ALTACE (ramipril) - BENTYL (dicyclomine) - CALCIUM DISODIUM VERSENATE (edetate calcium disodium) - CARDURA (doxazosin mesylate) - CATAPRES-TTS (clonidine HCl) - CEFTIN (cefuroxime axetil) - CEPTAZ (ceftazidime) - CEREDASE (alglucerase) - CLAFORAN (cefotaxime sodium) - COUMADIN (warfarin sodium) - FLAREX (fluorometholone acetate) - FLOXIN (ofloxacin) - FORTAZ (ceftazidime) - HYDREA (hydroxyurea,) - HYTRIN (terazosin HCl) - INVIRASE (saquinavir mesylate) - LIDOCAINE HCl - LUPRON DEPOT (leuprolide acetate) - MAXAQUIN (lomefloxacin HCl) - MAXIDEX (dexamethasone) - NOROXIN (norfloxacin) - NORVIR (ritonavir) - PRIMAXIN I.V. (imipenem/cilastatin sodium) - PRINIVIL (lisinopril) - PRINZIDE (lisinopril/hydrochlorothiazide) - SALAGEN (pilocarpine HCl) - TAMBOCOR (flecainide acetate) - TOBRADEX (tobramycin/dexamethasone) - ZINACEF (cefuroxime sodium)

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WARNINGS:

Revised with removal of the original ending phrase "and for young children" from previous sentence, which now reads "Patients with lead encephalopathy and cerebral edema may experience a lethal increase in intracranial pressure following intravenous infusion; the intramuscular route is preferred for these patients".

PRECAUTIONS:

Pediatric Use: Subsection revised with addition of the following sentences - "The intramuscular route is preferred by some for young pediatric patients. In cases where the intravenous route is necessary, avoid rapid infusion. (see WARNINGS). Urine flow must be monitored throughout therapy; Calcium Disodium Versenate therapy must be stopped if anuria or severe oliguria develops. (See General Precautions). At no time should the recommended daily dosage be exceeded. (See DOSAGE AND ADMINISTRATION)."

DOSAGE AND ADMINISTRATION:

Sentence denoting that the intramuscular route is used for all patients with overt lead poisoning revised, with the previous recommendation of this route for young children (now termed pediatric patients) changed to a statement that this route is preferred by some for young pediatric patients.

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CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY:

First paragraph of this section, which as before deals with results of chronic dietary administration (up to 24 months) of doxazosin mesylate that revealed no evidence of carcinogenic potential, was revised to indicate that the maximally tolerated doses were 40 mg/kg/day in rats and 120 mg/kg/day in mice. The highest doses evaluated in these studies are associated with AUCs (a measure of systemic exposure) 8 times (rat) and 4 times (mouse) the human AUC at a dose of 16 mg/day.

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PRECAUTIONS, Withdrawal subsection moved to WARNINGS section and revised :

WARNINGS, Withdrawal: Confusion 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. Regarding Catapres-TTS discontinuation, physicians are now advised to reduce the dose gradually over 2-4 days in order to avoid withdrawal symptomatology.

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ADVERSE REACTIONS: Section revised, with the postmarketing experience now summarized as follows:

Postmarketing Experience With Ceftin Products: In addition to the adverse events reported during clinical trials, the following adverse events have been observed during clinical practice in patients treated with Ceftin Tablets and Ceftin for Oral Suspension and were reported spontaneously. For some of these events, data are insufficient to allow an estimate of incidence or to establish causation.

General: Hypersensitivity reactions: anaphylaxis, angioedema, pruritus, rash, serum sickness-like reaction, urticaria.

Gastrointestinal: Pseudomembraneous colitis (see WARNINGS).

Hepatic: Jaundice.

Skin: Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

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PRECAUTIONS:

General: Last sentence of subsection revised to indicate that distal necrosis can occur after inadvertent intra-arterial administration of ceftazidime.

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WARNINGS:

Section revised to indicate that approximately 13% (versus 14%, as previously noted) of patients treated clinically and tested to date have developed IgG antibody to Ceredase during the first year of therapy.

PRECAUTIONS:

General: Subsection revised to include the report of one case of precocious puberty, with notation that the recent introduction of manufacturing steps designed to reduce the level of hCG in Ceredase reduces the likelihood of this occurrence.

ADVERSE REACTIONS:

Section revised to indicate that while menstrual abnormalities and false postive pregnancy tests have previously been reported, the introduction of manufacturing steps designed to reduce the level of hCG in Ceredase reduces the likelihood of these occurrences.

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DESCRIPTION, DOSAGE AND ADMINISTRATION, COMPATABILITY AND STABILITY, DIRECTIONS FOR USE, HOW SUPPLIED:

Multiple sections changed, as outlined [contact manufacturer for complete information/package insert].

DOSAGE AND ADMINISTRATION:

IV Administration: Revised to include notation that the safety and effectiveness of Claforan (sterile cefotaxime sodium) when administered by continuous intravenous infusion have not been established.

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CONTRAINDICATIONS:

Miscellaneous: Revised with addition of known hypersensitivity to warfarin or to any other component of this product to subsection list.

PRECAUTIONS:

Exogenous Factors: Subsection revised with additions to tables that delineate factors that may be responsible for increased PT/INR response: Classes of Drugs table (selective serotonin reuptake inhibitors added) and Specific Drugs Reported (azithromycin, fluoxetine and fluvoxamine added).

Exogenous Factors: Subsection revised with addition of 6-mercaptopurine to Specific Drugs Reported table that delineates factors that may be responsible for decreased PT/INR response.

ADVERSE REACTIONS:

Section revised with additions to the list of adverse reactions reported infrequently: allergic reactions, edema, rash, flatulence/bloating, fatigue, lethargy, malaise, dizziness, taste perversion, cold intolerance, and feeling cold and chills (the last added to paresthesia).

DOSAGE AND ADMINISTRATION:

Conversion From Heparin Therapy: Statement regarding coumadin and aPTT test revised - "Coumadin may increase the aPTT test, even in the absence of heparin [new information in italics].

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PRECAUTIONS:

Nursing Mothers: Revised to indicate that systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Flarex is administered to a nursing woman.

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WARNINGS:

The second paragraph detailing severe and sometimes fatal events that have been reported in patients receiving quinolones, including ofloxacin, has been revised to indicate that some of these events are due to hypersensitivity, with those occurring with ofloxacin treatment no longer characterized as extremely rare.

A new paragraph has been added that indicates the reporting of ruptures of the shoulder, hand and Achilles tendons that required surgical repair or resulted in prolonged disability with ofloxacin and other quinolones. Ofloxacin should be discontinued if pain, inflammation or tendon rupture is experienced by the patient, who should rest and refrain from exercise until the diagnosis of tendonitis or tendon rupture has been confidently excluded. Tendon rupture can occur at any time during or after therapy with ofloxacin.

The paragraph concerning syphilis and gonorrhea with respect to ofloxacin treatment has been revised to indicate that those patients treated with ofloxacin for gonorrhea who have a positive follow-up serologic test for syphilis after three months should be treated with an appropriate antimicrobial.

PRECAUTIONS:

Information for Patients: Section has been revised thusly: The statement that cautioned against taking mineral supplements, vitamins with iron or minerals, calcium-, aluminum- or magnesium-based antacids or sucralfate within two hours before or after ofloxacin has been removed.

The statement that ofloxacin can be taken without regard to meals has been removed.

A new statement has been added that indicates patients should be advised that ofloxacin treatment is to be discontinued and their physician informed if they experience pain, inflammation or tendon rupture, and to rest and refrain from exercise until the diagnosis of tendonitis or tendon rupture has been confidently excluded.

A new statement has been added that indicates the reporting of convulsions in patients taking quinolones, including ofloxacin, and that patients are to notify their physician before taking ofloxacin if they have a history of this condition.

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ADVERSE REACTIONS:

Revised to include skin ulcerations among listed dermatological adverse reactions.

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WARNINGS:

Revised to include a new paragraph that denotes the rare (probably less frequently than once every several thousand patients) association of terazosin and other Alpha1-antagonists with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Two or three dozen cases have been reported; because priapism can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of this condition (see PRECAUTIONS: Information for Patients).

PRECAUTIONS:

Information for Patients: A new paragraph has been added with regard to priapism, with notation that patients should be advised about the possibility of priapism resulting from treatment with Hytrin and other similar medications. Patients should know that this reaction to Hytrin is extremely rare, but if not brought to immediate medical attention, it can lead to permanent erectile dysfunction (impotence).

ADVERSE REACTIONS:

Hypertension: That there have been postmarketing surveillance reports of priapism has been added.

PATIENT INFORMATION ABOUT HYTRIN (HI-TRIN):

WARNINGS: Section revised to include information regarding priapism, including its seriousness and possible permanent sequelae (see above), with patients informed that they are to call their doctor or go to an emergency room as soon as possible if they have a prolonged abnormal erection.

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BOXED WARNING:

The previous BOXED WARNING stating that the indication for Invirase for the treatment of HIV infection was based on changes in surrogate markers, with (at the time) no results from controlled clinical trials evaluating the effect of Invirase-containing regimens on survival or clinical progression of HIV infection, has been removed.

INDICATIONS AND USAGE:

The stated basis for the indication of Invirase in combination with nucleoside analogues for the treatment of HIV infection when therapy is warranted is revised with the addition of a notation regarding a clinical study that showed a reduction in both mortality and AIDS-defining clinical events for patients who received Invirase in combination with HIVID (zalcitabine, ddC) compared to patients who received either HIVID or Invirase alone.

Description of Clinical Studies: Subsection revised to include new/upgraded information regarding relevant clinical studies [see complete subsection in package insert].

PRECAUTIONS:

Information for Patients: Subsection revised with a) deletion of statements that Invirase has not been shown to reduce the incidence or frequency of illnesses associated with advanced HIV infection, and that patients should be advised to remain under the care of a physician while using Invirase, and b) addition of statement that patients should be advised that Invirase should be used only in combination with an active nucleoside analogue regimen.

Laboratory Tests: Subsection revised with deletion of statement that no consistent alterations in standard laboratory tests have been associated with use of Invirase.

ADVERSE REACTIONS:

Thrombocytopenia and intracranial hemorrhage leading to death, peripheral vasoconstriction, and intestinal obstruction added to the list of rare occurrences of serious adverse experiences that have been reported during Invirase clinical trials and considered at least possibly related to the use of study drugs.

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ADVERSE REACTIONS:

Section revised to include reports from post-marketing surveillance and information regarding bone mineral density: Mood swings, including depression, have been reported as physiologic effect of decreased sex steroids. There have been very rare reports of suicidal ideation and attempt, with many, but not all, of these patients having a history of depression or other psychiatric illness. Patients should be counseled on the possibility of worsening of depression.

There have been rare reports of symptoms consistent with anaphylactoid or asthmatic process, with rash, urticaria and photosensitivity reactions also reported.

Localized reactions, including induration and abscess at the site of injection, have been reported.

Cardiovascular System: hypotension;

Hemic and Lymphatic System: decreased WBC;

Central/Peripheral Nervous System: peripheral neuropathy, spinal fracture/paralysis;

Musculoskeletal System: tenosynovitis-like symptoms;

Urogenital System: prostate pain.

See other Lupron Depot and Lupron Injection package inserts for other events reported in different patient populations.

Endometriosis: Subsection revised to indicate that in controlled study in endometriosis patients, patients tested at six or twelve months after discontinuation of therapy showed mean bone density return to within 2% of pretreatment.

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WARNINGS:

A new paragraph has been added that indicates the reporting of ruptures of the shoulder, hand and Achilles tendons that required surgical repair or resulted in prolonged disability with lomefloxacin. Lomefloxacin should be discontinued if pain, inflammation or tendon rupture is experienced by the patient, who should rest and refrain from exercise until the diagnosis of tendonitis or tendon rupture has been confidently excluded. Tendon rupture can occur at any time during or after therapy with lomefloxacin.

PRECAUTIONS:

Information for Patients: Revised to include a new statement that indicates patients should be advised that lomefloxacin treatment is to be discontinued and their physician informed if they experience pain, inflammation or tendon rupture, and to rest and refrain from exercise until the diagnosis of tendonitis or tendon rupture has been confidently excluded.

[September 27, 1996: G.D. Searle]

PRECAUTIONS:

Information for Patients: Revised to further specify that the risk of developing photosensitivity from sunlight may be reduced by taking the lomefloxacin daily dose at least 12 hours before exposure to the sun (e.g., in the evening).

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PRECAUTIONS:

Nursing Mothers: Revised to indicate that systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Maxidex Ophthalmic Suspension is administered to a nursing woman.

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WARNINGS:

A new paragraph has been added that indicates the reporting of ruptures of the shoulder, hand and Achilles tendons that required surgical repair or resulted in prolonged disability with norfloxacin. Norfloxacin should be discontinued if pain, inflammation or tendon rupture is experienced by the patient, who should rest and refrain from exercise until the diagnosis of tendonitis or tendon rupture has been confidently excluded. Tendon rupture can occur at any time during or after therapy with norfloxacin.

PRECAUTIONS:

Information for Patients: A new statement has been added that indicates patients should be advised that norfloxacin treatment is to be discontinued and their physician informed if they experience pain, inflammation or tendon rupture, and to rest and refrain from exercise until the diagnosis of tendonitis or tendon rupture has been confidently excluded.

ADVERSE REACTIONS:

Musculoskeletal: Tendon rupture added to list of adverse reactions.

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BOXED WARNING:

Revised with addition of ergot alkaloid preparations to list of drugs that when co-administered with Norvir may result in potentially serious and/or life-threatening adverse events due to possible effects of Norvir on the hepatic metabolism of certain drugs.

CONTRAINDICATIONS:

Revised with addition of dihydroergotamine, ergotamine and pimozide to list of drugs in which ritonavir is expected to produce large increases in plasma concentrations.

Revised with addition of notation that post-marketing reports of co-administration of ritonavir with ergotamine or dihydroergotamine have been associated with acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities; thus, these drugs should not be co-administered with ritonavir.

Revised to indicate that co-administration of ritonavir with specified highly metabolized sedatives and hypnotics is expected (revised from "likely") to produce large increases in these agents, with caution against co-administeration with ritonavir as before.

WARNINGS:

Allergic reactions including urticaria, mild skin eruptions, bronchospasm and angioedema have been reported, as have rare cases of anaphylaxis and Stevens-Johnson syndrome.

PRECAUTIONS:

Hemophilia: There have been reports of increased bleeding, including spontaneous skin hemotomas and hemoarthrosis, in patients with hemophilia type A and B treated with protease inhibitors, with some patients being given additional factor VIII. In more than half of the reported cases, protease inhibitor treatment was continued or reintroduced; a causal relationship has not been established.

Laboratory Tests: Cholesterol added to list of laboratory tests with which ritonavir has been associated with alterations.

DRUG INTERACTIONS:

Effects on ritonavir: Agents which increase CYP3A activity are (revised from "would be") expected to increase ritonavir clearance.

Effects on co-administered drugs: Numerous revisions made to this subsection, as clinical drug interaction studies with ritonavir and some commonly administered drugs have been conducted. Drugs that may need dose adjustment based on information from these studies are listed in this subsection in alphabetical order, with didanosine added and saquinavar information revised [see complete subsection in package insert].

In addition, Table 3 summarizes some commonly administered drugs, categorized by the predicted magnitude of interaction that could result if co-administered with ritonavir [see complete subsection in package insert].

Post-Marketing Experience with Drugs Listed in Table 3: Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine, nefazodone or fluoxetine; the possibility of drug interaction cannot be excluded.

ADVERSE REACTIONS:

Post-Marketing Experience: There have been postmarketing reports of seizure, and hyperglycemia in individuals with/without known diabetes history has been reported; a cause and effect relationship has not been established. Dehydration, usually associated with gastrointestinal symptoms and sometimes resulting in hypotension, syncope or renal insufficiency, has been reported, while syncope, orthostatic hypotension and renal insufficiency without known dehydration have also been reported.

OVERDOSAGE:

Revised to indicate that a postmarketing case of renal failure with eosinophilia has been reported with ritonavir overdose.

DOSAGE AND ADMINISTRATION:

Revised to indicate that dose titration may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels, and that patients should be aware that frequently observed adverse events, such as mild to moderate gatrointestinal disturbances and parathesias, may diminish as therapy is continued.

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ADVERSE REACTIONS:

Granulocytic Patients: Subsection has been removed.

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WARNINGS:

Fetal/Neonatal Morbidity and Mortality: Revised to present data from studies of pregnant mice, rats and rabbits (in which no teratogenic effects were seen) in terms of maximum recommended human daily dose (MRHDD) on a body surface area basis, rather than the previously utilized mg/kg/day [see complete subsection in package insert].

PRECAUTIONS:

Carcinogenesis, Mutagenesis, Impairment of Fertility: As with WARNINGS, revised to present data from rodent studies in terms of MRHDD on a body surface area, rather than mg/kg/day, basis [see complete subsection in package insert].

Nursing Mothers: Revised to indicate that given the potential for serious adverse events in nursing infants from ACE inhibitors, it should be decided whether to discontinue Prinivil, taking into account the importance of the drug to the mother.

OVERDOSAGE:

Revised to indicate that no rats, and 1 of 20 mice, died after receiving a single oral dose of 20 g/kg.

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WARNINGS:

Pregnancy, Lisinopril-Hydrochlorothiazide: Revised to present data from studies of pregnant mice and rats in terms of maximum recommended human daily dose (MRHDD) on a body surface area basis, rather than the previously utilized mg/kg/day [see complete subsection in package insert].

Lisinopril, Fetal/Neonatal Morbidity and Mortality: Revised to present data from studies of pregnant mice, rats and rabbits (in which no teratogenic effects were seen) in terms of maximum recommended human daily dose (MRHDD) on a body surface area basis, rather than the previously utilized mg/kg/day [see complete subsection in package insert].

Hydrochlorothiazide: This entire subsection has been revised: Oral administration to pregnant mice (doses up to 3000 mg/kg/day) and rats (doses up to 1000 mg/kg/day) during their respective periods of major organogenesis produced no evidence of fetal harm, with these doses > 150 times MRHDD on a body surface area basis. Thiazides cross the placental barrier and appear in cord blood, with a risk of fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions that have occurred in adults.

PRECAUTIONS:

Carcinogenesis, Mutagenesis, Impairment of Fertility, Lisinopril: Revised to present data from rodent studies in terms of MRHDD on a body surface area, rather than mg/kg/day, basis [see complete subsection in package insert].

Carcinogenesis, Mutagenesis, Impairment of Fertility, Hydrochlorothiazide: Revised to present data from rodent studies in terms of MRHDD on a body surface area, rather than mg/kg/day, basis [see complete subsection in package insert].

Nursing Mothers: Revised to indicate that given the potential for serious adverse events in nursing infants from ACE inhibitors and hydrochlorothiazide, it should be decided whether to discontinue Prinzide, taking into account the importance of the drug to the mother.

OVERDOSAGE:

Lisinopril: Revised to indicate that no rats, and 1 of 20 mice, died after receiving a single oral dose of 20 g/kg.

Hydrochlorothiazide: Revised to indicate that no rats or mice died after receiving a single oral dose of 10 g/kg.

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WARNINGS:

Ocular: First paragraph of this subsection (which began "Careful examination of the fundus" and ended "this finding is not known") is deleted in its entirety. The revised Ocular subsection is now comprised by the original second paragraph (which begins "Ocular formulations of pilocarpine" and ends "performing hazardous activities in reduced lighting") [see complete subsection in package insert].

Cardiovascular Disease: Revised by replacing phrase "cardiovascular disease" with significant cardiovascular disease in the last sentence.

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WARNINGS:

Subsection that incorporates results of the Cardiac Arrhythmia Suppression Trial (CAST) results revised to note that while applicability of these results to other populations (e.g., those without recent myocardial infarction) is uncertain, at present it is prudent to consider the risks of using Class 1c agents (including Tambocor), coupled with lack of evidence of improved survival, generally unacceptable in patients without life-threatening ventricular arrhythmias, even if they are experiencing unpleasant, but not life-threatening, symptoms or signs.

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PRECAUTIONS:

Nursing Mothers: Revised to indicate that systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Tobradex Ophthalmic Ointment is administered to a nursing woman.

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WARNINGS:

Pseudomembraneous colitis statements contained in the section revised, with the notation regarding in vitro binding of toxin to cholestyramine and colestipol resins removed. In addition, statements were revised to indicate that when the diagnosis of pseudomembraneous colitis has been made, appropriate therapeutic measures should be initiated. Mild cases are usually responsive to drug discontinuation alone, while in moderate to severe cases consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis. The recommendations for treatment when the colitis is not relieved by drug discontinuation or is severe remain as before.

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