ASACOL (mesalamine) - AZACTAM (aztreonam) - BSS PLUS - CATAPRES (clonidine HCl) - CIPRO I.V. (ciprofloxacin) - CYSTAGON (cysteamine bitartrate) - DDAVP (desmopressin acetate) - DIFLUCAN (fluconazole) - DOVONEX (calcipotriene) - HUMATROPE [somatropin (rDNA origin)] - IOPIDINE (apraclonidine HCl) - ISONIAZID - PENTAM 300 (pentamidine isethionate) - PRILOSEC (omeprazole) - PROSCAR (finasteride)

ADVERSE REACTIONS:

Respiratory/Pulmonary: Eosinophilic pneumonia added to list of adverse reactions.

Hematologic: Aplastic anemia (rare) added to list of adverse reactions.

Laboratory Abnormalities: AST/ALT notation corrected to "Elevated AST(SGOT) or ALT(SGPT)".

Return to Quick Reference

ADVERSE REACTIONS:

Dermatologic: Rare cases of toxic epidermal necrolysis have been reported in association with aztreonam in patients undergoing bone marrow transplant with multiple risk factors including sepsis, radiation therapy and other concomitantly administered drugs associated with toxic epidermal necrolysis.

Return to Quick Reference

WARNINGS and PRECAUTIONS:

Both sections revised to indicate that BSS Plus should not be used until Part I is fully reconstituted with Part II.

Return to Quick Reference

PRECAUTIONS:

Withdrawal subsection moved to WARNINGS section and revised.

WARNINGS:

Withdrawal: Tremor added to symptoms that can result after sudden cessation of clonidine. As the likelihood of such reactions is apparently greater after administration of higher doses or continuation of concomitant beta-blocker, special caution is advised in these situations. Rare instances of cerebrovascular accidents added to others (hypertensive encephalopathy, death) that have been reported after clonidine withdrawal. Because children commonly have gastrointestinal illnesses that lead to vomiting, they may be particularly susceptible to hypertensive episodes resulting from abrupt inability to take medication.

Return to Quick Reference

ADVERSE REACTIONS:

Post-marketing Adverse Events: The following adverse reactions have been added: agitation, delirium, myoclonus and methemoglobinemia.

Return to Quick Reference

WARNINGS:

Revised to indicate that gastrointestinal ulceration and bleeding have been reported with cysteamine bitartrate. Physicians are cautioned to remain alert for signs of these adverse events, and that they should inform patients and/or guardians about signs/symptoms of serious G.I. toxicity and what steps to take should they occur. Revised to indicate that there has been one post-marketing report of interstitial nephritis with early renal failure, with no establishment of a causal relationship between this event and cysteamine bitartrate therapy.

PRECAUTIONS:

General: Reports of gastrointestinal ulceration and bleeding noted, while Laboratory Tests noted need for physician monitoring and informing patients/guardians regarding these adverse events.

ADVERSE REACTIONS:

Digestive: Gastrointestinal ulceration and bleeding added.

Urogenital: Interstitial nephritis, renal failure (see WARNINGS) added.

OVERDOSAGE:

Revised to indicate second report of overdosage, with this case involving accidental ingestion of a 200-250 mg/kg dose by a healthy 13 month old child, who experienced vomiting and dehydration. After hospitalization and administration of fluids, a full recovery was made.

Return to Quick Reference

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY:

Section revised to state that there have been no long-term studies in animals to assess the carcinogenic, mutagenic, or impairment of fertility potential of DDAVP.

Return to Quick Reference

PRECAUTIONS:

Pregnancy: Remains Category C: section revised to indicate that there have been reports of multiple congenital abnormalities in infants whose mothers were treated for 3 or more months with high dose (400-800 mg/day) fluconazole for coccidiomycosis (an unindicated use). The relationship between fluconazole use and these events is unclear.

ADVERSE REACTIONS:

Hematopoietic and Lymphatic: Neutropenia and agranulocytosis added to further define previously noted leukopenia.

Return to Quick Reference

ADVERSE REACTIONS:

Revised to indicate that in open label use of Dovonex for periods up to one year, approximately 25% of patients experienced skin irritation, and approximately 10% worsening of psoriasis.

Return to Quick Reference

PRECAUTIONS:

Patients should be monitored carefully for any malignant transformations of skin lesions. Growth hormone has not been shown to increase the incidence of scoliosis, while progression of scoliosis can occur in children who experience rapid growth. Because growth hormone increases growth rate, patients with a history of scoliosis who are treated with growth hormone should be monitored for progression of scoliosis.

ADVERSE REACTIONS: Addition of the following adverse drug events:

Metabolic: Infrequent, mild and transient peripheral or generalized edema;

Musculoskeletal: Rare carpal tunnel syndrome;

Skin: Rare increased growth of pre-existing nevi - patients should be monitored carefully for malignant transformation;

Endocrine: Rare gynecomastia; rare pancreatitis.

Return to Quick Reference

WARNINGS:

Section added indicating Iopidine Ophthalmic Solution is for topical ophthalmic use only.

Return to Quick Reference

BOXED WARNING:

Revised as follows (new text in italics): "Severe and sometimes fatal hepatitis (replaces "heptitis") associated with isoniazid therapy has been reported and may occur or (replaces "and") may develop even after many months of treatment. The risk of developing hepatitis is age related. Approximate case rates by age are: less than 1 (replaces "0") per 1,000 for persons under 20 years of age, 3 per 1,000 for persons in the 20-34 year age group, 12 per 1,000 for persons in the 35-49 year age group, 23 per 1,000 for persons in the 50-64 year age group, and 8 per 1,000 for persons over 65 years of age. The risk of hepatitis is increased with daily consumption of alcohol. Precise data to provide a fatality rate for isoniazid-related hepatitis is not available; however, in a U.S. Public Health Service Surveillance Study of 13,838 persons taking isoniazid, there were 8 deaths among 174 cases of hepatitis.

"Therefore, patients given isoniazid should be carefully monitored and interviewed at monthly intervals. For persons 35 and older, in addition to monthly symptom reviews, hepatic enzymes (specifically, AST and ALT (formerly SGOT and SGPT, respectively)) should be measured prior to starting isoniazid therapy and periodically throughout treatment. Isoniazid- associated hepatitis usually occurs during the first three months of treatment. (replaces "Serum transaminase concentration becomes elevated in about 10-20 percent of patients, usually during the first few months of therapy but it can occur at any time.") Usually, enzyme levels return to normal despite continuance of drug, but in some cases progressive liver dysfunction occurs. Other factors associated with an increased risk of hepatitis include daily use of alcohol, chronic liver disease and injection drug use. A recent report suggests an increased risk of fatal hepatitis associated with isoniazid amoung women, particularly black and Hispanic women. The risk may also be increased during the post partum period. More careful monitoring should be considered in these groups, possibly including more frequent laboratory monitoring. If abnormalities of liver function exceed three to five times the upper limit of normal, discontinuation of isoniazid should be strongly considered. Liver function tests are not a substitute for a clinical evaluation at monthly intervals or for the prompt assessment of signs or symptoms of adverse reactions occurring between regularly scheduled evaluations. Patients should be instructed to immediately report signs or symptoms consistent with liver damage or other adverse effects. (replaces "report immediately any of the prodromal symptoms of hepatitis, such as"). These include any of the following: unexplained anorexia, nausea, vomiting, dark urine, icterus, rash, persistent paresthesias of the hands and feet, persistent fatigue, weakness (", malaise" deleted) or fever of greater than 3 days duration and/or abdominal tenderness, especially right upper quadrant discomfort. If these symptoms appear or if signs suggestive of hepatic damage are detected, isoniazid should be discontinued promptly, since (replaces "sine") continued use of the drug in these cases has been reported to cause a more severe form of liver damage.

"Patients with tuberculosis who have hepatitis attributed to isoniazid should be given appropriate treatment with alternative drugs. If isoniazid must be reinstituted, it should be reinstituted only after symptoms and laboratory abnormalities have cleared. The drug should be restarted in very small and gradually (replaces "graually") increasing doses and should be withdrawn immediately if there is any indication of recurrent liver involvement.

"Preventive treatment should be deferred in persons with acute hepatic diseases."

CLINICAL PHARMACOLOGY (New Section):

Contains information (such as regards timing of peak blood levels after oral administration, excretion, metabolism [includingdifferences in acetylation by ethnicity], and pyridoxine [vitamin B6] deficiency) previouslyincluded under DESCRIPTION [see package insert/labeling].

Mechanism of Action (New Subsection):

Second paragraph relates to safety: All bold: "Isoniazid resistant Mycobacterium tuberculosis bacilli develop rapidly when isoniazid monotherapy is administered."

INDICATIONS AND USAGE (previously called INDICATIONS):

Section has undergone extensive revision [see packageinsert/labeling]. With regard to safety, note the following:

"Isoniazid is recommended for all forms of tuberculosis in which organisms are susceptible. However, active tuberculosis must be treated with multiple concomitant antituberculosis medications to prevent the emergence of drug resistance. Single-drug treatment of active tuberculosis with isoniazid, or any other medication, is inadequate therapy."

CONTRAINDICATIONS:

Section revised - "Isoniazid is contraindicated in patients who develop severe hypersensitivity reactions, including drug-induced hepatitis; previous isoniazid-associated hepatic injury; severe adverse reactions to isoniazid ("," removed) such as drug fever, chills, ("and" removed) arthritis; and acute liver disease of any etiology.

PRECAUTIONS:

Revised and now subdivided into subsections:

General: "All drugs should be stopped and an evaluation made at the first sign of a hypersensitivity reaction. If isoniazid therapy must be reinstituted, the drug should be given only after symptoms have cleared. The drug should be restarted in very small and gradually increasing doses and should be withdrawn immediately if there is any indication of recurrent hypersensitivity reaction."

"Use of isoniazid should be carefully monitored in the following:

1. (prior #2) Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of isoniazid hepatitis.
   
2. (prior #3) Patients with active (replaces "current") chronic liver disease or severe renal dysfunction.
   
3. Age >35.
   
4. Concurrent use of any chronically administered medication.
   
5. History of previous discontinuation of isoniazid.
   
6. Existence of peripheral neuropathy or conditions predisposing to neuropathy.
   
7. Pregnancy.
   
8. Injection drug use.
   
9. Women belonging to minority groups, particularly in the post-partum period.
   
10. HIV seropositive patients."

"Periodic ophthalmologic examinations during isoniazid therapy are recommended when visual symptoms occur." has been deleted. (NB: See below for revision involving PRECAUTION regarding concurrent use of phenytoin).

Laboratory Tests: "Because there is a higher frequency of isoniazid associated hepatitis among certain patient groups, including Age >35, daily users of alcohol, chronic liver disease, injection drug use and women belonging to minority groups, particularly in the post-partum period, transaminase measurements should be obtained prior to starting and monthly during preventative therapy, or more frequently as needed. If any of the values exceed three to five times the upper limit of normal, isoniazid should be temporarily discontinued and consideration given to restarting therapy."

Drug interactions: "Food: Isoniazid should not be administered with food. Studies have shown that the bioavailability of isoniazid is reduced significantly when administered with food.

"Acetaminophen: a report of severe acetaminophen toxicity was reported in a patient receiving Isoniazid. It is believed that the toxicity may have resulted from a previously unrecognized interaction between isoniazid and acetaminophen and a molecular basis for this interaction has been proposed. However, current evidence suggests that isoniazid does induce P-450IIE1, a mixed-function oxidase enzyme that appears to generate the toxic metabolites, in the liver. Furthermore it has been proposed that isoniazid resulted in induction of P-450IIE1 in the patients liver which, in turn, resulted in a greater proportion of the ingested acetaminophen being converted to the toxic metabolites. Studies have demonstrated that pretreatment with isoniazid potentiates acetaminophen hepatotoxicity in rats^1,2.

"Carbamazepine: Isoniazid is known to slow the metabolism of carbamazepine and increase its serum levels. Carbamazepine levels should be determined prior to concurrent administration with isoniazid, signs and symptoms of carbamazepine toxicity should be monitored closely, and appropriate dosage adjustment of the anticonvulsant should be made³.

"Ketoconazole: Potential interaction of Ketoconazole and Isoniazid may exist. When Ketoconazole is given in combination with isoniazid and rifampin the AUC of ketoconazole is decreased by as much as 88% after 5 months of concurrent Isoniazid and Rifampin therapy⁴.

Phenytoin: NB: Prior labeling contained the following PRECAUTION regarding concurrent use of phenytoin: "1. Patients who are receiving phenytoin concurrently. Isoniazid may decrease the excretion of phenytoin or may enhance its effects. To avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant should be made."

Revised to: "Isoniazid may increase serum levels of phenytoin. To avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant should be made^5,6."

"Theophylline: A recent study has shown that concomitant administration of isoniazid and theophylline may cause elevated plasma levels of theophylline, and in some instances a slight decrease in the elimination of isoniazid. Since the therapeutic range of theophylline is narrow, theophylline serum levels should be monitored closely, and appropriate dosage adjustments of theophylline should be made⁷.

"Valproate: A recent case study has shown a possible increase in the plasma level of valproate when co-administered with isoniazid. Plasma valproate concentration should be monitored when isoniazid and valproate are co-administered, and appropriate dosage adjustments of valproate should be made⁵."

Prior Sections USAGE IN PREGNANCY AND LACTATION and CARCINOGENESIS have been replaced by these new subections:

Carcinogenesis and Mutagenesis: "Isoniazid has been shown (replaces "reported") to induce pulmonary tumors in a number of strains of mice. Isoniazid has not been shown to be carcinogenic in humans. (Note: a diagnosis of mesothelioma in a child with prenatal exposure to isoniazid and no other apparent risk factors has been reported). Isoniazid has been found to be weakly mutagenic in strains TA 100 and TA 1535 of Salmonella typhimurium (Ames assay) without metabolic activation.

Pregnancy: Prior notation regarding animals studies in pregnancy and usage in pregancy: "It has been reported that in both rats and rabbits, isoniazid may exert an embryocidal effect when administered orally during pregnancy, although no isoniazid-related congenital anomalies have been found in reproduction studies in mammalian species (mice, rats, and rabbits). Isoniazid should be prescribed during pregnancy only when therapeutically necessary. The benefit of preventive therapy should be weighed against a possible risk to the fetus. Preventive treatment generally should be started after delivery because of the increased risk of tuberculosis for new mothers."

has been replaced by: "Teratogenic effects: Pregnancy Category C: Isoniazid has been shown to have an embryocidal effect in rats and rabbits when given orally during pregnancy. Isoniazid was not teratogenic in reproduction studies in mice, rats and rabbits. There are no adequate and well-controlled studies in pregnant women. Isoniazid should be used as a treatment for active tuberculosis during pregnancy because the benefit justifies the potential risk to the fetus. The benefit of preventive therapy also should be weighed against a possible risk to the fetus. Preventive therapy generally should be started after delivery to prevent putting the fetus at risk of exposure; the low levels of isoniazid in breast milk do not threaten the neonate. Since isoniazid is known to cross the placental barrier, neonates of isoniazid treated mothers should be carefully observed for any evidence of adverse affects."

Nonteratogenic effects: Prior statement revised - "Since isoniazid is known to cross the placental barrier ("and to pass into maternal breast milk" deleted), neonates ("and breast-fed infants" deleted) of isoniazid-treated mothers should be carefully observed for any evidence of adverse effects."

Nursing Mothers: "The small concentrations of isoniazid in breast milk do not produce toxicity in the nursing newborn; therefore, breast feeding should not be discouraged. However, because levels of isoniazid are so low in breast milk, they can not be relied upon for prophylaxis or therapy of nursing infants."

ADVERSE REACTIONS:

Hepatic Reactions: Revised as follows - "See boxed warning. Elevated serum transaminase (SGOT; SGPT), bilirubinemia, bilirubinuria, jaundice, and occasionally severe and sometimes fatal hepatitis. The common prodromal symptoms of hepatitis are anorexia, nausea, vomiting, fatigue, malaise, and weakness. Mild hepatic dysfunction, evidenced by mild and transient elevation of serum transaminase levels occurs in 10 to 20 percent of patients taking isoniazid. (replaces "Mild and transient elevation of serum transaminase levels, occurs in 10 to 20 percent of persons taking isoniazid.") This (replaces "The") abnormality usually appears in the first 1 to 3 (replaces "4 to 6") months of treatment but can occur at any time during therapy. In most instances, enzyme levels return to normal, ("with no necessity to discontinue medication." deleted), and generally, there is no necessity to discontinue medication during the period of mild serum transaminase elevation. In occasional instances, progressive liver damage occurs, with accompanying symptoms. If the SGOT value exceeds three to five times the upper limit of normal, discontinuation of the isoniazid should be strongly considered. (replaces "In these cases, the drug should be discontinued immediately."). The frequency of progressive liver damage increases with age. It is rare in persons under 20, but occurs in up to 2.3 percent of those over 50 years of age."

OVERDOSAGE:

Section revised to indicate that untreated or inadequately treated cases of gross isoniazid overdosage, 80-150 mg/kg, can cause neurotoxicity (Amer J Respir Crit Care Med 1994;149:1359-1374). This is in addition to previous notes that these cases can terminate fatally, but that good response has been reported in most patients brought under adequate treatment within the first few hours after drug ingestion.

In addition, the section has been revised to include separate subsections that specifically outline the management of overdosage in the Asymptomatic Patient and Symptomatic Patient; provide General information as to which blood samples to obtain; discuss the Rapid Control of Metabolic Acidosis; and discuss Dialysis [see complete section in package insert].

DOSAGE AND ADMINISTRATION:

Section has undergone extensive revision [see package insert/labeling]. With regard to safety, note the following:

"The above treatment guidelines apply only when the disease is caused by organisms that are susceptible to the standard antituberculous agents. Because of the impact of resistance to isoniazid and rifampin on the response to therapy, it is essential that physicians initiating therapy for tuberculosis be familiar with the prevalence of drug resistance in their communities. It is suggested that ethambutol not be used in children whose visual acuity cannot be monitored."

"Pregnant Women with Tuberculosis: The options listed above must be adjusted for the pregnant patient. Streptomycin interferes with in utero development of the ear and may cause congenital deafness. Routine use of pyrazinamide is also not recommended in pregnancy because of inadequate teratogenicity data. The initial treatment regimen should consist of isoniazid and rifampin. Ethambutol should be included unless primary isoniazid resistance is unlikely (isoniazid resistance rate documented to be less than 4%)."

REFERENCES:

1. Murphy R, et al: Annals of Internal Medicine 1990; November 15;113:799-800.
2. Burke RF, et al: Res Commun Chem Pathol Pharmacol 1990; July;69:115-118.
3. Fleenor MF, et al: Chest (United States) [letter] 1991; June;99(6):1554.
4. Baciewicz AM and Baciewicz Jr. FA: Arch Int Med 1993; September;153:1970-1971.
5. Jonville AP, et al: European Journal of Clinical Pharmacol (Germany) 1991;40(2): 198.
6. American Thoracic Society/Centers for Disease Control: Treatment of Tuberculosis and Tuberculosis Infection in Adults and Children. Amer J Respir Crit Care Med 1994;149: 1359-1374.
7. Hoglund P, et al: European Journal of Respir Dis (Denmark) 1987; February; 70(2): 110-116.
8. Committee on Infectious Diseases American Academy of Pediatrics: 1994, Red Book: Report of the Committee on Infectious Diseases;23 edition:487.
9. Schraufnagel DE: Testing for Isoniazid; Chest (United States) 1990;August; 98(2): 314-316.

Return to Quick Reference

CLINICAL PHARMACOLOGY:

Revised to reflect new data on steady state, clearance, terminal half-lives, metabolism/urinary excretion, and tissue distribution [see complete section in package insert].

CONTRAINDICATIONS:

Contraindicated in patients with a history of hypersensitivity to pentamidine isethionate.

WARNINGS:

Warning with regard to severe hypotension revised to specify single IM or IV dose, and that it is more likely with rapid IV administration.

PRECAUTIONS:

Ventricular tachycardia, pancreatitis, and Stevens-Johnson syndrome added to list of conditions in which pentamidine isethionate should be used cautiously. Infusion period extended from 60 to 60-120 minutes when administered IV.

Renal and Hepatic Impairment: Efficacy or safety of alternative Pentam 300 dosing protocols have not been established for patients with impaired renal or hepatic function.

Laboratory Tests: Serum bilirubin specified as bilirubin test to be carried out before, during and after therapy.

Drug Interactions: No drug interaction studies have been conducted with Pentam. Because the nephrotoxic effects may be additive, the concomitant or sequential use of pentamidine isethionate and other nephrotoxic drugs (such as aminoglycosides, amphotericin B, cisplatin, foscarnet or vancomycin) should be closely monitored and avoided, if possible.

Pregnancy: Remains Category C: should not be given to a pregnant woman unless the potential benefits are judged to outweigh the unknown risks.

PRECAUTIONS:

Nursing mothers (new subsection): It is unknown whether pentamidine isethionate is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from pentamidine isethionate, 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. As many drugs are excreted in human milk, pentamidine isethionate should not be given to a nursing mother unless the potential benefits are judged to outweigh the unknown risks.

ADVERSE REACTIONS:

CAUTION: Revised to note nephrotoxic events (increased creatinine, impaired renal function, azotemia, and renal failure) are common with parenteral administration. The following revisions/additions were made regarding the most frequently reported spontaneous adverse events (1 to 30%) reported in clinical trials (regardless of their relation to pentamidine isethionate therapy):

SYSTEM:	EVENT:	%	(previous %)
Cardiovascular	Hypotension	5	(4)
Hematologic	Leukopenia	10.4	(7.5)
	Thrombocytopenia	2.6	(0.9)
Metabolic	Hypoglycemia	5.9	(3.5)
Urogenital	Azotemia	8.5
	Elevated serum creatine	23.6	(23.1)
	Elevated BUN	6.6
	Impaired renal function	28.8

See package insert for complete list of adverse events with a frequency of less than 1% incidence (no causal relationship to treatment has been established for these adverse events). From postmarketing clinical experience, the following have been reported: cough, diabetes mellitus/ketoacidosis, dyspnea, infiltration (extravasation - see WARNINGS) and torsades de pointes.

DOSAGE AND ADMINISTRATION:

CAUTION: Therapy for longer than 21 days, which has been done, may be associated with increased toxicity. Intravenous Injection: Infusion period as per PRECAUTIONS; IV pentamidine isethionate solutions are incompatible with fluconazole and foscarnet sodium.

Return to Quick Reference

PRILOSEC (omeprazole)
[Aug 9, 1996: Astra Merck]

ADVERSE REACTIONS:

Metabolic/Nutritional: Hyponatremia added to list of adverse reactions.

OVERDOSAGE:

Section revised to include new information from rare reports of Prilosec overdosages, in which doses ranged from 320-900 mg (16-45X usual recommended clinical dose). The variable manifestations included confusion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache and dry mouth. Symptoms were transient, with no serious clinical outcome reported; there is no known specific antidote for omeprazole overdosage.

Return to Quick Reference

PROSCAR (finasteride)
[Aug 28, 1996: Merck]

CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS sections (package insert) and WARNING ABOUT PROSCAR AND PREGNANCY section (patient package insert) revised to reflect new information on concentration of finasteride in semen. As a result, previous semen exposure precaution with respect to pregnancy has been deleted in relevant sections. Previous WARNINGS/PRECAUTIONS notations against the handling of crushed Proscar tablets by a woman when she is pregnant or may potentially be pregnant remain, with minor editorial changes.

PRECAUTIONS:

Pregnancy Category X: In addition to notation that Proscar is not indicated for use in women, a new paragraph outlines results of relevant animal studies [see complete subsection in package insert].

Return to Quick Reference