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Friday, September 23, 2016

Zofran Injection

Dosage Form: injection
FULL PRESCRIBING INFORMATION

Indications and Usage for Zofran Injection

Prevention of Nausea and Vomiting Associated with Initial and Repeat Courses of Emetogenic Cancer Chemotherapy

Zofran Injection is indicated for the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin [see Clinical Studies (14.1)].

ZOFRAN is approved for patients aged 6 months and older.

Prevention of Postoperative Nausea and/or Vomiting

Zofran Injection is indicated for the prevention of postoperative nausea and/or vomiting. As with other antiemetics, routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients in whom nausea and/or vomiting must be avoided postoperatively, Zofran Injection is recommended even when the incidence of postoperative nausea and/or vomiting is low. For patients who do not receive prophylactic Zofran Injection and experience nausea and/or vomiting postoperatively, Zofran Injection may be given to prevent further episodes [see Clinical Studies (14.3)].

ZOFRAN is approved for patients aged 1 month and older.

Zofran Injection Dosage and Administration

Prevention of Nausea and Vomiting Associated with Initial and Repeat Courses of Emetogenic Chemotherapy

Zofran Injection should be diluted in 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection before administration.

Adults

The recommended adult intravenous dosage of ZOFRAN is a single 32-mg dose or three 0.15-mg/kg doses. A single 32-mg dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. Efficacy of the 32-mg single dose beyond 24 hours has not been established. The recommended infusion rate should not be exceeded [see Overdosage(10)]. With the three-dose (0.15-mg/kg) regimen, the first dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. Subsequent doses (0.15 mg/kg) are administered 4 and 8 hours after the first dose of ZOFRAN.

Pediatrics

For pediatric patients 6 months through 18 years of age, the intravenous dosage of ZOFRAN is three 0.15-mg/kg doses [see Clinical Studies (14.1) and Clinical Pharmacology (12.3)]. The first dose is to be administered 30 minutes before the start of moderately to highly emetogenic chemotherapy. Subsequent doses (0.15 mg/kg) are administered 4 and 8 hours after the first dose of ZOFRAN. The drug should be infused intravenously over 15 minutes.

Prevention of Postoperative Nausea and Vomiting

Zofran Injection should not be mixed with solutions for which physical and chemical compatibility have not been established. In particular, this applies to alkaline solutions as a precipitate may form.

Adults

The recommended adult intravenous dosage of ZOFRAN is 4 mg undiluted administered intravenously in not less than 30 seconds, preferably over 2 to 5 minutes, immediately before induction of anesthesia, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring within 2 hours after surgery. Alternatively, 4 mg undiluted may be administered intramuscularly as a single injection for adults. While recommended as a fixed dose for patients weighing more than 40 kg, few patients above 80 kg have been studied. In patients who do not achieve adequate control of postoperative nausea and vomiting following a single, prophylactic, preinduction, intravenous dose of ondansetron 4 mg, administration of a second intravenous dose of 4 mg ondansetron postoperatively does not provide additional control of nausea and vomiting.

Pediatrics

For pediatric patients 1 month through 12 years of age, the dosage is a single 0.1-mg/kg dose for patients weighing 40 kg or less, or a single 4-mg dose for patients weighing more than 40 kg. The rate of administration should not be less than 30 seconds, preferably over 2 to 5 minutes immediately prior to or following anesthesia induction, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring shortly after surgery. Prevention of further nausea and vomiting was only studied in patients who had not received prophylactic ZOFRAN.

Stability and Handling

After dilution, do not use beyond 24 hours. Although Zofran Injection is chemically and physically stable when diluted as recommended, sterile precautions should be observed because diluents generally do not contain preservative.

Zofran Injection is stable at room temperature under normal lighting conditions for 48 hours after dilution with the following intravenous fluids: 0.9% Sodium Chloride Injection, 5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, and 3% Sodium Chloride Injection.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

Precaution: Occasionally, ondansetron precipitates at the stopper/vial interface in vials stored upright. Potency and safety are not affected. If a precipitate is observed, resolubilize by shaking the vial vigorously.

Dosage Adjustment for Patients with Impaired Hepatic Function

In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), a single maximal daily dose of 8 mg infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is recommended. There is no experience beyond first-day administration of ondansetron in these patients [see Clinical Pharmacology (12.3)].

Dosage Forms and Strengths

Zofran Injection, 2 mg/mL is a clear, colorless, nonpyrogenic, sterile solution available as a 2 mL single dose vial and 20 mL multidose vial.

Contraindications

Zofran Injection is contraindicated for patients known to have hypersensitivity (e.g., anaphylaxis) to this product or any of its components. Anaphylactic reactions have been reported in patients taking ondansetron. [See Adverse Reactions (6.2)].

The concomitant use of apomorphine with ondansetron is contraindicated based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron.

Warnings and Precautions

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis and bronchospasm, have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists.

Electrocardiographic Changes

ECG changes including QT interval prolongation have been seen in patients receiving ondansetron. In addition, post-marketing cases of Torsade de Pointes have been reported in patients using ondansetron. Avoid ZOFRAN in patients with congenital long QT syndrome. ECG monitoring is recommended in patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias, or patients taking other medicinal products that lead to QT prolongation.

Masking of Progressive Ileus and Gastric Distension

The use of ZOFRAN in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and gastric distention.

Effect on Peristalsis

ZOFRAN is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The following adverse reactions have been reported in clinical trials of adult patients treated with ondansetron, the active ingredient of intravenous ZOFRAN at a dosage of three 0.15-mg/kg doses or as a single 32-mg dose. A causal relationship to therapy with ZOFRAN (ondansetron) was unclear in many cases.

Chemotherapy-Induced Nausea and Vomiting

Table 1. Adverse Reactions Reported in > 5% of Adult Patients Who Received Ondansetron at a Dosage of Three 0.15-mg/kg Doses or as a Single 32-mg Dose
	Number of Adult Patients With Reaction
Adverse Reaction	Zofran Injection 0.15 mg/kg x 3 n = 419	Zofran Injection 32 mg x 1 n = 220	Metoclopramide n = 156	Placebo n = 34
Diarrhea	16%	8%	44%	18%
Headache	17%	25%	7%	15%
Fever	8%	7%	5%	3%

Cardiovascular

Rare cases of angina (chest pain), electrocardiographic alterations, hypotension, and tachycardia have been reported.

Gastrointestinal

Constipation has been reported in 11% of chemotherapy patients receiving multiday ondansetron.

Hepatic

In comparative trials in cisplatin chemotherapy patients with normal baseline values of aspartate transaminase (AST) and alanine transaminase (ALT), these enzymes have been reported to exceed twice the upper limit of normal in approximately 5% of patients. The increases were transient and did not appear to be related to dose or duration of therapy. On repeat exposure, similar transient elevations in transaminase values occurred in some courses, but symptomatic hepatic disease did not occur.

Integumentary

Rash has occurred in approximately 1% of patients receiving ondansetron.

Neurological

There have been rare reports consistent with, but not diagnostic of, extrapyramidal reactions in patients receiving Zofran Injection, and rare cases of grand mal seizure.

Other

Rare cases of hypokalemia have been reported.

Postoperative Nausea and Vomiting

The adverse reactions in Table 2 have been reported in ≥ 2% of adults receiving ondansetron at a dosage of 4 mg intravenous over 2 to 5 minutes in clinical trials.

Table 2. Adverse Reactions Reported in ≥ 2% (and With Greater Frequency than the Placebo Group) of Adult Patients Receiving Ondansetron at a Dosage of 4 mg Intravenous over 2 to 5 Minutes
Adverse Reactiona,b	Zofran Injection 4 mg Intravenous n = 547 patients	Placebo n = 547 patients
Headache	92 (17%)	77 (14%)
Drowsiness/sedation	44 (8%)	37 (7%)
Injection site reaction	21 (4%)	18 (3%)
Fever	10 (2%)	6 (1%)
Cold sensation	9 (2%)	8 (1%)
Pruritus	9 (2%)	3 (< 1%)
Paresthesia	9 (2%)	2 (< 1%)

a Adverse Reactions: Rates of these reactions were not significantly different in the ondansetron and placebo groups

b Patients were receiving multiple concomitant perioperative and postoperative medications

Pediatric Use

Rates of adverse reactions were similar in both the ondansetron and placebo groups in pediatric patients receiving ondansetron (a single 0.1-mg/kg dose for pediatric patients weighing 40 kg or less, or 4 mg for pediatric patients weighing more than 40 kg) administered intravenously over at least 30 seconds. Diarrhea was seen more frequently in patients taking ZOFRAN (2%) compared to placebo (<1%) in the 1 month to 24 month age group. These patients were receiving multiple concomitant perioperative and postoperative medications.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ondansetron. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to ondansetron.

Cardiovascular

Arrhythmias (including ventricular and supraventricular tachycardia, premature ventricular contractions, and atrial fibrillation), bradycardia, electrocardiographic alterations (including second-degree heart block, QT/QTc interval prolongation, and ST segment depression), palpitations, and syncope. Rarely and predominantly with intravenous ondansetron, transient ECG changes including QT/QTc interval prolongation have been reported [see Warnings and Precautions (5.2)].

General

Flushing. Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylatic reactions, angioedema, bronchospasm, cardiopulmonary arrest, hypotension, laryngeal edema, laryngospasm, shock, shortness of breath, stridor) have also been reported. A positive lymphocyte transformation test to ondansetron has been reported, which suggests immunologic sensitivity to ondansetron.

Hepatobiliary

Liver enzyme abnormalities have been reported. Liver failure and death have been reported in patients with cancer receiving concurrent medications including potentially hepatotoxic cytotoxic chemotherapy and antibiotics.

Local Reactions

Pain, redness, and burning at site of injection.

Lower Respiratory

Hiccups

Neurological

Oculogyric crisis, appearing alone, as well as with other dystonic reactions. Transient dizziness during or shortly after intravenous infusion.

Skin

Urticaria

Eye Disorders

Cases of transient blindness, predominantly during intravenous administration, have been reported. These cases of transient blindness were reported to resolve within a few minutes up to 48 hours. Transient blurred vision, in some cases associated with abnormalities of accommodation, have also been reported.

Drug Interactions

Drugs Affecting Cytochrome P-450 Enzymes

Ondansetron does not appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver . Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron [see Clinical Pharmacology (12.3)]. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs.

Apomorphine

Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of apomorphine with ondansetron is contradindicated [see Contraindications (4)].

Phenytoin, Carbamazepine, and Rifampin

In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs [see Clinical Pharmacology (12.3)].

Tramadol

Although there are no data on pharmacokinetic drug interactions between ondansetron and tramadol, data from two small studies indicate that concomitant use of ondansetron may result in reduced analgesic activity of tramadol. Patients on concomitant ondansetron self administered tramadol more frequently in these studies, leading to an increased cumulative dose in patient controlled administration (PCA) of tramadol.

Chemotherapy

In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron.

In a crossover study in 76 pediatric patients, intravenous ondansetron did not increase blood levels of high-dose methotrexate.

Temazepam

The coadministration of ondansetron had no effect on the pharmacokinetics and pharmacodynamics of temazepam.

Alfentanil and Atracurium

Ondansetron does not alter the respiratory depressant effects produced by alfentanil or the degree of neuromuscular blockade produced by atracurium. Interactions with general or local anesthetics have not been studied.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B. Reproduction studies have been performed in pregnant rats and rabbits at intravenous doses up to 4 mg/kg per day (approximately 1 and 2 times the recommended human intravenous dose of 32 mg/day, respectively, based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to ondansetron. 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.

Nursing Mothers

Ondansetron is excreted in the breast milk of rats. It is not known whether ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ondansetron is administered to a nursing woman.

Pediatric Use

Little information is available about the use of ondansetron in pediatric surgical patients younger than 1 month of age. [See Clinical Studies(14.2)]. Little information is available about the use of ondansetron in pediatric cancer patients younger than 6 months of age. [See Clinical Studies(14.1) and Dosage and Administration (2)].

The clearance of ondansetron in pediatric patients 1 month to 4 months of age is slower and the half-life is ~2.5 fold longer than patients who are > 4 to 24 months of age. As a precaution, it is recommended that patients less than 4 months of age receiving this drug be closely monitored. [See Clinical Pharmacology (12.3)].

Geriatric Use

Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in US- and foreign-controlled clinical trials, 862 were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment is not needed in patients over the age of 65 [see Clinical Pharmacology (12.3)].

Hepatic Impairment

In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), clearance is reduced and apparent volume of distribution is increased with a resultant increase in plasma half-life [see Clinical Pharmacology (12.3)]. In such patients, a total daily dose of 8 mg should not be exceeded [see Dosage and Administration (2.3)].

Renal Impairment

Although plasma clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min), no dosage adjustment is recommended [see Clinical Pharmacology (12.3)].

Drug Abuse and Dependence

Animal studies have shown that ondansetron is not discriminated as a benzodiazepine nor does it substitute for benzodiazepines in direct addiction studies.

Overdosage

There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy. Individual intravenous doses as large as 150 mg and total daily intravenous doses as large as 252 mg have been inadvertently administered without significant adverse events. These doses are more than 10 times the recommended daily dose.

In addition to the adverse reactions listed above, the following events have been described in the setting of ondansetron overdose: “Sudden blindness” (amaurosis) of 2 to 3 minutes’ duration plus severe constipation occurred in one patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in another patient that took 48 mg of ondansetron hydrochloride tablets. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed. In all instances, the events resolved completely.

Zofran Injection Description

The active ingredient of Zofran Injection is ondansetron hydrochloride, a selective blocking agent of the serotonin 5-HT3 receptor type. Its chemical name is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate. It has the following structural formula:

The empirical formula is C18H19N3O•HCl•2H2O, representing a molecular weight of 365.9.

Ondansetron HCl is a white to off-white powder that is soluble in water and normal saline.

Each 1 mL of aqueous solution in the 2 mL single-dose vial contains 2 mg of ondansetron as the hydrochloride dihydrate; 9 mg of sodium chloride, USP; and 0.5 mg of citric acid monohydrate, USP and 0.25 mg of sodium citrate dihydrate, USP as buffers in Water for Injection, USP.

Each 1 mL of aqueous solution in the 20 mL multidose vial contains 2 mg of ondansetron as the hydrochloride dihydrate; 8.3 mg of sodium chloride, USP; 0.5 mg of citric acid monohydrate, USP and 0.25 mg of sodium citrate dihydrate, USP as buffers; and 1.2 mg of methylparaben, NF and 0.15 mg of propylparaben, NF as preservatives in Water for Injection, USP.

Zofran Injection is a clear, colorless, nonpyrogenic, sterile solution for intravenous use. The pH of the injection solution is 3.3 to 4.0.

Zofran Injection - Clinical Pharmacology

Mechanism of Action

Ondansetron is a selective 5-HT3 receptor antagonist. While ondansetron’s mechanism of action has not been fully characterized, it is not a dopamine-receptor antagonist.

Pharmacodynamics

In normal volunteers, single intravenous doses of 0.15 mg/kg of ondansetron had no effect on esophageal motility, gastric motility, lower esophageal sphincter pressure, or small intestinal transit time. In another study in six normal male volunteers, a 16-mg dose infused over 5 minutes showed no effect of the drug on cardiac output, heart rate, stroke volume, blood pressure, or electrocardiogram (ECG). However, no thorough QT study has been conducted with ondansetron. Multiday administration of ondansetron has been shown to slow colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin concentrations.

In a gender-balanced pharmacodynamic study (n = 56), ondansetron 4 mg administered intravenously or intramuscularly was dynamically similar in the prevention of nausea and vomiting using the ipecacuanha model of emesis.

Pharmacokinetics

In normal adult volunteers, the following mean pharmacokinetic data have been determined following a single 0.15-mg/kg intravenous dose.

Table 3. Pharmacokinetics in Normal Adult Volunteers
Age-group (years)	n	Peak Plasma Concentration (ng/mL)	Mean Elimination Half-life (h)	Plasma Clearance (L/h/kg)
19-40	11	102	3.5	0.381
61-74	12	106	4.7	0.319
≥ 75	11	170	5.5	0.262

Absorption

A study was performed in normal volunteers (n = 56) to evaluate the pharmacokinetics of a single 4-mg dose administered as a 5-minute infusion compared to a single intramuscular injection. Systemic exposure as measured by mean AUC were equivalent, with values of 156 [95% CI 136, 180] and 161 [95% CI 137, 190] ng•h/mL for intravenous and intramuscular groups, respectively. Mean peak plasma concentrations were 42.9 [95% CI 33.8, 54.4] ng/mL at 10 minutes after intravenous infusion and 31.9 [95% CI 26.3, 38.6] ng/mL at 41 minutes after intramuscular injection. In normal volunteers (19 to 39 years old, n = 23), the peak plasma concentration was 264 ng/mL following a single 32-mg dose administered as a 15-minute intravenous infusion.

Distribution

Plasma protein binding of ondansetron as measured in vitro was 70% to 76%, over the pharmacologic concentration range of 10 to 500 ng/mL. Circulating drug also distributes into erythrocytes.

Metabolism

Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation.

Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron. The metabolites are observed in the urine.

In vitro metabolism studies have shown that ondansetron is a substrate for multiple human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 plays a predominant role while formation of the major in vivo metabolites is apparently mediated by CYP1A2. The role of CYP2D6 in ondansetron in vivo metabolism is relatively minor.

The pharmacokinetics of intravenous ondansetron did not differ between subjects who were poor metabolisers of CYP2D6 and those who were extensive metabolisers of CYP2D6, further supporting the limited role of CYP2D6 in ondansetron disposition in vivo.

Elimination

In normal volunteers (19 to 39 years old, n = 23), following a single 32-mg dose administered as a 15-minute intravenous infusion, the mean elimination half-life was 4.1 hours. Systemic exposure to 32 mg of ondansetron was not proportional to dose as measured by comparing dose-normalized AUC values to an 8-mg dose. This is consistent with a small decrease in systemic clearance with increasing plasma concentrations.

In adult cancer patients, the mean elimination half-life was 4.0 hours, and there was no difference in the multidose pharmacokinetics over a 4-day period.

Geriatrics

A reduction in clearance and increase in elimination half-life are seen in patients over 75 years of age. In clinical trials with cancer patients, safety and efficacy were similar in patients over 65 years of age and those under 65 years of age; there was an insufficient number of patients over 75 years of age to permit conclusions in that age-group. No dosage adjustment is recommended in the elderly.

Pediatrics

Pharmacokinetic samples were collected from 74 cancer patients 6 to 48 months of age, who received a dose of 0.15 mg/kg of intravenous ondansetron every 4 hours for 3 doses during a safety and efficacy trial. These data were combined with sequential pharmacokinetics data from 41 surgery patients 1 month to 24 months of age, who received a single dose of 0.1 mg/kg of intravenous ondansetron prior to surgery with general anesthesia, and a population pharmacokinetic analysis was performed on the combined data set. The results of this analysis are included in Table 4 and are compared to the pharmacokinetic results in cancer patients 4 to 18 years of age.

Table 4. Pharmacokinetics in Pediatric Cancer Patients 1 Month to 18 Years of Age
Subjects and Age Group	N	CL (L/h/kg)	Vdss (L/kg)	T½ (h)
		Geometric Mean		Mean
Pediatric Cancer Patients 4 to 18 years of age	N = 21	0.599	1.9	2.8
Population PK Patientsa 1 month to 48 months of age	N = 115	0.582	3.65	4.9

a Population PK (Pharmacokinetic) Patients: 64% cancer patients and 36% surgery patients.

Based on the population pharmacokinetic analysis, cancer patients 6 to 48 months of age who receive a dose of 0.15 mg/kg of intravenous ondansetron every 4 hours for 3 doses would be expected to achieve a systemic exposure (AUC) consistent with the exposure achieved in previous pediatric studies in cancer patients (4 to 18 years of age) at similar doses.

In a study of 21 pediatric patients (3 to 12 years of age) who were undergoing surgery requiring anesthesia for a duration of 45 minutes to 2 hours, a single intravenous dose of ondansetron, 2 mg (3 to 7 years) or 4 mg (8 to 12 years), was administered immediately prior to anesthesia induction. Mean weight-normalized clearance and volume of distribution values in these pediatric surgical patients were similar to those previously reported for young adults. Mean terminal half-life was slightly reduced in pediatric patients (range, 2.5 to 3 hours) in comparison with adults (range, 3 to 3.5 hours).

In a study of 51 pediatric patients (1 month to 24 months of age) who were undergoing surgery requiring general anesthesia, a single intravenous dose of ondansetron, 0.1 or 0.2 mg/kg, was administered prior to surgery. As shown in Table 5, the 41 patients with pharmacokinetic data were divided into 2 groups, patients 1 month to 4 months of age and patients 5 to 24 months of age, and are compared to pediatric patients 3 to 12 years of age.

Table 5. Pharmacokinetics in Pediatric Surgery Patients 1 Month to 12 Years of Age
Subjects and Age Group	N	CL (L/h/kg)	Vdss (L/kg)	T½ (h)
		Geometric Mean		Mean
Pediatric Surgery Patients 3 to 12 years of age	N = 21	0.439	1.65	2.9
Pediatric Surgery Patients 5 to 24 months of age	N = 22	0.581	2.3	2.9
Pediatric Surgery Patients 1 month to 4 months of age	N = 19	0.401	3.5	6.7

In general, surgical and cancer pediatric patients younger than 18 years tend to have a higher ondansetron clearance compared to adults leading to a shorter half-life in most pediatric patients. In patients 1 month to 4 months of age, a longer half-life was observed due to the higher volume of distribution in this age group.

In a study of 21 pediatric cancer patients (4 to 18 years of age) who received three intravenous doses of 0.15 mg/kg of ondansetron at 4-hour intervals, patients older than 15 years of age exhibited ondansetron pharmacokinetic parameters similar to those of adults.

Renal Impairment

Due to the very small contribution (5%) of renal clearance to the overall clearance, renal impairment was not expected to significantly influence the total clearance of ondansetron. However, ondansetron mean plasma clearance was reduced by about 41% in patients with severe renal impairment (creatinine clearance < 30 mL/min). This reduction in clearance is variable and was not consistent with an increase in half-life. No reduction in dose or dosing frequency in these patients is warranted.

Hepatic Impairment

In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared to 5.7 hours in those without hepatic impairment. In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), clearance is reduced 2-fold to 3-fold and apparent volume of distribution is increased with a resultant increase in half-life to 20 hours. In patients with severe hepatic impairment, a total daily dose of 8 mg should not be exceeded.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenic effects were not seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 and 30 mg/kg per day, respectively (approximately 2.5 and 3.8 times the recommended human intravenous dose of 32 mg/day, based on body surface area).

Ondansetron was not mutagenic in standard tests for mutagenicity.

Oral administration of ondansetron up to 15 mg/kg per day (approximately 3.8 times the recommended human intravenous dose, based on body surface area) did not affect fertility or general reproductive performance of male and female rats.

Clinical Studies

The clinical efficacy of ondansetron hydrochloride, the active ingredient of ZOFRAN, was assessed in clinical trials as described below.

Chemotherapy-Induced Nausea and Vomiting

Adults

In a double-blind study of three different dosing regimens of Zofran Injection, 0.015 mg/kg, 0.15 mg/kg, and 0.30 mg/kg, each given three times during the course of cancer chemotherapy, the 0.15-mg/kg dosing regimen was more effective than the 0.015-mg/kg dosing regimen. The 0.30-mg/kg dosing regimen was not shown to be more effective than the 0.15-mg/kg dosing regimen.

Cisplatin-Based Chemotherapy

In a double-blind study in 28 patients, Zofran Injection (three 0.15-mg/kg doses) was significantly more effective than placebo in preventing nausea and vomiting induced by cisplatin-based chemotherapy. Therapeutic response was as shown in Table 6.

Table 6. Therapeutic Response in Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-Day Cisplatin Therapya in Adults
	Zofran Injection (0.15 mg/kg x 3)	Placebo	P Valueb
Number of patients	14	14
Treatment response 0 Emetic episodes 1-2 Emetic episodes 3-5 Emetic episodes More than 5 emetic episodes/rescued	2 (14%) 8 (57%) 2 (14%) 2 (14%)	0 (0%) 0 (0%) 1 (7%) 13 (93%)	0.001
Median number of emetic episodes	1.5	Undefinedc
Median time to first emetic episode (h)	11.6	2.8	0.001
Median nausea scores (0-100)d	3

Z-Tuss 2

Generic Name: chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine (KLOR fen IR a meen, gwye FEN e sin, HYE droe KOE done, SOO doe ee FED rin)

Brand Names: Z-Tuss 2

What is Z-Tuss 2 (chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine)?

Chlorpheniramine is an antihistamine that reduces the natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.

Guaifenesin is an expectorant. It helps loosen mucus congestion in your chest and throat, making it easier to cough out through your mouth.

Hydrocodone is a narcotic cough suppressant similar to codeine. Hydrocodone affects the signals in the brain that trigger cough reflex.

Pseudoephedrine is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose).

The combination of chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine is used to treat sinus congestion, runny nose, sneezing, itching, watery eyes, cough, and chest congestion caused by allergies, upper respiratory infections, or the common cold.

This medication will not treat a cough that is caused by smoking, asthma, or emphysema.

Chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Z-Tuss 2 (chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine)?

Do not use this medication if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take a cough and cold medicine before the MAO inhibitor has cleared from your body. Hydrocodone may be habit-forming and should be used only by the person it was prescribed for. Never share this medication with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it. Do not give this medication to a child younger than 6 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Ask a doctor or pharmacist before using any other cough, cold, allergy, or sleep medicine. Chlorpheniramine, guaifenesin, and pseudoephedrine are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains an antihistamine, decongestant, or expectorant.

What should I discuss with my healthcare provider before taking Z-Tuss 2 (chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine)?

Do not use a cough or cold medicine if you have used an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you take cough or cold medicine before the MAO inhibitor has cleared from your body.

To make sure you can safely take this medication, tell your doctor if you have any of these other conditions:

heart disease or high blood pressure;

asthma, COPD, sleep apnea, or other breathing disorders;

diabetes;

glaucoma;

a thyroid disorder;

epilepsy or other seizure disorder;

kidney or liver disease;

enlarged prostate or urination problems;

a stomach or intestinal disorder;

a history of head injury or brain tumor;

Addison's disease or other adrenal gland disorders; or

a history of drug or alcohol addiction.

FDA pregnancy category C. It is not known whether this medication will harm an unborn baby. Hydrocodone may cause addiction or withdrawal symptoms in a newborn if the mother takes the medication during pregnancy. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. This medication may pass into breast milk and could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Hydrocodone may be habit-forming and should be used only by the person it was prescribed for. Never share this medication with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it. Older adults may be more likely to have side effects from this medication.

How should I take Z-Tuss 2 (chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label. Cough or cold medicine is usually taken for only a short time until your symptoms clear up.

Do not give this medication to a child younger than 6 years old. Always ask a doctor before giving a cough or cold medicine to a child. Death can occur from the misuse of cough and cold medicines in very young children. Take this medication with food or milk if it upsets your stomach.

Measure liquid medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.

Drink plenty of water or other fluids to help loosen congestion and prevent dry mouth or throat. Talk with your doctor if your symptoms do not improve after 7 days of treatment, or if you have a fever with a headache, cough, or skin rash.

If you need surgery, tell the surgeon ahead of time if you have taken a cold medicine within the past few days.

This medication can cause you to have unusual results with allergy skin tests. Tell any doctor who treats you that you are taking an antihistamine.

Store at room temperature, away from heat, light, and moisture. Keep track of the amount of medicine used from each new bottle. Hydrocodone is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription.

What happens if I miss a dose?

Since cough or cold medicine is usually taken only as needed, you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of hydrocodone can be fatal.

Overdose symptoms may include fast or uneven heart rate, extreme drowsiness, feeling restless or hyperactive, confusion, hallucinations, warmth or redness in your face, cold or clammy skin, blue-colored lips or fingernails, weak or shallow breathing, fainting, or seizure (convulsions).

What should I avoid while taking Z-Tuss 2 (chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine)?

This medication may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert. Drinking alcohol can increase certain side effects of chlorpheniramine, guaifenesin, or hydrocodone. Ask a doctor or pharmacist before using any other cough, cold, allergy, or sleep medicine. Chlorpheniramine, guaifenesin, and pseudoephedrine are contained in many combination medicines. Taking certain products together can cause you to get too much of a certain drug. Check the label to see if a medicine contains an antihistamine, decongestant, or expectorant.

Z-Tuss 2 (chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop taking this medication and call your doctor at once if you have a serious side effect such as:

severe dizziness, fainting, anxiety, restless feeling, nervousness, or tremor;

fast, pounding, or uneven heartbeats;

slow heartbeat, weak pulse, shallow breathing;

confusion, hallucinations, unusual thoughts or behavior;

ringing in your ears;

painful or difficult urination;

pale skin, easy bruising or bleeding, unusual weakness; or

increased blood pressure (severe headache, blurred vision, trouble concentrating, chest pain, numbness, seizure).

Less serious side effects may include:

dizziness, drowsiness, headache;

blurred vision;

dry mouth, nose, or throat;

nausea, stomach pain, constipation; or

restless or excitability (especially in children).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Z-Tuss 2 (chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine)?

Before taking this medication, tell your doctor if you regularly use other medicines that make you sleepy (such as narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). They can add to sleepiness caused by chlorpheniramine, guaifenesin, or hydrocodone.

Tell your doctor about all other medicines you use, especially:

sibutramine (Meridia);

memantine (Namenda);

methyldopa (Aldomet);

reserpine;

an antidepressant such as amitriptyline (Elavil), clomipramine (Anafranil), imipramine (Janimine, Tofranil), and others; or

a beta-blocker such as atenolol (Tenormin), carteolol (Cartrol), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), timolol (Blocadren), and others.

This list is not complete and other drugs may interact with chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Z-Tuss 2 resources

Z-Tuss 2 Drug Interactions
Z-Tuss 2 Support Group
0 Reviews for Z-Tuss 2 - Add your own review/rating

Compare Z-Tuss 2 with other medications

Cold Symptoms
Cough and Nasal Congestion

Where can I get more information?

Your pharmacist can provide more information about chlorpheniramine, guaifenesin, hydrocodone, and pseudoephedrine.

Zinotic Drops

Pronunciation: KLOR-oh-ZYE-le-nol/pram-OX-een/GLIS-er-in/zink
Generic Name: Chloroxylenol/Pramoxine/Glycerin/Zinc Ear Drops
Brand Name: Examples include Zinotic and Zinotic ES

Zinotic Drops are used for:

Treating certain infections of the outer ear. It is also used to control pain and itching caused by these infections. It may also be used for other conditions as determined by your doctor.

Zinotic Drops are an antibacterial, anesthetic, and skin protectant combination. It works by killing sensitive bacteria or fungi and temporarily relieving ear pain. An ingredient in Zinotic Drops also helps the medicine penetrate into the skin.

Do NOT use Zinotic Drops if:

you are allergic to any ingredient in Zinotic Drops

your eardrum is perforated

Contact your doctor or health care provider right away if any of these apply to you.

Before using Zinotic Drops:

Some medical conditions may interact with Zinotic Drops. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

if you are pregnant, planning to become pregnant, or are breast-feeding

if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement

if you have allergies to medicines, foods, or other substances

if you have other ear problems

Some MEDICINES MAY INTERACT with Zinotic Drops. Because little, if any, of Zinotic Drops are absorbed into the blood, the risk of it interacting with another medicine is low.

Ask your health care provider if Zinotic Drops may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Zinotic Drops:

Use Zinotic Drops as directed by your doctor. Check the label on the medicine for exact dosing instructions.

Zinotic Drops are only for the ear. Do not get it in your eyes, nose, or mouth. If you get Zinotic Drops in any of these areas, rinse well with cool water.

Thoroughly clean and dry the outer ear before using Zinotic Drops.

Before using, hold the ear drop container in your hand for 1 or 2 minutes to avoid dizziness that may result from putting cold drops into the ear.

Lie down or tilt your head so that the affected ear faces up. For adults, gently pull the earlobe up and back to straighten the ear canal. For children, gently pull the earlobe down and back to straighten the ear canal. Drop the medicine into the ear canal. Keep the ear facing up for 5 minutes so the medicine can run to the bottom of the ear canal. A clean cotton plug may be gently inserted into the ear canal to prevent medicine from leaking out. Repeat, if necessary, in the other ear.

To prevent germs from contaminating your medicine, do not touch the applicator to any surface, including the ear. Keep the container tightly closed.

Wash your hands immediately after using Zinotic Drops.

Using Zinotic Drops at the same times each day will help you remember to use it.

To clear up your infection completely, use Zinotic Drops for the full course of treatment. Keep using it even if you feel better in a few days.

Do not use Zinotic Drops if it turns brown or contains particles.

If you miss a dose of Zinotic Drops, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Zinotic Drops.

Important safety information:

Do NOT use more than the recommended dose or use for longer than 10 days without checking with your doctor.

If your symptoms do not get better within 10 days or if they get worse, check with your doctor.

Do not use Zinotic Drops for other ear problems without first checking with your doctor.

Talk with your doctor before using any other medicines in your ear.

Be sure to use Zinotic Drops for the full course of therapy. If you do not, Zinotic Drops may not clear up your infection completely. The bacteria could also become less sensitive to this or other medicines. This could make the infection harder to treat in the future.

Long-term or repeated use of Zinotic Drops may cause a second infection. Tell your doctor if signs of a second infection occur. Your medicine may need to be changed to treat this.

Zinotic Drops may cause harm if it is swallowed. If you may have taken it by mouth, contact your poison control center or emergency room right away.

Zinotic Drops should be used with extreme caution in CHILDREN younger than 2 years old; safety and effectiveness in these children have not been confirmed.

PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Zinotic Drops while you are pregnant. It is not known if Zinotic Drops are found in breast milk. If you are or will be breast-feeding while you use Zinotic Drops, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Zinotic Drops:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Mild burning, irritation, redness, stinging, or dryness at the affected area.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); pain or swelling at the affected area; severe or persistent burning, irritation, redness, or stinging.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Zinotic side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Zinotic Drops:

Store Zinotic Drops at room temperature, between 68 and 77 degrees F (20 and 25 degrees C), in the original container. Do not freeze. Store away from heat and light. Keep Zinotic Drops out of the reach of children and away from pets.

General information:

If you have any questions about Zinotic Drops, please talk with your doctor, pharmacist, or other health care provider.

Zinotic Drops are to be used only by the patient for whom it is prescribed. Do not share it with other people.

If your symptoms do not improve or if they become worse, check with your doctor.

Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Zinotic Drops. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

More Zinotic resources

Zinotic Side Effects (in more detail)
Zinotic Use in Pregnancy & Breastfeeding
Zinotic Support Group
1 Review for Zinotic - Add your own review/rating

Compare Zinotic with other medications

Acute Otitis Externa
Otitis Externa

Zinc/Vitamin B12/Vitamin C Lozenges

Pronunciation: zink/VYE-ta-min
Generic Name: Zinc/Vitamin B12/Vitamin C
Brand Name: Zinc Plus Lozenges

Zinc/Vitamin B12/Vitamin C Lozenges are used for:

Treating or preventing low levels of vitamin B, C, and zinc. It may also be used for other conditions as determined by your doctor.

Zinc/Vitamin B12/Vitamin C Lozenges are a vitamin and mineral combination. It works by providing vitamins and minerals to the body to help meet nutritional needs.

The FDA has not approved Zinc/Vitamin B12/Vitamin C Lozenges to treat these conditions.

Do NOT use Zinc/Vitamin B12/Vitamin C Lozenges if:

you are allergic to any ingredient in Zinc/Vitamin B12/Vitamin C Lozenges

Contact your doctor or health care provider right away if any of these apply to you.

Before using Zinc/Vitamin B12/Vitamin C Lozenges:

Some medical conditions may interact with Zinc/Vitamin B12/Vitamin C Lozenges. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you

if you are pregnant, planning to become pregnant, or are breast-feeding

if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement

if you have allergies to medicines, foods, or other substances

Some MEDICINES MAY INTERACT with Zinc/Vitamin B12/Vitamin C Lozenges. However, no specific interactions with Zinc/Vitamin B12/Vitamin C Lozenges are known at this time.

Ask your health care provider if Zinc/Vitamin B12/Vitamin C Lozenges may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Zinc/Vitamin B12/Vitamin C Lozenges:

Use Zinc/Vitamin B12/Vitamin C Lozenges as directed by your doctor. Check the label on the medicine for exact dosing instructions.

Take Zinc/Vitamin B12/Vitamin C Lozenges by mouth with food.

Do not swallow, crush, or chew lozenges. Place the lozenge in mouth and allow it to slowly dissolve. Do not eat, drink, or smoke while the lozenge is dissolving.

Do not eat or drink fruit juices Â½ an hour before or after dissolving the lozenge because it may decrease the effectiveness of Zinc/Vitamin B12/Vitamin C Lozenges.

Do not take tetracyclines (eg, doxycycline) within 2 hours before or after you take Zinc/Vitamin B12/Vitamin C Lozenges.

If you miss a dose of Zinc/Vitamin B12/Vitamin C Lozenges, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Zinc/Vitamin B12/Vitamin C Lozenges.

Important safety information:

Do not take large doses of vitamins (megadoses or megavitamin therapy) while you use Zinc/Vitamin B12/Vitamin C Lozenges unless your doctor tells you to.

Zinc/Vitamin B12/Vitamin C Lozenges has zinc in it. Before you start any new medicine, check the label to see if it has zinc in it too. If it does or if you are not sure, check with your doctor or pharmacist.

Zinc/Vitamin B12/Vitamin C Lozenges should be used with extreme caution in CHILDREN; they may be more likely to chew or choke on the lozenges.

PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Zinc/Vitamin B12/Vitamin C Lozenges while you are pregnant. It is not known if Zinc/Vitamin B12/Vitamin C Lozenges are found in breast milk. If you are or will be breast-feeding while you use Zinc/Vitamin B12/Vitamin C Lozenges, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Zinc/Vitamin B12/Vitamin C Lozenges:

All medicines may cause side effects, but many people have no, or minor, side effects. No COMMON side effects have been reported with Zinc/Vitamin B12/Vitamin C Lozenges. Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue).

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Zinc/Vitamin B12/Vitamin C Lozenges:

Store Zinc/Vitamin B12/Vitamin C Lozenges at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Zinc/Vitamin B12/Vitamin C Lozenges out of the reach of children and away from pets.

General information:

If you have any questions about Zinc/Vitamin B12/Vitamin C Lozenges, please talk with your doctor, pharmacist, or other health care provider.

Zinc/Vitamin B12/Vitamin C Lozenges are to be used only by the patient for whom it is prescribed. Do not share it with other people.

If your symptoms do not improve or if they become worse, check with your doctor.

Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Zinc/Vitamin B12/Vitamin C Lozenges. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

More Zinc/Vitamin B12/Vitamin C resources

Zinc/Vitamin B12/Vitamin C Use in Pregnancy & Breastfeeding
Zinc/Vitamin B12/Vitamin C Drug Interactions
Zinc/Vitamin B12/Vitamin C Support Group
4 Reviews for Zinc/Vitamin B12/Vitamin C - Add your own review/rating

Compare Zinc/Vitamin B12/Vitamin C with other medications

Vitamin/Mineral Supplementation and Deficiency

Zovirax Topical

Generic Name: acyclovir (Topical route)

ay-SYE-kloe-vir

Commonly used brand name(s)

In the U.S.

Zovirax

In Canada

Acyclovir

Available Dosage Forms:

Cream

Ointment

Therapeutic Class: Antiviral

Pharmacologic Class: Viral DNA Polymerase Inhibitor

Chemical Class: Guanosine Nucleoside Analog

Uses For Zovirax

Acyclovir belongs to the family of medicines called antivirals. Antivirals are used to treat infections caused by viruses. Usually they work for only one kind or group of virus infections.

Topical acyclovir is used to treat the symptoms of herpes simplex virus infections of the skin, mucous membranes, and genitals (sex organs). Although topical acyclovir will not cure herpes simplex, it may help relieve the pain and discomfort and may help the sores (if any) heal faster. Topical acyclovir may also be used for other conditions as determined by your doctor.

Acyclovir is available only with your doctor's prescription.

Before Using Zovirax

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Studies on this medicine have been done only in adult patients, and there is no specific information comparing use of topical acyclovir in children with use in other age groups.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults. Although there is no specific information comparing the use of topical acyclovir in the elderly with use in other age groups, this medicine is not expected to cause different side effects or problems in older people than it does in younger adults.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Tizanidine

Varicella Virus Vaccine

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Fosphenytoin

Phenytoin

Valproic Acid

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Proper Use of Zovirax

Acyclovir may come with patient information about herpes simplex infections. Read this information carefully. If you have any questions, check with your health care professional.

Do not use this medicine in the eyes.

Acyclovir is best used as soon as possible after the signs and symptoms of herpes infection (for example, pain, burning, or blisters) begin to appear.

Use a finger cot or rubber glove when applying this medicine. This will help keep you from spreading the infection to other areas of your body and will prevent the transmission of the infection to other persons . Apply enough medicine to completely cover all the sores (blisters). A 1.25-centimeter (approximately ½-inch) strip of ointment applied to each area of the affected skin measuring 5 × 5 centimeters (approximately 2 × 2 inches) is usually enough, unless otherwise directed by your doctor.

To help clear up your herpes infection, continue using acyclovir for the full time of treatment, even if your symptoms begin to clear up after a few days. Do not miss any doses. However, do not use this medicine more often or for a longer time than your doctor ordered.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For topical dosage form (cream):
- For herpes simplex infection:
  - Adults—Apply to the affected area(s), four to six times a day, for up to ten days.
  - Children—Use and dose must be determined by your doctor.

For topical dosage form (ointment):
- For herpes simplex infection:
  - In the U.S.
  - Adults—Apply to the affected area(s), every three hours, for a total of six times a day, for seven days.
  - Children—Use and dose must be determined by your doctor.
  - In Canada
  - Adults—Apply to the affected area(s), four to six times a day, for up to ten days.
  - Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using Zovirax

Women with genital herpes may be more likely to get cancer of the cervix (opening to the womb). Therefore, it is very important that Pap tests be taken at least once a year to check for cancer. Cervical cancer can be cured if found and treated early.

If your symptoms do not improve within 1 week, or if they become worse, check with your doctor.

Consider the possibility of viral resistance to acyclovir if little or no improvement in symptoms during therapy.

The areas affected by herpes should be kept as clean and dry as possible. Also, wear loose-fitting clothing to avoid irritating the sores (blisters).

Herpes infection of the genitals can be caught from or spread to your partner during any sexual activity. Although you may get herpes even though your sexual partner has no symptoms, the infection is more likely to be spread if sores are present. This is true until the sores are completely healed and the scabs have fallen off. The use of a condom (prophylactic) may help prevent the spread of herpes. However, spermicidal (sperm-killing) jelly or a diaphragm will not help prevent the spread of herpes. Therefore, it is best to avoid any sexual activity if either you or your partner has any symptoms of herpes. It is also important to remember that acyclovir will not keep you from spreading herpes to others.

Zovirax Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

Mild pain, burning, or stinging

Less common

Itching

Rare

Itching, stinging, or redness of the genital area

skin rash

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Zovirax Topical side effects (in more detail)

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Zoladex

Dosage Form: implant
FULL PRESCRIBING INFORMATION

Indications and Usage for Zoladex

Stage B2-C Prostatic Carcinoma

Zoladex is indicated for use in combination with flutamide for the management of locally confined Stage T2b-T4 (Stage B2-C) carcinoma of the prostate. Treatment with Zoladex and flutamide should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy [see Dosage and Administration (2.1) and Clinical Studies (14.1)].

Prostatic Carcinoma

Zoladex is indicated in the palliative treatment of advanced carcinoma of the prostate [see Dosage and Administration (2.2) and Clinical Studies (14.2)].

Endometriosis

Zoladex is indicated for the management of endometriosis, including pain relief and reduction of endometriotic lesions for the duration of therapy. Experience with Zoladex for the management of endometriosis has been limited to women 18 years of age and older treated for 6 months [see Dosage and Administration (2.3) and Clinical Studies (14.3)].

Endometrial Thinning

Zoladex is indicated for use as an endometrial-thinning agent prior to endometrial ablation for dysfunctional uterine bleeding [see Dosage and Administration (2.4) and Clinical Studies (14.4)].

Advanced Breast Cancer

Zoladex is indicated for use in the palliative treatment of advanced breast cancer in pre- and perimenopausal women.

The estrogen and progesterone receptor values may help to predict whether Zoladex therapy is likely to be beneficial [see Dosage and Administration (2.6), Clinical Pharmacology (12.1), and Clinical Studies (14.5)].

The automatic safety feature of the syringe aids in the prevention of needlestick injury.

Zoladex Dosage and Administration

Zoladex, at a dose of 3.6 mg, should be administered subcutaneously every 28 days into the anterior abdominal wall below the navel line using an aseptic technique under the supervision of a physician [see Dosage and Administration (2.7)].

While a delay of a few days is permissible, every effort should be made to adhere to the 28-day schedule.

Stage B2-C Prostatic Carcinoma

When Zoladex is given in combination with radiotherapy and flutamide for patients with Stage T2b-T4 (Stage B2-C) prostatic carcinoma, treatment should be started 8 weeks prior to initiating radiotherapy and should continue during radiation therapy. A treatment regimen using a Zoladex 3.6 mg depot 8 weeks before radiotherapy, followed in 28 days by the Zoladex 10.8 mg depot, can be administered. Alternatively, four injections of 3.6 mg depot can be administered at 28-day intervals, two depots preceding and two during radiotherapy.

Prostatic Carcinoma

For the management of advanced prostate cancer, Zoladex is intended for long-term administration unless clinically inappropriate.

Endometriosis

For the management of endometriosis, the recommended duration of administration is 6 months.

Currently, there are no clinical data on the effect of treatment of benign gynecological conditions with Zoladex for periods in excess of 6 months.

Retreatment cannot be recommended for the management of endometriosis since safety data for retreatment are not available. If the symptoms of endometriosis recur after a course of therapy, and further treatment with Zoladex is contemplated, consideration should be given to monitoring bone mineral density. Clinical studies suggest the addition of Hormone Replacement Therapy (estrogens and/or progestins) to Zoladex is effective in reducing the bone mineral loss which occurs with Zoladex alone without compromising the efficacy of Zoladex in relieving the symptoms of endometriosis. The addition of Hormone Replacement Therapy may also reduce the occurrence of vasomotor symptoms and vaginal dryness associated with hypoestrogenism. The optimal drugs, dose and duration of treatment has not been established.

Endometrial Thinning

For use as an endometrial-thinning agent prior to endometrial ablation, the dosing recommendation is one or two depots (with each depot given four weeks apart). When one depot is administered, surgery should be performed at four weeks. When two depots are administered, surgery should be performed within two to four weeks following administration of the second depot.

Breast Cancer

For the management of advanced breast cancer, Zoladex is intended for long-term administration unless clinically inappropriate.

Renal or Hepatic Impairment

No dosage adjustment is necessary for patients with renal or hepatic impairment.

Administration Technique

The proper method of administration of Zoladex is described in the instructions that follow.

1. Put the patient in a comfortable position with the upper part of the body slightly raised. Prepare an area of the anterior abdominal wall below the navel line with an alcohol swab.

2. Examine the foil pouch and syringe for damage. Remove the syringe from the opened foil pouch and hold the syringe at a slight angle to the light. Check that at least part of the Zoladex implant is visible.

3. Grasp the red plastic safety tab and pull away from the syringe, and discard. Remove needle cover. Unlike liquid injections, there is no need to remove air bubbles as attempts to do so may displace the Zoladex implant.

4. Holding the syringe around the protective sleeve, using an aseptic technique, pinch the skin of the patient’s anterior abdominal wall below the navel line. With the bevel of the needle facing up, insert the needle at a 30 to 45 degree angle to the skin in one continuous deliberate motion until the protective sleeve touches the patient’s skin.

NOTE: The Zoladex syringe cannot be used for aspiration. If the hypodermic needle penetrates a large vessel, blood will be seen instantly in the syringe chamber. If a vessel is penetrated, withdraw the needle and inject with a new syringe elsewhere.

5. Do not penetrate into muscle or peritoneum.

6. To administer the Zoladex implant and to activate the protective sleeve, grasp the barrel at the finger grip and depress the plunger until you cannot depress it any further. If the plunger is not depressed fully, the protective sleeve will NOT activate. When the protective sleeve ‘clicks’, the protective sleeve will automatically begin to slide to cover the needle.

NOTE: The needle does not retract.

7. Withdraw the needle and allow protective sleeve to slide and cover needle. Dispose of the syringe in an approved sharps collector.

NOTE: In the unlikely event of the need to surgically remove Zoladex, it may be localized by ultrasound.

Dosage Forms and Strengths

Zoladex is supplied as a sterile and totally biodegradable D,L-lactic and glycolic acids copolymer (13.3-14.3 mg/dose) impregnated with goserelin acetate equivalent to 3.6 mg of goserelin in a disposable syringe device fitted with a 16-gauge x 36 +/- 0.5 mm siliconized hypodermic needle with protective needle sleeve [SafeSystem™ Syringe] (NDC 0310-0950-36).

Contraindications

Hypersensitivity

Anaphylactic reactions to Zoladex have been reported in the medical literature. Zoladex is contraindicated in those patients who have a known hypersensitivity to GnRH, GnRH agonist analogues or any of the components in Zoladex [see Warnings and Precautions (5.6) and Adverse Reactions (6.10)].

Pregnancy

Zoladex is contraindicated during pregnancy unless Zoladex is being used for palliative treatment of advanced breast cancer. Zoladex can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus. There is an increased risk for pregnancy loss due to expected hormone changes that occur with Zoladex treatment [see Use in Specific Populations (8.1)].

Warnings and Precautions

Women of Childbearing Potential and Pregnancy

Before starting treatment with Zoladex, pregnancy must be excluded for women using Zoladex for benign gynecological conditions. Women of childbearing potential should be advised to avoid becoming pregnant.

Effective nonhormonal contraception must be used by all premenopausal women during Zoladex therapy and for 12 weeks following discontinuation of therapy. When used every 28 days, Zoladex usually inhibits ovulation and stops menstruation; however, pregnancy prevention is not ensured. Effects on reproductive function are expected to occur with chronic administration as a result of the anti-gonadotrophic properties of the drug.

Based on mechanism of action in humans and findings of increased pregnancy loss in animal studies, Zoladex can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy for the palliative treatment of breast cancer, then the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

Tumor Flare Phenomenon

Initially, Zoladex, like other GnRH agonists, causes transient increases in serum levels of testosterone in men with prostate cancer, and estrogen in women with breast cancer. Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostate or breast cancer, may occasionally develop during the first few weeks of Zoladex treatment. A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically.

As with other GnRH agonists, isolated cases of ureteral obstruction and spinal cord compression have been observed in patients with prostate cancer. If spinal cord compression or renal impairment secondary to ureteral obstruction develops, standard treatment of these complications should be instituted. For extreme cases in prostate cancer patients, an immediate orchiectomy should be considered.

Hyperglycemia and Diabetes

Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes [see Adverse Reactions (6.10) and Patient Counseling Information (17.1)].

Cardiovascular Diseases

Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice [see Patient Counseling Information (17.1)].

Hypercalcemia

As with other GnRH agonists or hormonal therapies (antiestrogens, estrogens, etc.), hypercalcemia has been reported in some prostate and breast cancer patients with bone metastases after starting treatment with Zoladex. If hypercalcemia does occur, appropriate treatment measures should be initiated.

Hypersensitivity

Hypersensitivity, antibody formation and acute anaphylactic reactions have been reported with GnRH agonist analogues [see Contraindications (4.1) and Adverse Reactions (6.10)].

Of 115 women worldwide treated with Zoladex and tested for development of binding to goserelin following treatment with Zoladex, one patient showed low-titer binding to goserelin. On further testing of this patient's plasma obtained following treatment, her goserelin binding component was found not to be precipitated with rabbit antihuman immunoglobulin polyvalent sera. These findings suggest the possibility of antibody formation.

Cervical Resistance

The pharmacologic action of Zoladex on the uterus and cervix may cause an increase in cervical resistance. Therefore, care should be taken when dilating the cervix for endometrial ablation.

Adverse Reactions

Stage B2-C Prostatic Carcinoma

Treatment with Zoladex and flutamide did not add substantially to the toxicity of radiation treatment alone. The following adverse experiences were reported during a multicenter clinical trial comparing Zoladex + flutamide + radiation versus radiation alone. The most frequently reported (greater than 5%) adverse experiences are listed below:

Table 1 ADVERSE EVENTS DURING ACUTE RADIATION THERAPY (within first 90 days of radiation therapy)
	(n=231) flutamide + Zoladex + Radiation	(n = 235) Radiation Only
	% All	% All
Rectum/Large Bowel	80	76
Bladder	58	60
Skin	37	37

Table 2 ADVERSE EVENTS DURING LATE RADIATION PHASE (after 90 days of radiation therapy)
	(n=231) flutamide + Zoladex + Radiation	(n = 235) Radiation Only
	% All	% All
Diarrhea	36	40
Cystitis	16	16
Rectal Bleeding	14	20
Proctitis	8	8
Hematuria	7	12

Additional adverse event data was collected for the combination therapy with radiation group over both the hormonal treatment and hormonal treatment plus radiation phases of the study. Adverse experiences occurring in more than 5% of patients in this group, over both parts of the study, were hot flashes (46%), diarrhea (40%), nausea (9%), and skin rash (8%).

Prostatic Carcinoma

Zoladex has been found to be generally well tolerated in clinical trials. Adverse reactions reported in these trials were rarely severe enough to result in the patients' withdrawal from Zoladex treatment. As seen with other hormonal therapies, the most commonly observed adverse events during Zoladex therapy were due to the expected physiological effects from decreased testosterone levels. These included hot flashes, sexual dysfunction and decreased erections.

Tumor Flare Phenomenon: Initially, Zoladex, like other GnRH agonists, causes transient increases in serum levels of testosterone. A small percentage of patients experienced a temporary worsening of signs and symptoms, usually manifested by an increase in cancer-related pain which was managed symptomatically. Isolated cases of exacerbation of disease symptoms, either ureteral obstruction or spinal cord compression, occurred at similar rates in controlled clinical trials with both Zoladex and orchiectomy. The relationship of these events to therapy is uncertain [see Warnings and Precautions (5.2)].

In the controlled clinical trials of Zoladex versus orchiectomy, the following events were reported as adverse reactions in greater than 5% of the patients.

Table 3 TREATMENT RECEIVED
	Zoladex (n=242)	ORCHIECTOMY (n=254)
ADVERSE EVENT	%	%
* Complications related to surgery were reported in 18% of the orchiectomy patients, while only 3% of Zoladex patients reported adverse reactions at the injection site. The surgical complications included scrotal infection (5.9%), groin pain (4.7%), wound seepage (3.1%), scrotal hematoma (2.8%), incisional discomfort (1.6%) and skin necrosis (1.2%).
Hot Flashes	62	53
Sexual Dysfunction	21	15
Decreased Erections	18	16
Lower Urinary Tract Symptoms	13	8
Lethargy	8	4
Pain (worsened in the first 30 days)	8	3
Edema	7	8
Upper Respiratory Infection	7	2
Rash	6	1
Sweating	6	4
Anorexia	5	2
Chronic Obstructive Pulmonary Disease	5	3
Congestive Heart Failure	5	1
Dizziness	5	4
Insomnia	5	1
Nausea	5	2
Complications of Surgery	0	18*

The following additional adverse reactions were reported in greater than 1% but less than 5% of the patients treated with Zoladex: CARDIOVASCULAR - arrhythmia, cerebrovascular accident, hypertension, myocardial infarction, peripheral vascular disorder, chest pain; CENTRAL NERVOUS SYSTEM - anxiety, depression, headache; GASTROINTESTINAL - constipation, diarrhea, ulcer, vomiting; HEMATOLOGIC - anemia; METABOLIC/NUTRITIONAL - gout, hyperglycemia, weight increase; MISCELLANEOUS - chills, fever; UROGENITAL - renal insufficiency, urinary obstruction, urinary tract infection, breast swelling and tenderness.

Females

As would be expected with a drug that results in hypoestrogenism, the most frequently reported adverse reactions were those related to this effect.

Endometriosis

In controlled clinical trials comparing Zoladex every 28 days and danazol daily for the treatment of endometriosis, the following events were reported at a frequency of 5% or greater:

Table 4 TREATMENT RECEIVED
	Zoladex (n=411)	DANAZOL (n=207)
ADVERSE EVENT	%	%
Hot Flushes	96	67
Vaginitis	75	43
Headache	75	63
Emotional Lability	60	56
Libido Decreased	61	44
Sweating	45	30
Depression	54	48
Acne	42	55
Breast Atrophy	33	42
Seborrhea	26	52
Peripheral Edema	21	34
Breast Enlargement	18	15
Pelvic Symptoms	18	23
Pain	17	16
Dyspareunia	14	5
Libido Increased	12	19
Infection	13	11
Asthenia	11	13
Nausea	8	14
Hirsutism	7	15
Insomnia	11	4
Breast Pain	7	4
Abdominal Pain	7	7
Back Pain	7	13
Flu Syndrome	5	5
Dizziness	6	4
Application Site Reaction	6	-
Voice Alterations	3	8
Pharyngitis	5	2
Hair Disorders	4	11
Myalgia	3	11
Nervousness	3	5
Weight Gain	3	23
Leg Cramps	2	6
Increased Appetite	2	5
Pruritus	2	6
Hypertonia	1	10

The following adverse events not already listed above were reported at a frequency of 1% or greater, regardless of causality, in Zoladex-treated women from all clinical trials: WHOLE BODY - allergic reaction, chest pain, fever, malaise; CARDIOVASCULAR - hemorrhage, hypertension, migraine, palpitations, tachycardia; DIGESTIVE - anorexia, constipation, diarrhea, dry mouth, dyspepsia, flatulence; HEMATOLOGIC - ecchymosis; METABOLIC AND NUTRITIONAL - edema; MUSCULOSKELETAL - arthralgia, joint disorder; CNS - anxiety, paresthesia, somnolence, thinking abnormal; RESPIRATORY - bronchitis, cough increased, epistaxis, rhinitis, sinusitis; SKIN - alopecia, dry skin, rash, skin discoloration; SPECIAL SENSES - amblyopia, dry eyes; UROGENITAL - dysmenorrhea, urinary frequency, urinary tract infection, vaginal hemorrhage.

Endometrial Thinning

The following adverse events were reported at a frequency of 5% or greater in premenopausal women presenting with dysfunctional uterine bleeding in Trial 0022 for endometrial thinning. These results indicate that headache, hot flushes and sweating were more common in the Zoladex group than in the placebo group.

Table 5 ADVERSE EVENTS REPORTED AT A FREQUENCY OF 5% OR GREATER IN Zoladex AND PLACEBO TREATMENT GROUPS OF TRIAL 0022
	Zoladex 3.6 mg (n=180)	Placebo (n=177)
ADVERSE EVENT	%	%
Whole Body
Headache	32	22
Abdominal Pain	11	10
Pelvic Pain	9	6
Back Pain	4	7
Cardiovascular
Vasodilatation	57	18
Migraine	7	4
Hypertension	6	2
Digestive
Nausea	5	6
Nervous
Nervousness	5	3
Depression	3	7
Respiratory
Pharyngitis	6	9
Sinusitis	3	6
Skin and appendages
Sweating	16	5
Urogenital
Dysmenorrhea	7	9
Uterine Hemorrhage	6	4
Vulvovaginitis	5	1
Menorrhagia	4	5
Vaginitis	1	6

Breast Cancer

The adverse event profile for women with advanced breast cancer treated with Zoladex is consistent with the profile described above for women treated with Zoladex for endometriosis. In a controlled clinical trial (SWOG–8692) comparing Zoladex with oophorectomy in premenopausal and perimenopausal women with advanced breast cancer, the following events were reported at a frequency of 5% or greater in either treatment group regardless of causality.

Table 6 TREATMENT RECEIVED
	Zoladex (n=57)	OOPHORECTOMY (n=55)
ADVERSE EVENT	% of Pts.	% of Pts.
Hot Flashes	70	47
Tumor Flare	23	4
Nausea	11	7
Edema	5	0
Malaise/Fatigue/Lethargy	5	2
Vomiting	4	7

In the Phase II clinical trial program in 333 pre- and perimenopausal women with advanced breast cancer, hot flashes were reported in 75.9% of patients and decreased libido was noted in 47.7% of patients. These two adverse events reflect the pharmacological actions of Zoladex.

Injection site reactions were reported in less than 1% of patients.

Hormone Replacement Therapy

Clinical studies suggest the addition of Hormone Replacement Therapy (estrogens and/or progestins) to Zoladex may decrease the occurrence of vasomotor symptoms and vaginal dryness associated with hypoestrogenism without compromising the efficacy of Zoladex in relieving pelvic symptoms. The optimal drugs, dose and duration of treatment has not been established.

Changes in Bone Mineral Density

After 6 months of Zoladex treatment, 109 female patients treated with Zoladex showed an average 4.3% decrease of vertebral trabecular bone mineral density (BMD) as compared to pretreatment values. BMD was measured by dual-photon absorptiometry or dual energy x-ray absorptiometry. Sixty-six of these patients were assessed for BMD loss 6 months after the completion (posttherapy) of the 6-month therapy period. Data from these patients showed an average 2.4% BMD loss compared to pretreatment values. Twenty-eight of the 109 patients were assessed for BMD at 12 months posttherapy. Data from these patients showed an average decrease of 2.5% in BMD compared to pretreatment values. These data suggest a possibility of partial reversibility. Clinical studies suggest the addition of Hormone Replacement Therapy (estrogens and/or progestins) to Zoladex is effective in reducing the bone mineral loss which occurs with Zoladex alone without compromising the efficacy of Zoladex in relieving the symptoms of endometriosis. The optimal drugs, dose and duration of treatment has not been established [see Patient Counseling Information (17.1) and (17.2)].

Changes in Laboratory Values During Treatment

Plasma Enzymes: Elevation of liver enzymes (AST, ALT) have been reported in female patients exposed to Zoladex (representing less than 1% of all patients).

Lipids: In a controlled trial, Zoladex therapy resulted in a minor, but statistically significant effect on serum lipids. In patients treated for endometriosis at 6 months following initiation of therapy, danazol treatment resulted in a mean increase in LDL cholesterol of 33.3 mg/dL and a decrease in HDL cholesterol of 21.3 mg/dL compared to increases of 21.3 and 2.7 mg/dL in LDL cholesterol and HDL cholesterol, respectively, for Zoladex-treated patients. Triglycerides increased by 8.0 mg/dL in Zoladex-treated patients compared to a decrease of 8.9 mg/dL in danazol-treated patients.

In patients treated for endometriosis, Zoladex increased total cholesterol and LDL cholesterol during 6 months of treatment. However, Zoladex therapy resulted in HDL cholesterol levels which were significantly higher relative to danazol therapy. At the end of 6 months of treatment, HDL cholesterol fractions (HDL2 and HDL3) were decreased by 13.5 and 7.7 mg/dL, respectively, for danazol-treated patients compared to treatment increases of 1.9 and 0.8 mg/dL, respectively, for Zoladex-treated patients.

Post-Marketing

Hypersensitivity: Rarely, hypersensitivity reactions (including urticaria and anaphylaxis) have been reported in patients receiving Zoladex [see Contraindications (4.1) and Warnings and Precautions (5.6)].

Bone Mineral Density: There have been post-marketing reports of osteoporosis, decreased bone mineral density and bony fracture in men treated with Zoladex for prostate cancer [see Patient Counseling Information (17.1) and (17.2)].

Cardiovascular: Cases of serious venous and arterial thromboembolism have been reported in women receiving GnRH agonists, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and transient ischemic attack. Although a temporal relationship was reported in some cases, most cases were confounded by risk factors or concomitant medication use. It is unknown if there is a causal association between the use of GnRH analogs and these events.

Ovarian Cyst: As with other GnRH agonists, there have been reports of ovarian cyst formation and, when Zoladex 3.6 mg is used in combination with gonadotropins, of ovarian hyperstimulation syndrome (OHSS).

Changes in Blood Pressure: Changes in blood pressure, manifest as hypotension or hypertension, have been occasionally observed in patients administered Zoladex. The changes are usually transient, resolving either during continued therapy or after cessation of therapy with Zoladex. Rarely, such changes have been sufficient to require medical intervention including withdrawal of treatment from Zoladex.

Pituitary Apoplexy and Tumors: During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In a majority of these cases, a pituitary adenoma was diagnosed. Most of the pituitary apoplexy cases occurred within 2 weeks of the first dose, and some occurred within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. Very rare cases of pituitary tumors have been reported.

Glucose Tolerance: Reduction in glucose tolerance, manifesting as diabetes or loss of glycemic control in those with pre-existing diabetes, has been reported during treatment with GnRH agonists, including Zoladex [see Warnings and Precautions (5.3) and Patient Counseling Information (17.1)].

Other Adverse Reactions: Psychotic disorders have also been reported.

Drug Interactions

No formal drug-drug interaction studies have been performed. No confirmed interactions have been reported between Zoladex and other drugs.

Drug/Laboratory Test Interactions

Administration of Zoladex in therapeutic doses results in suppression of the pituitary-gonadal system. Because of this suppression, diagnostic tests of pituitary-gonadotropic and gonadal functions conducted during treatment and until the resumption of menses may show results which are misleading. Normal function is usually restored within 12 weeks after treatment is discontinued.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category D in patients with advanced breast cancer.

Pregnancy Category X in patients with endometriosis and endometrial thinning.

Zoladex is contraindicated during pregnancy unless Zoladex is being used for palliative treatment of advanced breast cancer. There are no adequate and well-controlled studies in pregnant women using Zoladex. Based on mechanism of action in humans and findings of increased pregnancy loss in animal studies, Zoladex can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus. There is an increased risk for pregnancy loss due to expected hormone changes that occur with Zoladex treatment.

Zoladex crosses the placenta in rats and rabbits following subcutaneous administration. Administration of goserelin to pregnant rats and rabbits during organogenesis resulted in increased preimplantation loss and increased resorptions. When pregnant rats received goserelin throughout gestation and lactation, there was a dose-related increase in umbilical hernia in offspring. In additional reproduction studies in rats, goserelin decreased fetus and pup survival. Human dose/exposure multiples could not be calculated from available animal data.

Actual animal doses: rat (≥ 2 mcg/kg/day for pregnancy loss; > 10 mcg/kg/day for umbilical hernia in offspring); rabbits (> 20 mcg/kg/day).

Nursing Mothers

It is not known if goserelin is excreted in human milk. Goserelin is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Zoladex, a decision should be made to either discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

There is no need for any dosage adjustment when administering Zoladex to male geriatric patients. Zoladex has not been studied in women over 65 years.

Renal Insufficiency

In clinical trials with the solution formulation of goserelin, male patients with impaired renal function (creatinine clearance < 20 mL/min) had a total body clearance and serum elimination half-life of 31.5 mL/min and 12.1 hours, respectively, compared to 133 mL/min and 4.2 hours for subjects with normal renal function (creatinine clearance > 70 mL/min). In females, the effects of reduced goserelin clearance due to impaired renal function on drug efficacy and toxicity are unknown. Pharmacokinetic studies in patients with renal impairment do not indicate a need for dose adjustment with the use of the depot formulation.

Hepatic Insufficiency

The total body clearances and serum elimination half-lives were similar between normal subjects and patients with moderate hepatic impairment (alanine transaminase < 3xULN and asparate aminotransferase < 3xULN) when treated with a 250 mcg subcutaneous formulation of goserelin. This pharmacokinetic study indicates that no dose adjustment is needed in patients with moderately impaired liver function. There is no pharmacokinetic data with goserelin in patients with severe hepatic insufficiency.

Overdosage

The pharmacologic properties of Zoladex and its mode of administration make accidental or intentional overdosage unlikely. There is no experience of overdosage from clinical trials. Animal studies indicate that no increased pharmacologic effect occurred at higher doses or more frequent administration. Subcutaneous doses of the drug as high as 1 mg/kg/day in rats and dogs did not produce any nonendocrine related sequelae; this dose is up to 250 times the est