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(Posted: 2/10/99)
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 1999 Physicians' Desk Reference (PDR), if drug's labeling included in the PDR.
|
(anagrelide HCl) |
(fexofenadine HCl fexofenadine HCl/ pseudoephedrine HCl) |
(ramipril) |
(irbesartan) |
|
(terbutaline sulfate) |
(balanced salt solution) |
(levocarnitine) |
(loratadine/ pseudoephedrine sulfate) |
|
(chlorothiazide) |
(fluticasone propionate) |
(fluticasone propionate) |
(lamotrigine) |
|
(levofloxacine) |
(gemfibrozil) |
|
|
|
(prednisolone Na phosphate) |
(porfimer Na) |
(ribavirin) |
(salmeterol xinafoate) |
|
(montelukast Na) |
(nisoldipine) |
(nafarelin acetate) |
(nitroglycerin) |
|
(dorzolamide HCl) |
|
"Fexofenadine has been shown to exhibit minimal (ca. 5%) metabolism. However, co-administration of fexofenadine with ketoconazole and erythromycin led to increased plasma levels of fexofenadine. Fexofenadine had no effect on the pharmacokinetics of erythromycin and ketoconazole."
First paragraph following the table titled "Effects on Steady-State Fexofenadine ..."
" The mechanisms of these interactions are unknown, and the potential for interaction with other azole antifungal or macrolide agents has not been studied. These changes in plasma levels were within the range of plasma levels achieved in adequate and well-controlled clinical trials. Fexofenadine has no effect on the pharmacokinetics of erythromycin or ketoconazole."
deleted and replaced with -
"The changes in plasma levels were within the range of plasma levels achieved in adequate and well-controlled clinical trials. The mechanism of these interactions has been evaluated in in vitro, in situ, and in vivo animal models. These studies indicate that ketoconazole or erythromycin co-administration enhances fexofenadine gastrointestinal absorption. In vivo animal studies also suggest that in addition to enhancing absorption, ketoconazole deceases fexofenadine gastrointestinal secretion, while erythromycin may also decrease biliary excretion."
First sentence -
"Information regarding acute overdosage is limited to experience from clinical trials conducted during the development of Allegra."
deleted and replaced with -
"Most reports of fexofenadine hydrochloride overdose contain limited information. However, dizziness, drowsiness, and dry mouth have been reported."
(Allegra-D Labeling)
First sentence -
"Information regarding acute overdosage is limited to experience from clinical trials conducted during the development of Allegra and the marketing history of pseudoephedrine hydrochloride."
deleted and replaced with -
"Most reports of fexofenadine hydrochloride overdose contain limited information. However, dizziness, drowsiness, and dry mouth have been reported. For the pseudoephedrine hydrochloride component of Allegra-D, information on acute overdose is limited to the marketing history of pseudoephedrine hydrochloride"
"Additionally, as with other ACE inhibitors, eosinophilic pneumonitis has been reported."
"The following adverse reactions have been reported in post-marketing experience: Rare cases of urticaria and angioedema (involving swelling of the face, lips, pharynx, and/or tongue) have been reported."
"No differences have been observed between adults and pediatric patients following use of this drug product."
Note: The following change appears in the 1999 PDR.
"Seizures have been reported to occur in patients with or without pre-existing seizure activity receiving either oral or intravenous levocarnitine. In patients with pre-existing seizure activity, an increase in seizure frequency and /or severity has been reported."
[Labeling changes for other dosage form not appearing in the 1999 PDR: Apr98]
[Other information related to this change: Letter]
"Pediatric patients" changed to "children" in the first sentence.
Text added to end of subsection -
"(See PRECAUTIONS, Pediatric Use.)"
[Other lableing changes not appearing in 1999 PDR: Oct98]
" In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions, with some patients presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with other inhaled corticosteroids in this clinical setting. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone propionate and these underlying conditions has not been established. (See ADVERSE REACTIONS)."
" In rare cases, patients on inhaled fluticasone propionate may present with systemic eosinophilic conditions, with some patients presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of fluticasone propionate. Cases of serious eosinophilic conditions have also been reported with other inhaled corticosteroids in this clinical setting. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between fluticasone propionate and these underlying conditions has not been established. (see PRECAUTIONS: Eosinophilic Conditions)."
"Plasma levels appear proportional to dose and do not demonstrate accumulation across time following multiple doses."
deleted.
Text added as new eleventh paragraph -
"Gemfibrozil is completely absorbed after oral administration of Lopid tablets, reaching peak plasma concentrations 1 to 2 hours after dosing. Gemfibrozil pharmacokinetics are affected by the timing of meals relative to time of dosing. In one study (2), both the rate and extent of absorption of the drug were significantly increased when administered 0.5 hours before meals. Average AUC was reduced by 14-44% when Lopid was administered after meals compared to 0.5 hours before meals. In a subsequent study (3), rate of absorption of Lopid was maximum when administered 0.5 hours before meals with the Cmax 50-60% greater than when given either with meals or fasting. In this study, there were no significant effects on AUC of timing of dose relative to meals (see DOSAGE AND ADMINISTRATION)."
Text added as new last sentence in section -
"Gemfibrozil is highly bound to plasma proteins and there is potential for displacement interactions with other drugs (see PRECAUTIONS)."
"A comparative carcinogenicity study was also done in rats comparing three drugs in this class: fenofibrate (10 and 60 mg/kg; 0.3 and 1.6 times the human dose), clofibrate (400 mg/kg; 1.6 times the human dose), and gemfibrozil (250mg/kg; 1.7 times the human dose). Pancreatic acinar adenomas were increased in males and females on fenofibrate; hepatocellular carcinoma adn pancreatic acinar adenomas were increased in males and hepatic neoplastic nodules in females treated with clofibrate; hepatic neoplastic nodules were increased in males and females treated with gemfibrozil while testicular interstitial cell (Leydig cell) tumors were increased in males on all three drugs."
"Long-term studies have been conducted in rats at 0.2 and ["2" deleted] 1.3 times the human ["dose" deleted] exposure (based on ["surface area, mg/meter 2" deleted] AUC). ["Based on two-week toxicokinetic studies, exposure (AUC) of the dose groups was estimated to be 0.2 and 1.3 times the human exposure." deleted] The incidence of benign liver nodules and liver carcinomas was significantly increased in high dose male rats. The incidence of liver carcinomas increased also in low dose males, but this increase was not statistically significant (p=0.1). Male rats had a dose-related and statistically significant increase of benign Leydig cell tumors. The higher dose female rats had a significant increase in the combined incidence of benign and malignant liver neoplasms.
"Long-term studies have been conducted in mice 0.1 and ["1" deleted] 0.7 times the human ["dose" deleted] exposure (based on ["surface area" deleted] AUC). ["Based on two-week toxicokinetic studies, exposure (AUC) of the dose groups was estimated to be 0.1 and 0.7 times the human exposure." deleted] There were no statistically significant differences from controls in the incidence of liver tumors, but the doses tested were lower than those shown to be carcinogenic with other fibrates."
5. Pregnancy Category - C: First sentence revised -
"Lopid has been shown to produce adverse effects in rats and rabbits at doses between 0.5 and 3 times the human dose (based on surface area) ["but no developmental toxicity or teratogenicity among offspring of either species" deleted]."
"The recommended dose for adults is 1200 mg administered in two divided doses 30 minutes before the morning and evening meal (see CLINICAL PHARMACOLOGY).
"Storage: Store below 30oC (86oF)."
deleted and replace with -
"Store at controlled room temperature 20o- 25oC (68o - 77oF) [see USP]. Protect from light and humidity."
"Safety and effectiveness in the pediatric population have not been established.
However, the relationship between hemodynamic effects of nitroglycerin
and dose in the pediatric population have been documented in the literature.
Note: Very low infusion rates may require that a more dilute concentration of nitroglycerin infusion solution be prepared:"
Other changes:
"CONTRAINDICATIONS AND WARNINGS
Combination Rebetol/Intron A therapy is contraindicated in women who are pregnant
and in the male partners of women who are pregnant. Extreme care must be taken
to avoid pregnancy during therapy and for 6 months after completion of treatment in
female patients, and in female partners of male patients who are taking combination
Rebetol/Intron A therapy. Women of childbearing potential and men must use
two reliable forms of effective contraception during treatment and during the
6-month posttreatment follow-up period. Significant teratogenic and/or embryocidal
["potential has" deleted] effects have been demonstrated for ribavirin in all
animal species studied. See CONTRAINDICATIONS and WARNINGS. Rebetol
monotherapy is not effective for the treatment of chronic hepatitis C and
should not be used for this indication. See WARNINGS"
"Combination Rebetol/Intron A therapy must not be used by women who are ["or may become" deleted] pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking combination Rebetol/Intron A therapy. Combination Rebetol/Intron A therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy . Women of childbearing potential and men must use two forms of effective contraception during treatment and during the ["6-month posttreatment follow-up period" deleted] 6 months after treatment has been concluded. Significant teratogenic and/or embryocidal ["potential has" deleted] effects have been demonstrated for ribavirin in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of Rebetol Capsules . If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment ["cessation" deleted] stops, physicians are encouraged to report such cases by calling (800) 727-7064. See boxed CONTRAINDICATIONS AND WARNING. See WARNINGS."
"Category X, may cause birth defects. See boxed CONTRAINDICATIONS AND WARNING. See CONTRAINDICATIONS."
"Combination Rebetol/Intron A therapy must not be used by women who are pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking combination Rebetol/Intron A therapy. Combination Rebetol/Intron A therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. ["It is also recommended that the patient be advised of the need to" deleted] Patients must perform a pregnancy test monthly during therapy and for 6 months posttherapy. Women of childbearing potential must be counseled about use of ["adequate" deleted] effective contraception (two reliable forms) prior to initiating therapy. Patients (male and female) must be advised of the teratogenic/embryocidal risks and ["should" deleted] must be ["advised" deleted] instructed to practice ["adequate" deleted] effective contraception during combination Rebetol/Intron A therapy and 6 for months posttherapy. Patients (male and female) should be advised to notify the physician immediately in the event of a pregnancy. (See CONTRAINDICATIONS.)"
Impairment of Fertility: Last paragraph revised (new text in italics) -
"Combination Rebetol/Intron therapy should be used with caution in fertile men. In ["a study" deleted] studies in mice to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of ["35" deleted] 15 to 150 mg/kg/day (estimated human equivalent of ["2.92" deleted] 1.25 - 12.5 mg/kg/day, based on body surface area adjustment for a 60 kg adult; ["0.2" deleted] 0.1 - 0.8 X the maximum human 24-hour dose of ribavirin) administered for 3 or 6 months, abnormalities in sperm occurred. Upon cessation of treatment, essentially total recovery from ribavririn-induced testicular toxicity was apparent within 1 or 2 spermatogenesis cycles. ["A follow-up study to further assess these findings is ongoing." deleted]"
"Because of the potential for beta-agonist interference with uterine contractility, use of Serevent Inhalation Aerosol for ["relief" deleted] prevention of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risks."
"The expected signs and symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the symptoms listed under ADVERSE REACTIONS, e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomnia."
Third paragraph, text added as new last sentence -
"Cardiac monitoring is recommended in cases of overdosage."
[Other information regarding these changes: December 1998 Letter]
"The reduction in systemic corticosteroid dose in patients receiving another leukotriene antagonist has been followed in rare cases by the occurrence of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy sometimes presenting itself as Churg-Strauss syndrome, a systemic eosinophilic vasculitis. Although a causal relationship with leukotriene receptor antagonism has not been established and the phenomenon was not observed in clinical trials with montelukast, caution and appropriate clinical monitoring are recommended when systemic corticosteroid reduction is considered in patients receiving Singulair."
deleted and replaced with -
Eosinophilic Conditions (new subsection): -
"In rare cases, patients on therapy with Singulair may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between SINGULAIR and these underlying conditions has not been established. (See ADVERSE REACTIONS)."
Pregnancy, Teratogenic Effects: Pregnancy Category B: Text added as new last paragraph -
"Merck & Co., Inc. maintains a registry to monitor the pregnancy outcomes of women exposed to Singulair while pregnant. Healthcare providers are encouraged to report any prenatal exposure to Singulair by calling the Pregnancy Registry at (800) 986-8999."
"In rare cases, patients on therapy with Singulair may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between Singulair and these underlying conditions has not been established. (See PRECAUTIONS, Eosinophilic Conditions)."
"Clinical studies of nisoldipine 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. Patients over 65 are expected to develop higher plasma concentrations of nisoldipine. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy."
"In a single controlled clinical trial, intranasal Synarel (nafarelin acetate) at a dose of 400 micrograms per day was shown to be clinically comparable to intramuscular leuprolide depot 3.75 mg monthly, for the treatment of the symptoms (dysmenorrhea, dyspareunia and pelvic pain) associated with endometriosis."
"After six months treatment with Synarel, bone mass as measured by dual x-ray bone densitometry (DEXA), decreased 3.2%. Mean total vertebral mass, re-examined by DEXA six months after completion of treatment, was 1.4% below pretreatment."
"Amplification of the vasodilatory effects of Tridil by sildenafil can result in severe hypotension. The time course and dose dependence of this interaction have not been studied. Appropriate supportive care has not been studied, but it seems reasonable to treat this as a nitrate overdose, with elevation of the extremities and with central volume expansion."
"They have been chosen for inclusion based on factors such as seriousness, frequency of reporting, possible causal connection to Trusopt, or a combination of these factors: signs and symptoms of systemic allergic reactions including angioedema, bronchospasm, pruritus, and urticaria; dizziness, paresthesia; ocular pain, transient myopia; dyspnea; contact dermatitis and throat irritation."
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