may increase the possibility of peripheral neuropathy (see WARNINGS).
Asthenia, vertigo, nystagmus, dizziness, headache, and
drowsiness also have been reported with the use of nitrofurantoin.
Benign intracranial hypertension (pseudotumor cerebri),
confusion, depression, optic neuritis, and psychotic reactions have been
reported rarely. Bulging fontanels, as a sign of benign intracranial
hypertension in infants, have been reported rarely.
Dermatologic: Exfoliative dermatitis and erythema
multiforme (including Stevens-Johnson syndrome) have been reported rarely.
Transient alopecia also has been reported.
Allergic: A lupus-like syndrome associated with
pulmonary reactions to nitrofurantoin has been reported. Also, angioedema;
maculopapular, erythematous, or eczematous eruptions; pruritus; urticaria;
anaphylaxis; arthralgia; myalgia; drug fever; chills; and vasculitis (sometimes
associated with pulmonary reactions) have been reported. Hypersensitivity
reactions represent the most frequent spontaneously-reported adverse events in
worldwide postmarketing experience with nitrofurantoin formulations.
Gastrointestinal: Nausea, emesis, and anorexia
occur most often. Abdominal pain and diarrhea are less common gastrointestinal
reactions. These dose-related reactions can be minimized by reduction of
dosage. Sialadenitis and pancreatitis have been reported. There have been
sporadic reports of pseudomembranous colitis with the use of nitrofurantoin.
The onset of pseudomembranous colitis symptoms may occur during or after
antimicrobial treatment (see WARNINGS).
Hematologic: Cyanosis secondary to
methemoglobinemia has been reported rarely.
Miscellaneous: As with other antimicrobial agents,
superinfections caused by resistant organisms, e.g., Pseudomonas species
or Candida species, can occur.
Laboratory Adverse Events: The following
laboratory adverse events have been reported with the use of nitrofurantoin:
increased AST (SGOT), increased ALT (SGPT), decreased hemoglobin, increased
serum phosphorus, eosinophilia, glucose-6-phosphate dehydrogenase deficiency
anemia (see WARNINGS), agranulocytosis, leukopenia, granulocytopenia,
hemolytic anemia, thrombocytopenia, megaloblastic anemia. In most cases, these
hematologic abnormalities resolved following cessation of therapy. Aplastic
anemia has been reported rarely.
Therapeutic indications
Macrodantin is specifically
indicated for the treatment of urinary tract infections when due to susceptible
strains of Escherichia coli, enterococci, Staphylococcus aureus,
and certain susceptible strains of Klebsiella and Enterobacter species.
Nitrofurantoin is not indicated
for the treatment of pyelonephritis or perinephric abscesses. To reduce the
development of drug-resistant bacteria and maintain the effectiveness of
Macrodantin and other antibacterial drugs, Macrodantin 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.
Nitrofurantoins lack the
broader tissue distribution of other therapeutic agents approved for urinary
tract infections. Consequently, many patients who are treated with Macrodantin
are predisposed to persistence or reappearance of bacteriuria. Urine specimens
for culture and susceptibility testing should be obtained before and after
completion of therapy. If persistence or reappearance of bacteriuria occurs
after treatment with Macrodantin, other therapeutic agents with broader tissue
distribution should be selected. In considering the use of Macrodantin, lower
eradication rates should be balanced against the increased potential for
systemic toxicity and for the development of antimicrobial resistance when
agents with broader tissue distribution are utilized.
Fertility, pregnancy and lactation
Teratogenic effects - Pregnancy Category B
Several reproduction studies
have been performed in rabbits and rats at doses up to six times the human dose
and have revealed no evidence of impaired fertility or harm to the fetus due to
nitrofurantoin. In a single published study conducted in mice at 68 times the
human dose (based on mg/kg administered to the dam), growth retardation and a
low incidence of minor and common malformations were observed. However, at 25
times the human dose, fetal malformations were not observed; the relevance of
these findings to humans is uncertain. There are, however, no adequate and
well-controlled studies in pregnant women. Because animal reproduction studies
are not always predictive of human response, this drug should be used during
pregnancy only if clearly needed.
Non-teratogenic effects
Nitrofurantoin has been shown
in one published transplacental carcinogenicity study to induce lung papillary
adenomas in the F1 generation mice at doses 19 times the human dose on a mg/kg
basis. The relationship of this finding to potential human carcinogenesis is
presently unknown. Because of the uncertainty regarding the human implications
of these animal data, this drug should be used during pregnancy only if
clearlyneeded.
Special warnings and precautions for use
WARNINGS
Pulmonary reactions
ACUTE, SUBACUTE, OR CHRONIC
PULMONARY REACTIONS HAVE BEEN OBSERVED IN PATIENTS TREATED W ITH
NITROFURANTOIN. IF THESE REACTIONS OCCUR, MACRODANTIN SHOULD BE DISCONTINUED
AND APPROPRIATE MEASURES TAKEN. REPORTS HAVE CITED PULMONARY REACTIONS AS A
CONTRIBUTING CAUSE OF DEATH.
CHRONIC PULMONARY REACTIONS
(DIFFUSE INTERSTITIAL PNEUMONITIS OR PULMONARY FIBROSIS, OR BOTH) CAN DEVELOP
INSIDIOUSLY. THESE REACTIONS OCCUR RARELY AND GENERALLY IN PATIENTS RECEIVING
THERAPY FOR SIX MONTHS OR LONGER. CLOSE MONITORING OF THE PULMONARY CONDITION
OF PATIENTS RECEIVING LONG-TERM THERAPY IS WARRANTED AND REQUIRES THAT THE
BENEFITS OF THERAPY BE WEIGHED AGAINST POTENTIAL RISKS (SEE RESPIRATORY
REACTIONS).
Hepatotoxicity
Hepatic reactions, including
hepatitis, cholestatic jaundice, chronic active hepatitis, and hepatic
necrosis, occur rarely. Fatalities have been reported. The onset of chronic
active hepatitis may be insidious, and patients should be monitored
periodically for changes in biochemical tests that would indicate liver injury.
If hepatitis occurs, the drug should be withdrawn immediately and appropriate
measures should be taken.
Neuropathy
Peripheral neuropathy, which
may become severe or irreversible, has occurred. Fatalities have been reported.
Conditions such as renal impairment (creatinine clearance under 60 mL per
minute or clinically significant elevated serum creatinine), anemia, diabetes
mellitus, electrolyte imbalance, vitamin B deficiency, and debilitating disease
may enhance the occurrence of peripheral neuropathy. Patients receiving
long-term therapy should be monitored periodically for changes in renal
function.
Optic neuritis has been
reported rarely in postmarketing experience with nitrofurantoin formulations.
Hemolytic anemia
Cases of hemolytic anemia of
the primaquine-sensitivity type have been induced by nitrofurantoin. Hemolysis
appears to be linked to a glucose-6-phosphate dehydrogenase deficiency in the
red blood cells of the affected patients. This deficiency is found in 10
percent of Blacks and a small percentage of ethnic groups of Mediterranean and
Near-Eastern origin. Hemolysis is an indication for discontinuing Macrodantin;
hemolysis ceases when the drug is withdrawn.
Clostridium difficile-associated diarrhea: Clostridium difficile associated
diarrhea (CDAD) has been reported with use of nearly all antibacterial agents,
including nitrofurantoin, and may range in severity from mild diarrhea to fatal
colitis. Treatment with antibacterial agents alters the normal flora of the
colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B
which contribute to the development of CDAD. Hypertoxin producing strains of C.
difficile cause increased morbidity and mortality, as these infections can
be refractory to antimicrobial therapy and may require colectomy. CDAD must be
considered in all patients who present with diarrhea following antibiotic use.
Careful medical history is necessary since CDAD has been reported to occur over
two months after the administration of antibacterial agents.
If CDAD is suspected or
confirmed, ongoing antibiotic use not directed against C. difficile may
need to be discontinued. Appropriate fluid and electrolyte management, protein
supplementation, antibiotic treatment of C. difficile, and surgical evaluation
should be instituted as clinically indicated.
PRECAUTIONS
General
Prescribing Macrodantin 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.
Carcinogenesis, Mutagenesis,
Impairment of Fertility
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 in
BDF1 mice revealed no evidence of carcinogenicity.
Nitrofurantoin presented
evidence of carcinogenic activity in female B6C3F1 mice as shown by increased
incidences of tubular adenomas, benign mixed tumors, and granulosa cell tumors
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 subcutaneous administration of 75
mg/kg nitrofurantoin to pregnant female mice, lung papillary adenomas of
unknown significance were observed in the F1 generation.
Nitrofurantoin has been shown
to induce point mutations in certain strains of Salmonella typhimurium and
forward mutations in L5178Y mouse lymphoma cells. Nitrofurantoin induced
increased numbers of sister chromatid exchanges and chromosomal aberrations in
Chinese hamster ovary cells but not in human cells in culture. Results of the
sex-linked recessive lethal assay in Drosophila were negative after
administration of nitrofurantoin by feeding or by injection. Nitrofurantoin did
not induce heritable mutation in the rodent models examined.
The significance of the
carcinogenicity and mutagenicity findings relative to the therapeutic use of
nitrofurantoin in humans is unknown.
The administration of high
doses of nitrofurantoin to rats causes temporary spermatogenic arrest; this is
reversible on discontinuing the drug. Doses of 10 mg/kg/day or greater in
healthy human males may, in certain unpredictable instances, produce a slight
to moderate spermatogenic arrest with a decrease in sperm count.
Pregnancy
Teratogenic effects - Pregnancy Category B
Several reproduction studies
have been performed in rabbits and rats at doses up to six times the human dose
and have revealed no evidence of impaired fertility or harm to the fetus due to
nitrofurantoin. In a single published study conducted in mice at 68 times the
human dose (based on mg/kg administered to the dam), growth retardation and a
low incidence of minor and common malformations were observed. However, at 25
times the human dose, fetal malformations were not observed; the relevance of
these findings to humans is uncertain. There are, however, no adequate and
well-controlled studies in pregnant women. Because animal reproduction studies
are not always predictive of human response, this drug should be used during
pregnancy only if clearly needed.
Non-teratogenic effects
Nitrofurantoin has been shown
in one published transplacental carcinogenicity study to induce lung papillary
adenomas in the F1 generation mice at doses 19 times the human dose on a mg/kg
basis. The relationship of this finding to potential human carcinogenesis is
presently unknown. Because of the uncertainty regarding the human implications
of these animal data, this drug should be used during pregnancy only if
clearlyneeded.
Labor and Delivery
See CONTRAINDICATIONS.
Nursing Mothers
Nitrofurantoin has been
detected in human breast milk in trace amounts.
Because of the potential for
serious adverse reactions from nitrofurantoin in nursing infants under
one month of age, a decision should be made whether to discontinue nursing or
to discontinue the drug, taking into account the importance of the drug to the
mother (see CONTRAINDICATIONS).
Pediatric Use
Macrodantin is contraindicated in infants below the age
of one month (see CONTRAINDICATIONS).
Geriatric Use
Clinical studies of Macrodantin 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. Spontaneous reports suggest a higher proportion of pulmonary
reactions, including fatalities, in elderly patients; these differences appear
to be related to the higher proportion of elderly patients receiving long-term
nitrofurantoin therapy. As in younger patients, chronic pulmonary reactions
generally are observed in patients receiving therapy for six months or longer
(see WARNINGS). Spontaneous reports also suggest an increased proportion
of severe hepatic reactions, including fatalities, in elderly patients (see WARNINGS).
In general, the greater frequency of decreased hepatic,
renal, or cardiac function, and of concomitant disease or other drug therapy
should be considered when prescribing Macrodantin. This drug is known to be
substantially excreted by the kidney, and the risk of toxic reactions to this
drug may be greater in patients with impaired renal function. Anuria, oliguria,
or significant impairment of renal function (creatinine clearance under 60 mL
per minute or clinically significant elevated serum creatinine) are
contraindications (see CONTRAINDICATIONS). Because elderly patients are
more likely to have decreased renal function, care should be taken in dose
selection, and it may be useful to monitor renal function.
Dosage (Posology) and method of administration
Macrodantin should be given with food to improve drug
absorption and, in some patients, tolerance.
Adults
50-100 mg four times a day --the lower dosage level is
recommended for uncomplicated urinary tract infections.
Pediatric Patients
5-7 mg/kg of body weight per 24 hours, given in four
divided doses (contraindicated under one month of age).
Therapy should be continued for one week or for at least
3 days after sterility of the urine is obtained. Continued infection indicates
the need for reevaluation.
For long-term suppressive therapy in adults, a reduction
of dosage to 50-100 mg at bedtime may be adequate. For long-term suppressive
therapy in pediatric patients, doses as low as 1 mg/kg per 24 hours, given in a
single dose or in two divided doses, may be adequate. SEE WARNINGS SECTION
REGARDING RISKS ASSOCIATED WITH LONG-TERM THERAPY.
Interaction with other medicinal products and other forms of interaction
SIDE EFFECTS
Respiratory
CHRONIC, SUBACUTE, OR ACUTE PULMONARY HYPERSENSITIVITY
REACTIONS MAY OCCUR.
CHRONIC PULMONARY REACTIONS OCCUR GENERALLY IN PATIENTS W
HO HAVE RECEIVED CONTINUOUS TREATMENT FOR SIX MONTHS OR LONGER. MALAISE,
DYSPNEA ON EXERTION, COUGH, AND ALTERED PULMONARY FUNCTION ARE COMMON
MANIFESTATIONS WHICH CAN OCCUR INSIDIOUSLY. RADIOLOGIC AND HISTOLOGIC FINDINGS
OF DIFFUSE INTERSTITIAL PNEUMONITIS OR FIBROSIS, OR BOTH, ARE ALSO COMMON
MANIFESTATIONS OF THE CHRONIC PULMONARY REACTION. FEVER IS RARELY PROMINENT.
THE SEVERITY OF CHRONIC PULMONARY REACTIONS AND THEIR
DEGREE OF RESOLUTION APPEAR TO BE RELATED TO THE DURATION OF THERAPY AFTER THE
FIRST CLINICAL SIGNS APPEAR. PULMONARY FUNCTION MAY BE IMPAIRED PERMANENTLY,
EVEN AFTER CESSATION OF THERAPY. THE RISK IS GREATER WHEN CHRONIC PULMONARY
REACTIONS ARE NOT RECOGNIZED EARLY.
In subacute pulmonary reactions, fever and eosinophilia
occur less often than in the acute form. Upon cessation of therapy, recovery
may require several months. If the symptoms are not recognized as being
drug-related and nitrofurantoin therapy is not stopped, the symptoms may become
more severe.
Acute pulmonary reactions are commonly manifested by
fever, chills, cough, chest pain, dyspnea, pulmonary infiltration with
consolidation or pleural effusion on x-ray, and eosinophilia. Acute reactions
usually occur within the first week of treatment and are reversible with
cessation of therapy. Resolution often is dramatic (see WARNINGS).
Changes in EKG (e.g., non-specific ST/T wave changes,
bundle branch block) have been reported in association with pulmonary
reactions.
Cyanosis has been reported rarely.
Hepatic: Hepatic reactions, including hepatitis,
cholestatic jaundice, chronic active hepatitis, and hepatic necrosis, occur
rarely (see WARNINGS).
Neurologic: Peripheral neuropathy, which may
become severe or irreversible, has occurred. Fatalities have been reported.
Conditions such as renal impairment (creatinine clearance under 60 mL per
minute or clinically significant elevated serum creatinine), anemia, diabetes
mellitus, electrolyte imbalance, vitamin B deficiency, and debilitating
diseases may increase the possibility of peripheral neuropathy (see WARNINGS).
Asthenia, vertigo, nystagmus, dizziness, headache, and
drowsiness also have been reported with the use of nitrofurantoin.
Benign intracranial hypertension (pseudotumor cerebri),
confusion, depression, optic neuritis, and psychotic reactions have been
reported rarely. Bulging fontanels, as a sign of benign intracranial
hypertension in infants, have been reported rarely.
Dermatologic: Exfoliative dermatitis and erythema
multiforme (including Stevens-Johnson syndrome) have been reported rarely.
Transient alopecia also has been reported.
Allergic: A lupus-like syndrome associated with
pulmonary reactions to nitrofurantoin has been reported. Also, angioedema;
maculopapular, erythematous, or eczematous eruptions; pruritus; urticaria;
anaphylaxis; arthralgia; myalgia; drug fever; chills; and vasculitis (sometimes
associated with pulmonary reactions) have been reported. Hypersensitivity
reactions represent the most frequent spontaneously-reported adverse events in
worldwide postmarketing experience with nitrofurantoin formulations.
Gastrointestinal: Nausea, emesis, and anorexia
occur most often. Abdominal pain and diarrhea are less common gastrointestinal
reactions. These dose-related reactions can be minimized by reduction of
dosage. Sialadenitis and pancreatitis have been reported. There have been
sporadic reports of pseudomembranous colitis with the use of nitrofurantoin.
The onset of pseudomembranous colitis symptoms may occur during or after
antimicrobial treatment (see WARNINGS).
Hematologic: Cyanosis secondary to
methemoglobinemia has been reported rarely.
Miscellaneous: As with other antimicrobial agents,
superinfections caused by resistant organisms, e.g., Pseudomonas species
or Candida species, can occur.
Laboratory Adverse Events: The following
laboratory adverse events have been reported with the use of nitrofurantoin:
increased AST (SGOT), increased ALT (SGPT), decreased hemoglobin, increased
serum phosphorus, eosinophilia, glucose-6-phosphate dehydrogenase deficiency
anemia (see WARNINGS), agranulocytosis, leukopenia, granulocytopenia,
hemolytic anemia, thrombocytopenia, megaloblastic anemia. In most cases, these
hematologic abnormalities resolved following cessation of therapy. Aplastic
anemia has been reported rarely.
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 nitrofurantoin onto the surface of magnesium trisilicate.
Uricosuric drugs, such as
probenecid and sulfinpyrazone, can inhibit renal tubular secretion of
nitrofurantoin. The resulting increase in nitrofurantoin 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 the presence of
nitrofurantoin, a false-positive reaction for glucose in the urine may occur.
This has been observed with Benedict's and Fehling's solutions but not with the
glucose enzymatic test.