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(Posted: 4/30/97)
Note: The following summaries include only those safety-related sections that have been modified, and therefore do not contain all the information needed for safe and effective prescribing. Contact the manufacturer for the complete labeling/package insert.
NB: Comparison made to 1997 Physicians' Desk Reference (PDR) if drug's labeling included in the PDR.
"In the case of overdosage, discontinue Augmentin, treat symptomatically, and institute supportive measures as required. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A study of 51 pediatric patients at a poison center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying.3
"Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin. Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of both amoxicillin and clavulanate. Both amoxicillin and clavulanate are removed from the circulation by hemodialysis. (See DOSAGE AND ADMINISTRATION for recommended dosing for patients with impaired renal function.)"
For Cleocin Phosphate only: Previous Table 1 - "Average Peak Serum Concentrations After Dosing with Clindamycin Phosphate" replaced with new Table 1 - "Average Peak and Trough Concentrations of Active Clindamycin After Dosing with Clindamycin Phosphate" (see table in package insert).
life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. [Paragraph bolded]
"Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of 'antibiotic-associated colitis.'
"After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug effective against C. difficile colitis."
"Clindamycin dosage modifications may not be necessary in patients with renal disease. In patients with moderate to severe liver disease, prolongation of clindamycin half-life has been found. However, it was postulated from studies that when given every eight hours, accumulation should rarely occur. Therefore, dosage modification in patients with liver disease may not be necessary. However, periodic liver enzyme determinations should be made when treating patients with severe liver disease."
Carcinogenesis, Mutagenesis, Impairment of Fertility (new subsection) : "Long term studies in animals have not been performed with clindamycin to evaluate carcinogenic potential. Genotoxicity tests performed included a rat micronucleus test and an Ames test. Both tests were negative. Fertility studies in rats treated orally with up to 300 mg/kg/day (31 times the human exposure based on mg/m2) revealed no effects on fertility or mating ability."
Pregnancy: Teratogenic effects (new name for subsection): Pregnancy category B added.
Sentence - "Safety for use in pregnancy has not been established" deleted and replaced with
"Reproduction studies have been performed in rats and mice using oral and parenteral doses of clindamycin up to 600 mg/kg/day (2.4 and 1.2 times [in Phosphate labeling] 4.5 and 2.3 times [in HCl labeling], respectively, the maximum human exposure based on mg/m2) and have revealed no evidence of harm to the fetus due to clindamycin. In one mouse strain, cleft palates were observed in treated fetuses; this outcome was not produced in other mouse strains or in other species and is, therefore, considered to be a strain specific effect.
"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."
Geriatric Use (new subsection): "Clinical studies of clindamycin did not include sufficient numbers of patients age 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience indicates that antibiotic-associated colitis and diarrhea (due to Clostridium difficile) seen in association with most antibiotics occur more frequently in the elderly (>60 years) and may be more severe. These patients should be carefully monitored for the development of diarrhea.
"Pharmacokinetic studies with clindamycin have shown no clinically important differences between young and elderly subjects with normal hepatic function and normal (age-adjusted) renal function after oral or intravenous administration."
Sentence added to subsection- "The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS)."
Skin and Mucous Membranes (new subsection in Phosphate labeling): "Pruritus, vaginitis, and rare instances of exfoliative dermatitis have been reported (See Hypersensitivity Reactions)." [N.B. - already appears in HCl labeling]
BLACK BOX WARNING (new - in caps and bolded):
"The incidence of severe, potentially life-threatening rash in pediatric patients, however, is very much higher than that reported in adults using Lamictal; specifically, reports from clinical trials suggest as many as 1 in 50 to 1 in 100 pediatric patients develop a potentially life-threatening rash. It bears emphasis, accordingly, that Lamictal is not approved for use in patients below the age of 16 (see INDICATIONS).
"Other than age, there are as yet no factors identified that are known to predict the risk of occurrence or the severity of rash associated with Lamictal. There are suggestions, yet to be proven, that the risk of rash may also be increased by 1) coadministration of Lamictal with valproic acid (VPA), 2) exceeding the recommended initial dose of Lamictal, or 3) exceeding the recommended dose escalation for Lamictal. However, cases have been reported in the absence of these factors.
"Nearly all cases of life-threatening rashes associated with Lamictal have occurred within 2 to 8 weeks of treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 6 months) . Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash.
"Although benign rashes also occur with Lamictal, it is not possible to predict reliably which rashes will prove to be life-threatening. Accordingly, Lamictal should be discontinued at the first sign of rash, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring."
Rash in the Pediatric Population (new subsection): "The incidence of severe, potentially life-threatening rash in pediatric patients is very much higher than that reported in adults using Lamictal. Specifically, reports from clinical trials suggest that as many as 1 in 50 to 1 in 100 pediatric patients develop a potentially life-threatening rash. It bears emphasis, accordingly, that Lamictal is not approved for use in patients below the age of 16 (see INDICATIONS)."
Hypersensitivity Reactions (new subsection): "Hypersensitivity reactions, some fatal or life threatening, have also occurred. Some of these reactions have included clinical features of multiorgan dysfunction such as hepatic abnormalities and evidence of disseminated intravascular coagulation. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Lamictal should be discontinued if an alternative etiology for the signs or symptoms cannot be established."
"Prior to initiation of treatment with Lamictal, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity ( e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately." [Paragraph bolded]
Acute Multiorgan Failure (new subsection): "Fatalities associated with multiorgan failure and various degrees of hepatic failure have been reported in five patients from among 7000 exposed during premarketing development of Lamictal. These cases occurred in association with other serious medical events (e.g., status epilepticus, overwhelming sepsis) making it impossible to identify the initiating cause."
Dermatological Events: Revised to read - "In clinical trials, approximately 10% of all patients exposed to Lamictal developed a rash. However, in these trials not all cases of rash were attributed to Lamictal; five percent (5%) of patients exposed to placebo developed a rash. The overall rate of discontinuation due to rash in patients participating in clinical trials (n=3501) was 3.8%. The incidence of rash appears to be increased among patients being treated with a multi-drug regimen that includes both VPA and EIAEDs. When VPA and Lamictal have been used as a two-drug combination, the incidence of rash is further increased; NOTE: Dosing recommendations for the use of Lamictal and VPA alone cannot be provided because of insufficient experience with that combination (see DOSAGE AND ADMINISTRATION). The incidence of rash also appears to increase with the magnitude of the initial dose and the subsequent rate of dose escalation (see DOSAGE AND ADMINISTRATION).
"Lamictal associated rashes do not appear to have unique identifying features. Typically, rash occurs in the first 4 to 6 weeks following treatment initiation. Maculopaular and/or erythematous eruptions are common. Rarely, more serious rashes with systemic involvement occur (see below). A benign initial appearance of a rash cannot predict an entirely benign outcome; however, a substantial number of patients devloping a rash on Lamictal have continued treatment without ill effect (see BOX WARNING).
Information for Patients: First paragraph changed from "Patients should be advised to notify their physician immediately if they develop a skin rash while taking Lamictal, or if they acutely develop any worsening of seizure control"
to "Prior to initiation of treatment with Lamictal, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately. In addition, the patient should notify his physician if worsening of seizure control occurs."
Pregnancy Exposure Registry: Statement, including phone number, revised - "To facilitate monitoring fetal outcomes of pregnant women exposed to lamotrigine, physicians are encouraged to register patients in the Antiepileptic Drug Pregnancy Registry by calling (888) 233-2334 (toll free)."
Pediatric Use: "(see BOX WARNING)" added.
Postmarketing and Other Experience: Disseminated intravascular coagulation, hypersensitivity reactions, and multiorgan failure added to alphabetical list.
Sentence deleted - "Evidence bearing on its safety and effectiveness in children is not available."
Sentence added and bolded - "Safety and effectiveness in pediatric patients below the age of 16 have not been established (see BOX WARNING)."
General Dosing Considerations: Paragraph added - "The risk of nonserious rash is increased when the recommended initial dose and/or rate of dose escalation of Lamictal is exceeded. There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may also be increased by 1) coadministration of Lamictal with valproic acid, 2) exceeding the recommended initial dose of Lamictal, or 3) exceeding the recommended dose escalation for Lamictal. However, cases have been reported in the absence of these factors (see BOX WARNING). Therefore, it is important that the dosing recommendations be followed closely."
Patients receiving VPA as one component of a combination regimen including EIAEDs: Sentence added at end of first paragraph - "To achieve maintenance, doses may be increased by 25 to 50 mg every 1 to 2 weeks (see Table 5)."
Patients receiving EIAEDs, but not VPA: Sentence added to end of first paragraph - "To achieve maintenance, doses may be increased by 100 mg every 1 to 2 weeks (see Table 5)."
Carcinogenesis, Mutagenesis, Impairment of Fertility (Section separated into 3 labeled subsections): Carcinogenicity: "The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively (approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose [MHRD] of 80 on a mg/m2 basis), produced no evidence of carcinogenicity." (Italicized words replace previous "at levels equivalent to approximately 7.5 and 9.0 times the maximum human dose (80mg) respectively").
Impairment of Fertility: "Two fertility studies conducted in rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that fluoxetine had no adverse effects on fertility." (Italicized words replace previous "approximately 5 and 9 times the maximum human dose (80mg) "). The sentence "A slight decrease in neonatal survival was noted, but this was probably associated with depressed maternal food consumption and suppressed weight gain." was deleted.
Pregnancy - Pregnancy Category C (changed from previous Category B): Previous subsection replaced by "In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the maximum recommended human dose [MRHD] of 80 mg on a mg/m2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m2 basis). Prozac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus."
Labor and Delivery: Sentence added after "The effect of Prozac on labor and delivery in humans is unknown" - "However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus."
Obsessive-Compulsive Disorder: Initial Treatment: Paragraph at end of subsection - "As with use of Prozac in depression, a lower or less frequent dosage should be used in patients with ['renal and/or' deleted] hepatic impairment. A lower or less frequent dosage should also be considered for ['patients, such as' deleted] the elderly (see Usage in the Elderly under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary. (see Liver disease and Renal Disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS)." (Italicized words added to previous paragraph.)
Bulimia Nervosa: Initial Treatment: Paragraph at end of subsection - "As with use of Prozac in depression and OCD, a lower or less frequent dosage should be used in patients with ['renal and/or' deleted] hepatic impairment. A lower or less frequent dosage should also be considered for ['patients, such as' deleted] the elderly (see Usage in the Elderly under PRECAUTIONS), and for patients with concurrent disease or on multiple concomitant medications. Dosage adjustments for renal impairment are not routinely necessary. (see Liver Disease and Renal Disease under CLINICAL PHARMACOLOGY, and Use in Patients with Concomitant Illness under PRECAUTIONS)." (Italicized words added to previous paragraph.)
Second paragraph changed from "The applicability of these results to other populations (e.g., those without recent myocardial infarctions) or to other antiarrhythmic drugs is uncertain, but at present it is prudent to consider any antiarrhythmic agent to have a significant risk in patients with structural heart disease."
to "....., but at present it is prudent to consider the risks of Class 1c agents, coupled with the lack of any evidence of improved survival, generally unacceptable in patients without life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant, but not life-threatening, symptoms or signs." [New information in italics.]
to "Propafenone did not affect fertility rates when administered orally to male and female rats at doses up to 270 mg/kg/day or when administered orally or intravenously to male rabbits at doses of 120 mg/kg/day or 3.5 mg/kg/day, respectively. On a body weight basis, the above noted oral doses in rat and rabbit are 18 times and 8 times, respectively, the maximum recommended daily human dose of 900 mg in a 60 kg person."
Pulmonary Disease: In the last sentence of the subsection - "..., or chronic obstructive pulmonary disease." changed to "..., or chronic obstructive pulmonary disease requiring pharmacotherapy."
"Oral administration of pilocarpine to male and female rats at a dosage of 18 mg/kg/day (approximately 5 times the maximum recommended dose for a 50 kg human when compared on the basis of body surface area (mg/m2) estimates) resulted in impaired reproductive function, including reduced fertility, decreased sperm motility, and morphologic evidence of abnormal sperm. It is unclear whether the reduction in fertility was due to effects on male animals, female animals, or both males and females. The data obtained in this study suggest that pilocarpine may impair the fertility of male and female humans. Salagen should be administered to individuals who are attempting to conceive a child only if the potential benefit justifies potential impairment of fertility."
Pregnancy: Teratogenic effects: Pregnancy Category C: In first sentence, "60 kg human" changed to "50 kg human".
New third sentence added - "In another study, oral administration of pilocarpine to female rats during gestation and lactation at a dosage of 36 mg/kg/day (approximately 10 times the maximum recommended dose for a 50 kg human when compared on the basis of body surface area (mg/m2) estimates) resulted in an increased incidence of stillbirths; decreased neonatal survival and reduced mean body weight of pups were observed at dosages of 18mg/kg/day (approximately 5 times the maximum recommended dose for a 50 kg human when compared on the basis of body surface area (mg/ m2) estimates) and above."
"Sulfonamides, including sulfonamide-containing products such as trimethoprim/sulfamethoxazole, should be discontinued at the first appearance of skin rash or any sign of adverse reaction. In rare instances, a skin rash may be followed by a more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, and serious blood disorders (see PRECAUTIONS).
"Clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura, or jaundice may be early indications of serious reactions.
"Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment.
"The sulfonamides should not be used for the treatment of group A beta-hemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever.
"Pseudomembranous colitis has been reported with nearly all antibacterial agents, including trimethoprim/sulfamethoxazole, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
"Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of 'antibiotic-associated colitis'.
"After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration would be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug effective against C. difficile."
[Note: In the IV labeling the paragraphs on sodium metabisulfite and benzyl alcohol remain unchanged following the above revision.]
Same change in ADVERSE REACTIONS as for Mallinckrodt Medical's Thallous Chloride product in February. (Click here to see change.)
"Ethionamide is extensively metabolized to active and inactive metabolites with less than 1% excreted as the free form in urine. Metabolism is presumed to occur in the liver and thus far 6 metabolites have been isolated: 2-ethylisonicotinamide, carbamoyl-dihydropyridine, thiocarbamoyl-dihydropyridine, S-oxocarbamoyl dihydropyridine, 2-ethylthioiso-nicotinamide, and ethionamide sulphoxide. The sulphoxide metabolite has been demonstrated to have antimicrobial activity against Mycobacterium tuberculosis. Trecator-SC has a plasma elimination half-life of approximately 2 hours after oral dosing."
"Trecator-SC (ethionamide) is primarily indicated for the treatment of active tuberculosis in patients with M. tuberculosis resistant to isoniazid or rifampin, or when there is intolerance on the part of the patient to other drugs. Its use alone in the treatment of tuberculosis results in the rapid development of resistance. It is essential, therefore, to give a suitable companion drug or drugs, the choice being based on the results of susceptibility tests. If the susceptibility tests indicate that the patient's organism is resistant to one of the first-line antituberculosis drugs (i.e., isoniazid or rifampin) yet susceptible to ethionamide, ethionamide should be accompanied by at least one drug to which the M. tuberculosis isolate is known to be susceptible6.
"If the tuberculosis is resistant to both isoniazid and rifampin, yet susceptible to ethionamide, ethionamide should be accompanied by at least two other drugs to which the M. tuberculosis is known to be susceptible6.
"Patient nonadherence to prescribed treatment can result in treatment failure and in the development of drug-resistant tuberculosis, which can be life-threatening and lead to other serious health risks. It is, therefore, essential that patients adhere to the drug regimen for the full duration of treatment. Directly observed therapy is recommended for all patients receiving treatment for tuberculosis. Patients in whom drug-resistant M. tuberculosis organisms are isolated should be managed in consultation with an expert in the treatment of drug-resistant tuberculosis."
"The use of Trecator-SC (ethionamide) alone in the treatment of tuberculosis results in rapid development of resistance. It is essential, therefore, to give a suitable companion drug or drugs, the choice being based on the results of susceptibility testing. However, therapy may be initiated prior to receiving the results of susceptibility test as deemed appropriate by the physician. Ethionamide should be administered with at least one, sometimes two, other drugs to which the organism is known to be susceptible (see "Indications and Usage"). Drugs which have been used as companion agents are rifampin, ethambutol, pyrazinamide, cycloserine, kanamycin, streptomycin, and isoniazid. The usual warnings, precautions, and dosage regimens for these companion drugs should be observed.
"Patient compliance is essential to the success of the antituberculosis therapy and to prevent the emergence of drug-resistant organisms. Therefore, patients should adhere to the drug regimen for the full duration of treatment. It is recommended that directly observed therapy be practiced when patients are receiving antituberculosis medication. Additional consultation from experts in the treatment of drug-resistant tuberculosis is recommended when patients develop drug-resistant organisms."
General (new subsection): "Ethionamide may potentiate the adverse effects of the other anti-tuberculous drugs administered concomitantly (see "DRUG INTERACTIONS"). Ophthalmologic examinations (including ophthalmoscopy) should be performed before and periodically during therapy with Trecator-SC."
Information for Patients (new subsection): "Patients should be advised to consult their physician should blurred vision or any loss of vision, with or without eye pain, occur during treatment.
"Excessive ethanol ingestion should be avoided because a psychotic reaction has been reported 3."
Laboratory Tests (new subsection): "Determination of serum transaminases (SGOT, SGPT) should be made prior to initiation of therapy and should be monitored monthly. If serum transaminases become elevated during therapy, ethionamide and the companion antituberculosis drug or drugs may be discontinued temporarily until the laboratory abnormalities have resolved. Ethionamide and the companion antituberculosis medication(s) then should be reintroduced sequentially to determine which drug (or drugs) is (are) responsible for the hepatotoxicity.
"Blood glucose determinations should be made prior to and periodically throughout therapy with Trecator-SC. Diabetic patients should be particularly alert for episodes of hypoglycemia.
"Periodic monitoring of thyroid function test is recommended as hypothyroidism, with or without goiter, has been reported with ethionamide therapy."
Drug Interactions (new subsection): Trecator-SC has been found to temporarily raise serum concentrations of isoniazid. Trecator-SC may potentiate the adverse effects of other antituberculosis drug administered concomitantly. In particular, convulsions have been reported when ethionamide is administered with cycloserine and special care should be taken when the treatment regimen includes both of these drugs. Excessive ethanol ingestion should be avoided because a psychotic reaction has been reported."
Nursing mothers: "Because no information is available on the excretion of ethionamide in human milk, Trecator-SC should be administered to nursing mothers only if the benefits outweigh the risks. Newborns who are breast-fed by mothers who are taking Trecator-SC should be monitored for adverse effects."
Pediatric Use: "Due to the fact that pulmonary tuberculosis resistant to primary therapy is rarely found in neonates, infants, and children, investigations have been limited in these age groups. At present, the drug should not be used in pediatric patients under 12 years of age except when the organisms are definitely resistant to primary therapy and systemic dissemination of the disease, or other life-threatening complications of tuberculosis, is judged to be imminent."
Gastrointestinal (new subsection): "'The most common side effect(s) of ethionamide are gastrointestinal'disturbances (disturbances replacing previously used 'intolerance') including nausea, vomiting, diarrhea, abdominal pain, excessive salivation, metallic taste, 'stomatitis', anorexia and weight loss. Adverse gastrointestinal effects appear to be dose related, with approximately 50% of patients unable to tolerate 1 Gm as a single dose. Gastrointestinal effects may be minimized by decreasing dosage, by changing the time of drug administration, or by the concurrent administration of an antiemetic agent."
Nervous System (new subsection): "Psychotic (psychotic replacing 'psychic') 'disturbances (including mental depression)', drowsiness, dizziness, restlessness, headache, and 'postural hypotension' have been reported with ethionamide. Rare reports of 'peripheral neuritis', 'optic neuritis', diplopia, blurred vision, and a 'pellagra-like syndrome' also have been reported. Concurrent administration of pyridoxine has been recommended to prevent or relieve neurotoxic effects."
Hepatic (new subsection): "Transient increase in serum bilirubin, SGOT, SGPT; 'Hepatitis'(with or without 'jaundice')."
Other (new subsection): "Hypersensitivity reactions including (previously used 'skin' deleted) 'rash', photosensitivity, 'thrombocytopenia' and purpura have been reported rarely. Hypoglycemia, 'gynecomastia', 'impotence', and acne also have occurred. The management of patients with diabetes mellitus may become more difficult in those receiving ethionamide." (changed from previously used 'increased difficulty in management of diabetes mellitus')
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