Virazole

ribavirin

Dosage Form: inhalation solution

PRESCRIBING INFORMATION

WARNINGS:

USE OF AEROSOLIZED Virazole IN PATIENTS REQUIRING MECHANICAL VENTILATOR ASSISTANCE SHOULD BE UNDERTAKEN ONLY BY PHYSICIANS AND SUPPORT STAFF FAMILIAR WITH THE SPECIFIC VENTILATOR BEING USED AND THIS MODE OF ADMINISTRATION OF THE DRUG. STRICT ATTENTION MUST BE PAID TO PROCEDURES THAT HAVE BEEN SHOWN TO MINIMIZE THE ACCUMULATION OF DRUG PRECIPITATE, WHICH CAN RESULT IN MECHANICAL VENTILATOR DYSFUNCTION AND ASSOCIATED INCREASED PULMONARY PRESSURES (SEE WARNINGS).

SUDDEN DETERIORATION OF RESPIRATORY FUNCTION HAS BEEN ASSOCIATED WITH INITIATION OF AEROSOLIZED Virazole USE IN INFANTS. RESPIRATORY FUNCTION SHOULD BE CAREFULLY MONITORED DURING TREATMENT. IF INITIATION OF AEROSOLIZED Virazole TREATMENT APPEARS TO PRODUCE SUDDEN DETERIORATION OF RESPIRATORY FUNCTION, TREATMENT SHOULD BE STOPPED AND REINSTITUTED ONLY WITH EXTREME CAUTION, CONTINUOUS MONITORING AND CONSIDERATION OF CONCOMITANT ADMINISTRATION OF BRONCHODILATORS (SEE WARNINGS).

Virazole IS NOT INDICATED FOR USE IN ADULTS. PHYSICIANS AND PATIENTS SHOULD BE AWARE THAT RIBAVIRIN HAS BEEN SHOWN TO PRODUCE TESTICULAR LESIONS IN RODENTS AND TO BE TERATOGENIC IN ALL ANIMAL SPECIES IN WHICH ADEQUATE STUDIES HAVE BEEN CONDUCTED (RODENTS AND RABBITS); (SEE CONTRAINDICATIONS).

Virazole Description

Virazole® is a brand name for ribavirin, a synthetic nucleoside with antiviral activity. Virazole for inhalation solution is a sterile, lyophilized powder to be reconstituted for aerosol administration. Each 100 mL glass vial contains 6 grams of ribavirin, and when reconstituted to the recommended volume of 300 mL with sterile water for injection or sterile water for inhalation (no preservatives added), will contain 20 mg of ribavirin per mL, pH approximately 5.5. Aerosolization is to be carried out in a Small Particle Aerosol Generator (SPAG-2) nebulizer only.

Ribavirin is 1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, with the following structural formula:

Ribavirin is a stable, white crystalline compound with a maximun solubility in water of 142 mg/mL at 25°C and with only a slight solubility in ethanol. The empirical formula is C8H12N4O5 and the molecular weight is 244.21.

Virazole - Clinical Pharmacology

Mechanism of Action

In cell cultures the inhibitory activity of ribavirin for respiratory syncytial virus (RSV) is selective. The mechanism of action is unknown. Reversal of the in vitro antiviral activity by guanosine or xanthosine suggests ribavirin may act as an analogue of these cellular metabolites.

Microbiology

Rivavirin has demonstrated antiviral activity against RSV in vitro1 and in experimentally infected cotton rats.2 Several clinical isolates of RSV were evaluated for ribavirin susceptibility by plaque reduction in tissue culture. Plaques were reduced 85-98% by 16 μg/mL; however, results may vary with the test system. The development of resistance has not been evaluated in vitro or in clinical trials.

In addition to the above, ribavirin has beeb shown to have in vitro activity against influenza A and B viruses and herpes simplex virus, but the clinical significance of these data is unknown.

Immunologic Effects

Neutralizing antibody responses to RSV were decreased in aerosolized Virazole treated infants compared to placebo treated infants.3 One study also showed that RSV-specific IgE antibody in bronchial secretions was decreased in patients treated with aerosolized Virazole. In rats, ribavirin administration resulted in lymphoid atrophy of the thymus, spleen and lymph nodes. Humoral immunity was reduced in guinea pigs and ferrets. Cellular immunity was also mildly depressed in animal studies. The clinical significance of these odservations is unknown.

Pharmacokinetics

Assay for Virazole in human materials is by a radioimmunoassay which detects ribavirin and at least one metabolite.

Virazole brand of ribavirin, when administered by aerosol, is absorbed systemically. Four pediatric patients inhaling Virazole aerosol administered by face mask for 2.5 hours each day for 3 days had plasma concentrations ranging from 0.44 to 1.55 µM, with a mean concentration of 0.76 µM. The plasma half-life was reported to be 9.5 hours. Three pediatric patients inhaling aerosolized Virazole administered by face mask or mist tent for 20 hours each day for 5 days had plasma concentrations ranging from 1.5 to 14.3 µM, with a mean concentration of 6.8 µM.

The bioavailability of aerosolized Virazole is unknown and may depend on the mode of aerosol delivery. After aerosol treatment, peak plasma concentrations of ribavirin are 85% to 98% less than the concentration that reduced RSV plaque formation in tissue culture. After aerosol treatment, respiratory tract secretions are likely to contain ribavirin in concentrations many fold higher than those required to reduce plaque formation. However, RSV is an intracellular virus and it is unknown whether plasma concentrations or respiratory secretion concentrations of the drug better reflect intracellular concentrations in the respiratory tract.

In man, rats, and rhesus monkeys, accumulation of ribavirin and/or metabolites in the red blood cells has been noted, plateauing in red cells in man in about 4 days and gradually declining with an apparent half-life of 40 days (the half-life of erythrocytes). The extent of accumulation of ribavirin following inhalation therapy is not well defined.

Animal Toxicology

Ribavirin, when administered orally or as an aerosol, produced cardiac lesions in mice, rats, and monkeys, when given at doses of 30, 36 and 120 mg/kg or greater for 4 weeks or more (estimated human equivalent doses of 4.8, 12.3 and 111.4 mg/kg for a 5 kg child, or 2.5, 5.1 and 40 mg/kg for a 60 kg adult, based on body surface area adjustment). Aerosolized ribavirin administered to developing ferrets at 60 mg/kg for 10 or 30 days resulted in inflammatory and possibly emphysematous changes in the lungs. Proliferative changes were seen in the lungs following exposure at 131 mg/kg for 30 days. The significance of these findings to human administration is unknown.

Indications and Usage for Virazole

Virazole is indicated for the treatment of hospitalized infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus. Treatment early in the course of severe lower respiratory tract infection may be necessary to achieve efficacy.

Only severe RSV lower respiratory tract infection should be treated with Virazole. The vast majority of infants and children with RSV infection have disease that is mild, self-limited, and does not require hospitalization or antiviral treatment. Many children with mild lower respiratory tract involvement will require shorter hospitalization than would be required for a full course of Virazole aerosol (3 to 7 days) and should not be treated with the drug. Thus the decision to treat with Virazole should be based on the severity of the RSV infection. The presence of an underlying condition such as prematurity, immunosuppression or cardiopulmonary disease may increase the severity of clinical manifestations and complications of RSV infection.

Use of aerosolized Virazole in patients requiring mechanical ventilator assistance should be undertaken only by physicians and support staff familiar with this mode of administration and the specific ventilator being used (seeWARNINGS, andDOSAGE AND ADMINISTRATION).

Diagnosis

RSV infection should be documented by a rapid diagnostic method such as demonstration of viral antigen in respiratory tract secretions by immunofluorescence3,4 or ELISA5 before or during the first 24 hours of treatment. Treatment may be initiated while awaiting rapid diagnostic test results. However, treatment should not be continued without documentation of RSV infection. Non-culture antigen detection techniques may have false positive or false negative results. Assessment of the clinical situation, the time of year and other parameters may warrant reevaluation of the laboratory diagnosis.

Description of Studies

Non-Mechanically-Ventilated Infants: In two placebo controlled trials in infants hospitalized with RSV lower respiratory tract infection, aerosolized Virazole treatment had a therapeutic effect, as judged by the reduction in severity of clinical manifestations of disease by treatment day 3.3,4 Treatment was most effective when instituted within the first 3 days of clinical illness. Virus titers in respiratory secretions were also significantly reduced with Virazole in one of these original studies.4 Additional controlled studies conducted since these initial trials of aerosolized Virazole in the treatment of RSV infection have supported these data.

Mechanically-Ventilated Infants: A randomized, double-blind, placebo controlled evaluation of aerosolized Virazole at the recommended dose was conducted in 28 infants requiring mechanical ventilation for respiratory failure caused by documented RSV infection.6 Mean age was 1.4 months (SD, 1.7 months). Seven patients had underlying diseases predisposing them to severe infection and 21 were previously normal. Aerosolized Virazole treatment significantly decreased the duration of mechanical ventilation required (4.9 vs. 9.9 days, p=0.01) and duration of required supplemental oxygen (8.7 vs. 13.5 days, p=0.01). Intensive patient management and monitoring techniques were employed in this study. These included endotracheal tube suctioning every 1 to 2 hours; recording of proximal airway pressure, ventilatory rate, and FlO2 every hour; and arterial blood gas monitoring every 2 to 6 hours. To reduce the risk of Virazole precipitation and ventilator malfunction, heated wire tubing, two bacterial filters connected in series in the expiratory limb of the ventilator (with filter changes every 4 hours), and water column pressure release valves to monitor internal ventilator pressures were used in connecting ventilator circuits to the SPAG-2.

Employing these techniques, no technical difficulties with Virazole administration were encountered during the study. Adverse events consisted of bacterial pneumonia in one case, staphyloccus bacteremia in one case and two cases of post-extubation stridor. None were felt to be related to Virazole administration.

Contraindications

Virazole is contraindicated in individuals who have shown hypersensitivity to the drug or its components, and in women who are or may become pregnant during exposure to the drug. Ribavirin has demonstrated significant teratogenic and/or embryocidal potential in all animal species in which adequate studies have been conducted (rodents and rabbits). Therefore, although clinical studies have not been performed, it should be assumed that Virazole may cause fetal harm in humans. Studies in which the drug has been administered systemically demonstrate that ribavirin is concentrated in the red blood cells and persists for the life of the erythrocyte.

Warnings

SUDDEN DETERIORATION OF RESPIRATORY FUNCTION HAS BEEN ASSOCIATED WITH INITIATION OF AEROSOLIZED Virazole USE IN INFANTS. Respiratory function should be carefully monitored during treatment. If initiation of aerosolized Virazole treatment appears to produce sudden deterioration of respiratory function, treatment should be stopped and reinstituted only with extreme caution, continuous monitoring, and consideration of concomitant administration of bronchodilators.

Use with Mechanical Ventilators

USE OF AEROSOLIZED Virazole IN PATIENTS REQUIRING MECHANICAL VENTILATOR ASSISTANCE SHOULD BE UNDERTAKEN ONLY BY PHYSICIANS AND SUPPORT STAFF FAMILIAR WITH THIS MODE OF ADMINISTRATION AND THE SPECIFIC VENTILATOR BEING USED. Strict attention must be paid to procedures that have been shown to minimize the accumulation of drug precipitate, which can result in mechanical ventilator dysfunction and associated increased pulmonary pressures. These procedures include the use of bacteria filters in series in the expiratory limb of the ventilator circuit with frequent changes (every 4 hours), water column pressure release valves to indicate elevated ventilator pressures, frequent monitoring of these devices and verification that ribavirin crystals have not accumulated within the ventilator circuitry, and frequent suctioning and monitoring of the patient (see Clinical Studies).

Those administering aerosolized Virazole in conjunction with mechanical ventilator use should be thoroughly familiar with detailed descriptions of these procedures as outlined in the SPAG-2 manual.

Precautions

General

Patients with severe lower respiratory tract infection due to respiratory syncytial virus require optimum monitoring and attention to respiratory and fluid status (see SPAG-2 manual).

Drug Interactions

Clinical studies of interactions of Virazole with other drugs commonly used to treat infants with RSV infections, such as digoxin, bronchodilators, other antiviral agents, antibiotics or anti-metabolites, have not been conducted. Interference by Virazole with laboratory tests has not been evaluated.

Carcinogenesis and Mutagenesis

Ribavirin increased the incidence of cell transformations and mutations in mouse Balb/c 3T3 (fibroblasts) and L5178Y (lymphoma) cells at concentrations of 0.015 and 0.03-5.0 mg/mL, respectively (without metabolic activation). Modest increases in mutation rates (3-4x) were observed at concentrations between 3.75-10.0 mg/mL in L5178Y cells in vitro with the addition of a metabolic activation fraction. In the mouse micronucleus assay, ribavirin was clastogenic at intravenous doses of 20-200 mg/kg, (estimated human equivalent of 1.67-16.7 mg/kg, based on body surface area adjustment for a 60 kg adult). Ribavirin was not mutagenic in a dominant lethal assay in rats at intraperitoneal doses between 50-200 mg/kg when administered for 5 days (estimated human equivalent of 7.14-28.6 mg/kg, based on body surface area adjustment; seePharmacokinetics).

In vivo carcinogenicity studies with ribavirin are incomplete. However, results of a chronic feeding study with ribavirin in rats, at doses of 16-100 mg/kg/day (estimated human equivalent of 2.3-14.3 mg/kg/day, based on body surface area adjustment for the adult), suggest that ribavirin may induce benign mammary, pancreatic, pituitary and adrenal tumors. Preliminary results of 2 oral gavage oncogenicity studies in the mouse and rat (18-24 months; doses of 20-75 and 10-40 mg/kg/day, respectively [estimated human equivalent of 1.67-6.25 and 1.43-5.71 mg/kg/day, respectively, based on body surface area adjustment for the adult]) are inconclusive as to the carcinogenic potential of ribavirin (seePharmacokinetics). However, these studies have demonstrated a relationship between chronic ribavirin exposure and increased incidences of vascular lesions (microscopic hemorrhages in mice) and retinal degeneration (in rats).

Impairment of Fertility

The fertility of ribavirin-treated animals (male or female) has not been fully investigated. However, in the mouse, administration of ribavirin at doses between 35-150 mg/kg/day (estimated human equivalent of 2.92-12.5 mg/kg/day, based on body surface area adjustment for the adult) resulted in significant seminiferous tubule atrophy, decreased sperm concentrations, and increased numbers of sperm with abnormal morphology. Partial recovery of sperm production was apparent 3-6 months following dose cessation. In several additional toxicology studies, ribavirin has been shown to cause testicular lesions (tubular atrophy) in adult rats at oral dose levels as low as 16 mg/kg/day (estimated human equivalent of 2.29 mg/kg/day, based on body surface area adjustment; seePharmacokinetics). Lower doses were not tested. The reproductive capacity of treated male animals has not been studied.

Pregnancy: Category X

Ribavirin has demonstrated significant teratogenic and/or embryocidal potential in all animal species in which adequate studies have been conducted. Teratogenic effects were evident after single oral doses of 2.5 mg/kg or greater in the hamster, and after daily oral doses of 0.3 and 1.0 mg/kg in the rabbit and rat, respectively (estimated human equivalent doses of 0.12 and 0.14 mg/kg, based on body surface area adjustment for the adult). Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced. Ribavirin caused embryolethality in the rabbit at daily oral dose levels as low as 1 mg/kg. No teratogenic effects were evident in the rabbit and rat administered daily oral doses of 0.1 and 0.3 mg/kg, respectively with estimated human equivalent doses of 0.01 and 0.04 mg/kg, based on body surface area adjustment (seePharmacokinetics). These doses are considered to define the “No Observable Teratogenic Effects Level” (NOTEL) for ribavirin in the rabbit and rat.

Following oral administration of ribavirin in the pregnant rat (1.0 mg/kg) and rabbit (0.3 mg/kg), mean plasma levels of drug ranged from 0.10-0.20 µM[0.024-0.049 µ/mL] at 1 hour after dosing, to undetectable levels at 24 hours. At 1 hour following the administration of 0.3 or 0.1 mg/kg in the rat and rabbit (NOTEL), respectively, mean plasma levels of drug in both species were near or below the limit of detection (0.05 µM; seePharmacokinetics).

Although clinical studies have not been performed, Virazole may cause fetal harm in humans. As noted previously, ribavirin is concentrated in red blood cells and persists for the life of the cell. Thus the terminal half-life for the systemic elimination of ribavirin is essentially that of the half-life of circulating erythrocytes. The minimum interval following exposure to Virazole before pregnancy may be safely initiated is unknown (seeCONTRAINDICATIONS,WARNINGS, andInformation for Health Care Personnel).

Nursing Mothers

Virazole has been shown to be toxic to lactating animals and their offspring. It is not known if Virazole is excreted in human milk.

Information for Health Care Personnel

Health care workers directly providing care to patients receiving aerosolized Virazole should be aware that ribavirin has been shown to be teratogenic in all animal species in which adequate studies have been conducted (rodents and rabbits). Although no reports of teratogenesis in offspring of mothers who were exposed to aerosolized Virazole during pregnancy have been confirmed, no controlled studies have been conducted in pregnant women. Studies of environmental exposure in treatment settings have shown that the drug can disperse into the immediate bedside area during routine patient care activities with highest ambient levels closest to the patient and extremely low levels outside of the immediate bedside area. Adverse reactions resulting from actual occupational exposure in adults are described below (seeAdverse Events in Health Care Workers). Some studies have documented ambient drug concentrations at the bedside that could potentially lead to systemic exposures above those considered safe for exposure during pregnancy (1/1000 of the NOTEL dose in the most sensitive animal species).7,8,9

A 1992 study conducted by the National Institute of Occupational Safety and Health (NIOSH) demonstrated measurable urine levels of ribavirin in health care workers exposed to aerosol in the course of direct patient care.7 Levels were lowest in workers caring for infants receiving aerosolized Virazole with mechanical ventilation and highest in those caring for patients being administered the drug via an oxygen tent or hood. This study employed a more sensitive assay to evaluate ribavirin levels in urine than was available for several previous studies of environmental exposure that failed to detect measurable ribavirin levels in exposed workers. Creatinine adjusted urine levels in the NIOSH study ranged from less than 0.001 to 0.140 µM of ribavirin per gram of creatinine in exposed workers. However, the relationship between urinary ribavirin levels in exposed workers, plasma levels in animal studies, and the specific risk of teratogenesis in exposed pregnant women is unknown.

It is good practice to avoid unnecessary occupational exposure to chemicals wherever possible. Hospitals are encouraged to conduct training programs to minimize potential occupational exposure to Virazole. Health care workers who are pregnant should consider avoiding direct care of patients receiving aerosolized Virazole. If close patient contact cannot be avoided, precautions to limit exposure should be taken. These include administration of Virazole in negative pressure rooms; adequate room ventilation (at least six air exchanges per hour); the use of Virazole aerosol scavenging devices; turning off the SPAG-2 device for 5 to 10 minutes prior to prolonged patient contact; and wearing appropriately fitted respirator masks. Surgical masks do not provide adequate filtration of Virazole particles. Further information is available from NIOSH’s Hazard Evaluation and Technical Assistance Branch and additional recommendations have been published in an Aerosol Consensus Statement by the American Respiratory Care Foundation and the American Association for Respiratory Care.10

Adverse Reactions

The description of adverse reactions is based on events from clinical studies (approximately 200 patients) conducted prior to 1986, and the controlled trial of aerosolized Virazole conducted in 1989-1990. Additional data from spontaneous post-marketing reports of adverse events in individual patients have been available since 1986.

Deaths

Deaths during or shortly after treatment with aerosolized Virazole have been reported in 20 cases of patients treated with Virazole (12 of these patients were being treated for RSV infections). Several cases have been characterized as “possibly related” to Virazole by the treating physician; these were in infants who experienced worsening respiratory status related to bronchospasm while being treated with the drug. Several other cases have been attributed to mechanical ventilator malfunction in which Virazole precipitation within the ventilator apparatus led to excessively high pulmonary pressures and diminished oxygenation. In these cases the monitoring procedures described in the current package insert were not employed (seeDescription of Studies,WARNINGS, andDOSAGE AND ADMINISTRATION).

Pulmonary and Cardiovascular

Pulmonary function significantly deteriorated during aerosolized Virazole treatment in six of six adults with chronic obstructive lung disease and in four of six asthmatic adults. Dyspnea and chest soreness were also reported in the latter group. Minor abnormalities in pulmonary function were also seen in healthy adult volunteers.

In the original study population of approximately 200 infants who received aerosolized Virazole, several serious adverse events occurred in severely ill infants with life-threatening underlying diseases, many of whom required assisted ventilation. The role of Virazole in these events is indeterminate. Since the drug’s approval in 1986, additional reports of similar serious, though non-fatal, events have been filed infrequently. Events associated with aerosolized Virazole use have included the following:

Pulmonary: Worsening of respiratory status, bronchospasm, pulmonary edema, hypoventilation, cyanosis, dyspnea, bacterial pneumonia, pneumothorax, apnea, atelectasis and ventilator dependence.

Cardiovascular: Cardiac arrest, hypotension, bradycardia and digitalis toxicity. Bigeminy, bradycardia and tachycardia have been described in patients with underlying congenital heart disease.

Some subjects requiring assisted ventilation experienced serious difficulties, due to inadequate ventilation and gas exchange. Precipitation of drug within the ventilatory apparatus, including the endotracheal tube, has resulted in increased positive end expiratory pressure and increased positive inspiratory pressure. Accumulation of fluid in tubing (“rain out”) has also been noted. Measures to avoid these complications should be followed carefully (seeDOSAGE AND ADMINISTRATION).

Hematologic

Although anemia was not reported with use of aerosolized Virazole in controlled clinical trials, most infants treated with the aerosol have not been evaluated 1 to 2 weeks post-treatment when anemia is likely to occur. Anemia has been shown to occur frequently with experimental oral and intravenous Virazole in humans. Also, cases of anemia (type unspecified), reticulocytosis and hemolytic anemia associated with aerosolized Virazole use have been reported through post-marketing reporting systems. All have been reversible with discontinuation of the drug.

Other

Rash and conjunctivitis have been associated with the use of aerosolized Virazole. These usually resolve within hours of discontinuing therapy. Seizures and asthenia associated with experimental intravenous Virazole therapy have also been reported.

Adverse Events in Health Care Workers

Studies of environmental exposure to aerosolized Virazole in health care workers administering care to patients receiving the drug have not detected adverse signs or symptoms related to exposure. However, 152 health care workers have reported experiencing adverse events through post-marketing surveillance. Nearly all were in individuals providing direct care to infants receiving aerosolized Virazole. Of 358 events from these 152 individual health care worker reports, the most common signs and symptoms were headache (51% of reports), conjunctivitis (32%), and rhinitis, nausea, rash, dizziness, pharyngitis, or lacrimation (10-20% each). Several cases of bronchospasm and/or chest pain were also reported, usually in individuals with known underlying reactive airway disease. Several case reports of damage to contact lenses after prolonged close exposure to aerosolized Virazole have also been reported. Most signs and symptoms reported as having occurred in exposed health care workers resolved within minutes to hours of discontinuing close exposure to aerosolized Virazole (also seeInformation for Health Care Personnel).

The symptoms of RSV in adults can include headache, conjunctivitis, sore throat and/or cough, fever, hoarseness, nasal congestion and wheezing, although RSV infections in adults are typically mild and transient. Such infections represent a potential hazard to uninfected hospital patients. It is unknown whether certain symptoms cited in reports from health care workers were due to exposure to the drug or infection with RSV. Hospitals should implement appropriate infection control procedures.

Overdosage

No overdosage with Virazole by aerosol administration has been reported in humans. The LD50 in mice is 2 g orally and is associated with hypoactivity and gastrointestinal symptoms (estimated human equivalent dose of 0.17 g/kg, based on body surface area conversion). The mean plasma half-life after administration of aerosolized Virazole for pediatric patients is 9.5 hours. Virazole is concentrated and persists in red blood cells for the life of the erythrocyte (seePharmacokinetics).

Virazole Dosage and Administration

BEFORE USE, READ THOROUGHLY THE VALEANT SMALL PARTICLE AEROSOL GENERATOR SPAG-2 OPERATOR’S MANUAL FOR SMALL PARTICLE AEROSOL GENERATOR OPERATING INSTRUCTIONS. AEROSOLIZED Virazole SHOULD NOT BE ADMINISTERED WITH ANY OTHER AEROSOL GENERATING DEVICE.

The recommended treatment regimen is 20 mg/mL Virazole as the starting solution in the drug reservoir of the SPAG-2 unit, with continuous aerosol administration for 12-18 hours per day for 3 to 7 days. Using the recommended drug concentration of 20 mg/mL the average aerosol concentration for a 12 hour delivery period would be 190 micrograms/liter of air. Aerosolized Virazole should not be administered in a mixture for combined aerosolization or simultaneously with other aerosolized medications.

Non-mechanically ventilated infants

Virazole should be delivered to an infant oxygen hood from the SPAG-2 aerosol generator. Administration by face mask or oxygen tent may be necessary if a hood cannot be employed (see SPAG-2 manual). However, the volume and condensation area are larger in a tent and this may alter delivery dynamics of the drug.

Mechanically Ventilated Infants

The recommended dose and administration schedule for infants who require mechanical ventilation is the same as for those who do not. Either a pressure or volume cycle ventilator may be used in conjunction with the SPAG-2. In either case, patients should have their endotracheal tubes suctioned every 1-2 hours, and their pulmonary pressures monitored frequently (every 2-4 hours). For both pressure and volume ventilators, heated wire connective tubing and bacteria filters in series in the expiratory limb of the system (which must be changed frequently, i.e., every 4 hours) must be used to minimize the risk of Virazole precipitation in the system and the subsequent risk of ventilator dysfunction. Water column pressure release valves should be used in the ventilator circuit for pressure cycled ventilators, and may be utilized with volume cycled ventilators (SEE SPAG-2 MANUAL FOR DETAILED INSTRUCTIONS).

Method of Preparation

Virazole brand of ribavirin is supplied as 6 grams of lyophilized powder per 100 mL vial for aerosol administration only. By sterile technique, reconstitute drug with a minimum of 75 mL of sterile USP water for injection or inhalation in the original 100 mL glass vial. Shake well. Transfer to the clean, sterilized 500 mL SPAG-2 reservoir and further dilute to a final volume of 300 mL with Sterile Water for Injection, USP, or Inhalation. The final concentration should be 20 mg/mL. Important: This water should NOT have had any antimicrobial agent or other substance added. The solution should be inspected visually for particulate matter and discoloration prior to administration. Solutions that have been placed in the SPAG-2 unit should be discarded at least every 24 hours and when the liquid level is low before adding newly reconstituted solution.

How is Virazole Supplied

Virazole (Ribavirin for Inhalation Solution, USP) is supplied in four packs containing 100 mL glass vials with 6 grams of Sterile, lyophilized drug (NDC 0187-0007-14) which is to be reconstituted with 300 mL Sterile Water for Injection or Sterile Water for Inhalation (no preservatives added) and administered only by a small particle aerosol generator (SPAG-2). Vials containing the lyophilized drug powder should be stored in a dry place at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). Reconstituted solutions may be stored, under sterile conditions, at room temperature (20-30°C, 68-86°F) for 24 hours. Solutions which have been placed in the SPAG-2 unit should be discarded at least every 24 hours.

REFERENCES

1. 
   

   Hruska JF, Bernstein JM, Douglas Jr., RG, and Hall CB. Effects of Virazole on respiratory syncytial virus in vitro. Antimicrob Agents Chemother 17:770-775, 1 1980.

   
   


2. 
   

   Hruska JF, Morrow PE, Suffin SC, and Douglas Jr., RG. In vivo inhibition of respiratory syncytial virus by Virazole. Antimicrob Agents Chemother 21:125-130, 1982.

   
   


3. 
   

   Taber LH, Knight V, Gilbert BE, McClung HW et al. Virazole aerosol treatment of bronchiolitis associated with respiratory tract infection in infants. Pediatrics 72:613-618, 1983.

   
   


4. 
   

   Hall CB, McBride JT, Walsh EE, Bell DM et al. Aerosolized Virazole treatment of infants with respiratory syncytial viral infection. N Engl J Med 308:1443-7, 1983.

   
   


5. 
   

   Hendry RM, Mclntosh K, Fahnestock ML, and Pierik LT. Enzymelinked immunosorbent assay for detection of respiratory syncytial virus infection J Clin Microbiol 16:329-33, 1982.

   
   


6. 
   

   Smith, David W., Frankel, Lorry R., Mather, Larry H., Tang, Allen T.S., Ariagno, Ronald L., Prober, Charles G. A Controlled Trial of Aerosolized Ribavirin in Infants Receiving Mechanical Ventilation for Severe Respiratory Syncytial Virus Infection. The New England Journal of Medicine 1991; 325:24-29.

   
   


7. 
   

   Decker, John, Shultz, Ruth A., Health Hazard Evaluation Report: Florida Hospital, Orlando, Florida. Cincinnati OH: U.S. Department of Health and Human Services, Public Health Service, Centers for NIOSH Report No. HETA 91-104-2229.*

   
   


8. 
   

   Barnes, D.J. and Doursew, M. Reference dose: Description and use in health risk assessments. Regul Tox. and Pharm. Vol. 8; p. 471-486, 1988.

   
   


9. 
   

   Federal Register Vol. 53 No. 126 Thurs. June 30, 1988 p. 24834-24847.

   
   


10. 
    

    American Association for Respiratory Care [1991]. Aerosol Consensus Statement-1991. Respiratory Care 36(9): 916-921.

    
    

*Copies of the Report may be purchased from National Technical Information Service, 5285 Port Royal Road, Springfield, VA 22161; Ask for Publication PB 93119-345

VALEANTTM

Manufactured for:

Valeant Pharmaceuticals North America

3300 Hyland Ave.

Costa Mesa, CA 92626 U.S.A.

Part No. 3497301EX00

Rev. 05-06

3497301EX00

Virazole  ribavirin  powder, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0187-0007 Route of Administration RESPIRATORY (INHALATION) DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength ribavirin (ribavirin) Active 6 GRAM  In 1 VIAL

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0187-0007-14 1 VIAL In 1 VIAL, GLASS None

Revised: 03/2007Valeant Pharmaceuticals, Inc.

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Hexalen

Pronunciation: al-TRET-a-meen
Generic Name: Altretamine
Brand Name: Hexalen

Because altretamine can cause blood problems (eg, bone marrow suppression, thrombocytopenia), blood tests must be done before starting Hexalen and at least once a month thereafter. Hexalen can also cause nervous system problems; therefore, nervous system tests must be done during treatment with this drug. Notify your doctor immediately if you develop signs of blood disorders or nervous system problems such as persistent fever or sore throat, easy bruising or bleeding, loss of coordination, mood changes, dizziness, or tingling of the hands or feet.

Hexalen is used for:

Treating certain types of cancer.

Hexalen is an antineoplastic alkylating agent. It is unknown exactly how Hexalen works.

Do NOT use Hexalen if:

• you are allergic to any ingredient in Hexalen


• you have shingles, chicken pox, an infection, severe bone marrow depression, or nerve problems

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

Before using Hexalen:

Tell your health care provider 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 bone marrow cancer, bone marrow depression, a history of low white blood cell count, or liver problems


• if you are receiving radiation

Some MEDICINES MAY INTERACT with Hexalen. Tell your health care provider if you are taking any other medicines, especially any of the following:

• MAO inhibitors (eg, phenelzine) because severe dizziness upon standing may occur


• Pyridoxine because the effectiveness of Hexalen may be decreased

This may not be a complete list of all interactions that may occur. Ask your health care provider if Hexalen 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 Hexalen:

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

• Take Hexalen with food or milk.


• Take Hexalen on the days indicated by your doctor.


• If nausea or vomiting occurs, ask your doctor, nurse, or pharmacist for ways to lessen these effects.


• If you miss a dose of Hexalen, check with your doctor or pharmacist. Doubling missed doses may increase nausea and vomiting.

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

Important safety information:

• Hexalen lowers your resistance to infection. To prevent infection, avoid contact with people who have colds or other infections. Do not touch your eyes or the inside of your nose unless you have thoroughly washed your hands first.


• Hexalen may reduce the number of blood cells needed for clotting. To prevent bleeding, avoid situations where bruising or injury may occur.


• LAB TESTS, such as blood tests including platelet counts, may be done to monitor your progress or to check for side effects. Be sure to keep all doctor and lab appointments.


• Use Hexalen with caution in the ELDERLY because they may be more sensitive to its effects, especially kidney function.


• Hexalen is not recommended for use in CHILDREN; safety and effectiveness have not been confirmed.


• PREGNANCY AND BREAST-FEEDING: Use of Hexalen during pregnancy has resulted in birth defects. If you think you may be pregnant, contact your doctor immediately. It is unknown if Hexalen is excreted in breast milk. Do not breast-feed while taking Hexalen.

Possible side effects of Hexalen:

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:

Nausea; vomiting.

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

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); cough; difficulty walking; dizziness; fever or chills; loss of coordination; mood changes; sores on the mouth or lips; sore throat; tingling or numbness of the hands or feet; unusual bruising or bleeding.

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: Hexalen 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 Hexalen:

Store Hexalen at room temperature between 59 and 86 degrees F (15 and 30 degrees C) in a tightly closed container, away from heat, moisture, and light. Do not store in the bathroom. Keep Hexalen out of the reach of children and away from pets.

General information:

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


• Hexalen is 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 Hexalen. 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

Copyright © 2012 Wolters Kluwer Health, Inc.

More Hexalen resources

• Hexalen Side Effects (in more detail)
• Hexalen Use in Pregnancy & Breastfeeding
• Drug Images
• Hexalen Drug Interactions
• Hexalen Support Group
• 0 Reviews for Hexalen - Add your own review/rating

• Hexalen Prescribing Information (FDA)


• Hexalen Advanced Consumer (Micromedex) - Includes Dosage Information


• Hexalen Concise Consumer Information (Cerner Multum)


• Hexalen Monograph (AHFS DI)


• Altretamine Professional Patient Advice (Wolters Kluwer)

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Intralipid

soybean oil

Dosage Form: I.V fat emulsion
Intralipid® 30%

A 30% I.V. Fat Emulsion in Excel® Container

Pharmacy Bulk Package Not For Direct Infusion

Intralipid Description

Intralipid® 30% (A 30% I.V. Fat Emulsion) Pharmacy Bulk Package is a sterile, non-pyrogenic fat emulsion intended as a source of calories and essential fatty acids for use in a pharmacy admixture program. It is made up of 30% Soybean Oil, 1.2% Egg Yolk Phospholipids, 1.7% Glycerin, and Water for Injection. In addition, sodium hydroxide has been added to adjust the pH so that the final product pH is 8. pH range is 6 to 8.9.

Intralipid® 30% Pharmacy Bulk Package is not intended for direct infusion. It is a sterile dosage form which contains several single doses for use in the preparation of three-in-one or total nutrient admixtures (TNAs) in a pharmacy admixture program.

The soybean oil is a refined natural product consisting of a mixture of neutral triglycerides of predominantly unsaturated fatty acids with the following structure:

where

The major component fatty acids are linoleic (44-62%), oleic (19-30%), palmitic (7-14%), linolenic (4-11%) and stearic (1.4-5.5%)1. These fatty acids have the following chemical and structural formulas:

Linoleic acid C18H32O2
Oleic acid C18H34O2
Palmitic acid C16H32O2
Linolenic acid C18H30O2
Stearic acid C18H36O2

Purified egg phosphatides are a mixture of naturally occurring phospholipids which are isolated from the egg yolk. These phospholipids have the following general structure:

Phosphatidylcholine		Phosphatidylethanolamine

Glycerin is chemically designated C3H8O3 and is a clear colorless, hygroscopic syrupy liquid. It has the following structural formula:

Intralipid® 30% (A 30% I.V. Fat Emulsion) has an osmolality of approximately 310 mOsmoL/kg water (which represents 200 mOsmol/liter of emulsion) and contains emulsified fat particles of approximately 0.5 micron size.

The total caloric value, including fat, phospholipid and glycerin, is 3.0 kcal per mL of Intralipid® 30%. The phospholipids present contribute 47 milligrams or approximately 1.5 mmol of phosphorus per 100 mL of the emulsion.

The primary container is manufactured from Excel® film, a polypropylene based material comprised of three co-extruded layers.

The plastic container is made from multilayered film specifically designed for parenteral drugs. It contains no plasticizers and exhibits virtually no leachables. The solution contact layer is a rubberized copolymer of ethylene and propylene. The container is nontoxic and biologically inert. The container-solution unit is a closed system and is not dependent upon entry of external air during administration. The container is overwrapped to provide protection from the physical environment and to provide an additional moisture barrier when necessary.

Intralipid - Clinical Pharmacology

Intralipid® is metabolized and utilized as a source of energy causing an increase in heat production, decrease in respiratory quotient and increase in oxygen consumption. The infused fat particles are cleared from the blood stream in a manner thought to be comparable to the clearing of chylomicrons.

Intralipid® will prevent the biochemical lesions of essential fatty acid deficiency (EFAD), and correct the clinical manifestations of the EFAD syndrome.

Indications and Usage for Intralipid

Intralipid® 30% Pharmacy Bulk Package is indicated for use in a pharmacy admixture program for the preparation of three-in-one or total nutrient admixtures (TNAs) to provide a source of calories and essential fatty acids for patients requiring parenteral nutrition for extended periods of time (usually for more than 5 days) and as a source of essential fatty acids for prevention of EFAD.

Contraindications

Intralipid® 30% PHARMACY BULK PACKAGE IS NOT INTENDED FOR DIRECT INTRAVENOUS ADMINISTRATION. DILUTING Intralipid® 30% TO A 10% OR 20% CONCENTRATION WITH AN INTRAVENOUS FLUID SUCH AS NORMAL SALINE OR OTHER DILUENT DOES NOT PRODUCE A DILUTION THAT IS EQUIVALENT IN COMPOSITION TO Intralipid® 10% OR 20% I.V. FAT EMULSIONS, AND SUCH A DILUTION SHOULD NOT BE GIVEN BY DIRECT INTRAVENOUS ADMINISTRATION. (FOR EXAMPLE, THROUGH A Y-CONNECTOR).

The administration of Intralipid® is contraindicated in patients with disturbances of normal fat metabolism such as pathologic hyperlipemia, lipoid nephrosis or acute pancreatitis if accompanied by hyperlipidemia. Intralipid® 30% (A 30% I.V. Fat Emulsion) is not intended for direct intravenous infusion.

Warnings

Deaths in preterm infants after infusion of intravenous fat emulsion have been reported in the medical literature.2 Autopsy findings included intravascular fat accumulation in the lungs. Treatment of premature and low birth weight infants with intravenous fat emulsion must be based upon careful benefit-risk assessment. Strict adherence to the recommended total daily dose is mandatory; hourly infusion rate should be as slow as possible in each case and the total fat should not in any case exceed 1 g fat/kg in four hours. Premature and small for gestational age infants have poor clearance of intravenous fat emulsion and increased free fatty acid plasma levels following fat emulsion infusion; therefore, serious consideration must be given to administration of less than the maximum recommended doses in these patients in order to decrease the likelihood of intravenous fat overload. The infant’s ability to eliminate the infused fat from the circulation must be carefully monitored (such as serum triglycerides and/or plasma free fatty acid levels). The lipemia must clear between daily infusions.

Caution should be exercised in administering of Intralipid® 30% to patients with severe liver damage, pulmonary disease, anemia or blood coagulation disorders, or when there is danger of fat embolism.

WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

Precautions

When Intralipid® is administered, the patients capacity to eliminate the infused fat from the circulation must be monitored by use of an appropriate laboratory determination of serum triglycerides. Overdosage must be avoided.

During long term intravenous nutrition with Intralipid®, liver function tests should be performed. If these tests indicate that liver function is impaired, the therapy should be withdrawn. Frequent (some advise daily) platelet counts should be done in neonatal patients receiving parenteral nutrition with Intralipid®.

Drug product contains no more than 25 mcg/L of aluminum.

Carcinogenesis, Mutagenesis, Impairment of Fertility.

Studies with Intralipid® have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

Pregnancy Category C: Animal reproduction studies have not been conducted with Intralipid®. It is also not known whether Intralipid® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Intralipid® should be given to a pregnant woman only if clearly needed.

Nursing Mothers: Caution should be exercised when Intralipid® is administered to a nursing woman.

Pediatric Use: See DOSAGE AND ADMINISTRATION.

AVOID OVERDOSAGE ABSOLUTELY.

Adverse Reactions

The adverse reactions observed can be separated into two classes:

1. Those more frequently encountered are due either to a) contamination of the intravenous catheter and result in sepsis, or to b) vein irritation by concurrently infused hypertonic solutions and may result in thrombophlebitis. These adverse reactions are inseparable from the hyperalimentation procedure with or without Intralipid®.


2. Less frequent reactions more directly related to Intralipid® are: a) immediate or early adverse reactions, each of which has been reported to occur in clinical trials, in an incidence of less than 1%: dyspnea, cyanosis, allergic reactions, hyperlipemia, hypercoagulability, nausea, vomiting, headache, flushing, increase in temperature, sweating, sleepiness, pain in the chest and back, slight pressure over the eyes, dizziness, and irritation at the site of infusion, and, rarely, thrombocytopenia in neonates; b) Delayed adverse reactions such as hepatomegaly, jaundice due to central lobular cholestasis, splenomegaly, thrombocytopenia, leukopenia, transient increases in liver function tests, and overloading syndrome (focal seizures, fever, leukocytosis, hepatomegaly. splenomegaly and shock).

The deposition of a brown pigmentation in the reticuloendothelial system, the so-called “intravenous fat pigment,” has been reported in patients infused with Intralipid®. The causes and significance of this phenomenon are unknown.

Overdosage

In the event of fat overload during therapy, stop the infusion containing Intralipid® 30% (A 30% I.V. Fat Emulsion) until visual inspection of the plasma, determination of triglyceride concentrations, or measurement of plasma light-scattering activity by nephelometry indicates the lipid has cleared. Re-evaluate the patient and institute appropriate corrective measures. See WARNINGS and PRECAUTIONS.

Intralipid Dosage and Administration

Intralipid® 30% (A 30% I.V. Fat Emulsion) Pharmacy Bulk Package should be administered only as a part of a three-in-one or total nutrient admixture via peripheral vein or by central venous infusion.

Directions For Proper Use of Pharmacy Bulk Package

Intralipid® 30% (A 30% I.V. Fat Emulsion) PHARMACY BULK PACKAGE IS NOT INTENDED FOR DIRECT INFUSION. The container closure may be penetrated only once using a suitable sterile transfer device or dispensing set which allows measured dispensing of the contents. The Pharmacy Bulk Package is to be used only in a suitable work area such as a laminar flow hood (or an equivalent clean air compounding area). Once the closure is penetrated, the contents should be dispensed as soon as possible; the transfer of contents to suitable TPN admixture containers must be completed within 4 hours of closure penetration. The bag should be stored below 25°C (77°F) after the closure has been entered. Date and time of container entry should be noted in the area designated on the container label.

Admixtures made using Intralipid 30% should be used promptly. See MIXING GUIDELINES AND LIMITATIONS section for admixture storage recommendations.

Adult Patients

The initial infusion rate of the nutrient admixture in adults should be the equivalent of 0.1 g fat/minute for the first 15 to 30 minutes of infusion. If no untoward reactions occur (see ADVERSE REACTIONS section), the infusion rate of the nutrient admixture can be increased to be equivalent to 0.2 g fat/minute. For adults, the admixture should not contain more than 330 mL of Intralipid® 30% on the first day of therapy. If the patient has no untoward reactions, the dose can be increased on the following day. The daily dosage should not exceed 2.5 g of fat/kg of body weight (8.3 mL of Intralipid® 30% per kg). Intralipid® should make up no more than 60% of the total caloric input to the patient. Carbohydrate and a source of amino acids should comprise the remaining caloric input.

Pediatric Patients

The dosage for premature infants starts at 0.5 g fat/kg body weight/24 hours (1.7 mL) Intralipid® 30% and may be increased in relation to the infant’s ability to eliminate fat. The maximum dosage recommended by the American Academy of Pediatrics is 3 g fat/kg/24 hours3.

The initial rate of infusion of the nutrient admixture in older pediatric patients should be no more than 0.01 g fat/minute for the first 10 to 15 minutes. If no untoward reactions occur, the rate can be changed to permit infusion of 0.1 g of fat/kg/hour. The daily dosage should not exceed 3 g of fat/kg of body weight3.  Intralipid® should make up no more than 60% of the total caloric input to the patient. Carbohydrate and a source of amino acids should comprise the remaining caloric input.

Essential Fatty Acid Deficiency

When Intralipid® is administered to correct essential fatty acid deficiency, eight to ten percent of the caloric input should be supplied by Intralipid® in order to provide adequate amounts of linoleic and linolenic acids. When EFAD occurs together with stress, the amount of Intralipid® needed to correct the deficiency may be increased.

Administration

See MIXING GUIDELINES AND LIMITATIONS section for information regarding mixing this fat emulsion with other parenteral fluids.

Intralipid® 30% (A 30% I.V. Fat Emulsion) is not for direct infusion. It must be infused as part of an admixture into a central or peripheral vein.

The flow rate of the admixture should be controlled with an infusion pump. Filters of less than 1.2 micron pore size must not be used with admixtures containing Intralipid® 30%. Conventional administration sets and TPN pooling bags contain polyvinyl chloride (PVC) components that have DEHP (diethyl hexyl phthalate) as a plasticizer. Fat-containing fluids such as Intralipid® extract DEHP from these PVC components. Therefore it may be advisable to use a non-DEHP administration set for infusing admixtures which contain Intralipid®.

Do not use any bag in which there appears to be an oiling out on the surface of the emulsion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

MIXING GUIDELINES AND LIMITATIONS

Intralipid® 30% PHARMACY BULK PACKAGE IS NOT INTENDED FOR DIRECT INFUSION. It must be combined with total parenteral nutrition (TPN) fluids so that the resulting admixture has a final concentration of not more than 20% fat (0.2 g fat per mL of admixture). The following table may be used as a guide:

Volume of Intralipid® 30%		Required Minimum Volume of Dextrose/ Amino Acid Solutions		Final Volume of Admixture	Final fat Concentration
1 mL	+	0.5 mL	=	1.5 mL	20%
100 mL	+	50 mL	=	150 mL	20%
250 mL	+	125 mL	=	375 mL	20%
500 mL	+	250 mL	=	750 mL	20%

Investigations have been conducted which demonstrate the compatibility of Intralipid® 30% when properly mixed with either Novamine® (8.5%, 11.4% or 15%) or 8.5% Travasol® or 10% Travasol® Amino Acid Injections for use in Total Parenteral Nutrition (TPN) therapy. Because of the potential for life threatening events, caution should be taken to ensure that precipitates have not formed in any parenteral nutrition mixture. Perform all manipulations in a suitable work area, such as a laminar flow hood.

Failure to follow the Mixing Guidelines and Limitations below, including recommended storage temperature, storage time, order of mixing, etc., may result in an unstable admixture.

The following proper mixing sequence must be followed to minimize pH related problems by ensuring that typically acidic Dextrose Injections are not mixed with lipid emulsions alone:

1. Transfer Dextrose Injection to the TPN admixture Container


2. Transfer Amino Acid Injection


3. Transfer Intralipid® 30% (A 30% I.V. Fat Emulsion)

Note: Amino Acid Injection, Dextrose Injection and Intralipid® may be simultaneously transferred to the admixture container. Admixing should be accompanied by gentle agitation to avoid localized concentration effects.

These admixtures should be used promptly with storage under refrigeration (2-8°C) not to exceed 24 hours and must be completely used within 24 hours after removal from refrigeration.

It is essential that the admixture be prepared using strict aseptic techniques as this nutrient mixture is a good growth medium for microorganisms.

Additives other than those named above may be incompatible. Complete information is not available. Those additives known to be incompatible should not be used. Consult with pharmacist. If in the informed judgement of the prescribing physician, it is deemed advisable to introduce additives, use aseptic technique. Mix thoroughly when additives have been introduced. Do not store solutions containing additives (e.g., vitamins and minerals).

Additives must not be added directly to Intralipid® and in no case should Intralipid® be added to the TPN container first. Bags should be shaken gently after each addition to minimize localized concentration.

Supplemental electrolytes, trace metals or multivitamins may be required in accordance with the prescription of the attending physician.

The prime destabilizers of emulsions are excessive acidity (low pH) and inappropriate electrolyte content. Careful consideration should be given to additions of divalent cations (Ca++ and Mg++) which have been shown to cause emulsion instability. Amino acid solutions exert a buffering effect protecting the emulsion.

The admixture should be inspected carefully for “breaking or oiling out” of the emulsion. “Breaking or oiling out” is described as the separation of the emulsion and can be visibly identified by a yellowish streaking or the accumulation of yellowish droplets in the admixed emulsion. The admixture should also be examined for particulates. The admixture must be discarded if any of the above is observed.

How is Intralipid Supplied

Intralipid® 30% (A 30% I.V. Fat Emulsion) is supplied as a sterile emulsion in a Pharmacy Bulk Package in the following fill sizes:

500 mL: 0338-0520-03

STORAGE

Intralipid® 30% should not be stored above 25°C (77°F). Do not freeze Intralipid® 30%. If accidentally frozen, discard the bag.

REFERENCES

1. Padley FB: “Major Vegetable Fats,” The Lipid Handbook (Gunstone FD, Harwood JL, Padley FB, eds.), Chapman and Hall Ltd., Cambridge, UK (1986), pp. 88-9.


2. Levene MI, Wigglesworth JS, Desai R: Pulmonary fat accumulation after Intralipid® infusion in the preterm infant. Lancet 1980; 2(8199):815-8.


3. American Academy of Pediatrics: Use of intravenous fat emulsion in pediatric patients. Pediatrics 1981; 68:5(Nov) 738-43.

(Rev April 2000)

Manufactured for

Baxter Healthcare Corporation

Clintec Nutrition Division

Deerfield, IL 60015 USA

Manufactured by

Fresenius Kabi,

Uppsala, Sweden

Intralipid® is a registered trademark of Fresenius Kabi AB.

Novamine® is a registered trademark of Fresenius Kabi AB.

Travasol® is a registered trademark of Baxter Healthcare Corporation.

Instruction for Use - Intralipid® 30% Pharmacy Bulk Package Container

1. 

1. The integrity indicator (Oxalert™) A should be inspected before removing the overpouch. If the indicator is black the overpouch is damaged and the

    product should be discarded.

 

2. 

2. Remove the overwrap by tearing at the notch and pulling down along the container. The Oxalert™ sachet A and the oxygen absorber B should be disposed.

 

3. 

3. Remove set port cover lifting ring with thumb and forefinger and pulling upwards.

PACKAGE LABEL - PRINCIPAL DISPLAY - Intralipid 500 mL Container Label

NDC 0338-0520-03

Intrapilid® 30%

A 30% I.V. Fat Emulsion

500 mL Excel® Container

Rx only

Pharmacy Bulk Package

Not For Direct Infusion

For Intravenous Use

Intralipid  soybean oil  emulsion

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0338-0520 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SOYBEAN OIL (SOYBEAN OIL) SOYBEAN OIL 30 g  in 100 mL

Inactive Ingredients Ingredient Name Strength EGG PHOSPHOLIPIDS 1.2 g  in 100 mL GLYCERIN 1.7 g  in 100 mL SODIUM HYDROXIDE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0338-0520-03 500 mL In 1 BAG None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA019942	04/01/2004

Labeler - Baxter Healthcare Corporation (005083209)

Registrant - Fresenius Kabi Deutschland GmbH (315520085)

Establishment
Name	Address	ID/FEI	Operations
Fresenius Kabi AB Uppsala		559785113	ANALYSIS, MANUFACTURE

Revised: 02/2011Baxter Healthcare Corporation

More Intralipid resources

• Intralipid Side Effects (in more detail)
• Intralipid Dosage
• Intralipid Drug Interactions
• Intralipid Support Group
• 0 Reviews · Be the first to review/rate this drug

Aspirin Tablets 300mg (POM)

Due to technical difficulties in printing the label-leaflet format, please find the relevant text below. Text is representative of the leaflet portion of label-leaflet spec no 50134509.

Aspirin 300mg Tablets

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

Index

1. What Aspirin tablets are and what they are used for

2. Before you take

3. How to take

4. Possible side effects

5. How to store

6. Further information

What Aspirin tablets are and what they are used for

Aspirin tablets belong to a group of medicines which have analgesic (pain relieving), anti-inflammatory (inflammation reducing) and anti-pyretic (temperature reducing) properties.

These tablets may be used for the relief of:

• headache, toothache, migraine, neuralgia (nerve pain), sore throat or period pains.


• symptoms of influenza, feverishness, rheumatic pains, sciatica (nerve pain of the leg/back), lumbago (lower back pain), fibrositis (muscular rheumatism), muscular aches and pains.

The tablets may also be used to prevent blood clots especially after a heart attack or in patients with unstable angina or reduced blood flow in the brain.

Before you take

Do not take Aspirin tablets and tell your doctor if you have:

• an allergy (hypersensitivity) to aspirin, salicylates or non-steroidal anti-inflammatory drugs (NSAIDs) or other ingredients in the product. You may have developed difficulty breathing, a runny nose, itchy skin or swelling after taking aspirin or a NSAID previously (see section 6)


• a stomach ulcer or a history of ulcers or indigestion


• 
  nasal polyps associated with asthma


• 
  haemophilia or other blood clotting disorder or are taking medicines to thin the blood.

Important warning:

There is a possible association between aspirin and Reye's Syndrome when given to children. Reye's syndrome is a very rare disease, which can be fatal. For this reason aspirin should not be given to children aged under 16 years, unless on the advice of a doctor.

Check with your doctor or pharmacist before taking Aspirin tablets if you have:

• 
  asthma or allergies


• 
  heart, liver or kidney problems or gout


• an overactive thyroid gland


• 
  dehydration
  


• 
  anaemia or suffer from a deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD) this can cause episodes of anaemia after eating certain foods such as fava beans (favism)


• systemic lupus erythematosus (SLE) or other connective tissue disease.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Especially:

• medicines to prevent blood clotting such as warfarin, dipyridamole and heparin


• metoclopramide or domperidone (to prevent sickness)


• diuretics ("water tablets") e.g. spironolactone, frusemide, acetazolamide (to treat high blood pressure)


• medicines which make your urine more alkaline such as antacids, citrates


• probenecid, sulphinpyrazone (to treat gout)


• methotrexate (to treat some cancers, psoriasis and rheumatic disease)


• antidiabetics


• phenytoin or sodium valproate (to treat epilepsy)


• corticosteroids (to suppress the immune system)


• mifepristone (to induce abortion)


• other non-steroidal anti-inflammatory drugs - NSAIDs (eg ibuprofen or naproxen)


• medicines which can cause hearing problems (vancomycin).

Pregnancy and breast-feeding

Avoid taking Aspirin tablets during pregnancy especially in the last 3 months of pregnancy or whilst breast-feeding. Ask your doctor or pharmacist for advice before taking this medicine.

Surgery and tests

If you need to have an operation including having your teeth removed or blood and urine tests, tell your doctor or dentist you are taking this medicine.

How to take

Always take Aspirin tablets exactly as your doctor has told you. If you are not sure, check with your doctor or pharmacist.

Avoid alcohol whilst taking this medicine.

Swallow the tablets with a glass of water.

Doses:

Adults, including the elderly
: 1 or 2 tablets every 3 to 4 hours as required. No more than 12 tablets in any 24 hour period.

Children under 16 years old
: Not recommended.

For prevention of blood clots: 1 tablet once a day.

If you take more than you should

If you (or someone else) swallow a lot of tablets at the same time, or you think a child may have swallowed any contact your nearest hospital casualty department or tell your doctor immediately. Symptoms of an overdose include ringing in the ears, spinning sensation, fast breathing rate, changes in some of the chemicals in the body, heart or kidney failure, fever or coma.

If you forget to take the tablets

Do not take a double dose to make up for a forgotten dose. If you forget to take a dose take it as soon as you remember it and then take the next dose at the right time. Do not take more than one dose in any 4 hour period.

Possible side effects

Like all medicines, Aspirin tablets can cause side effects, although not everybody gets them. Please tell your doctor or pharmacist if you notice any of the following effects or any effects not listed.

Allergic reactions - runny nose, itchy skin, swelling of the face, lips, throat or tongue, worsening of asthma.

Gastrointestinal system - stomach ulcers or bleeding which can be severe (you may develop bloody or black tarry stools, severe stomach pain and vomit blood), stomach irritation (mild stomach pain, heartburn and feeling sick) and inflammation of the liver.

Blood - anaemia, changes in numbers and types of blood cells. If you have an increase in number of nose bleeds or notice that you bruise more easily or have more infections talk to your doctor.

Ears - ringing or buzzing in the ear.

Salicylism - if you take large doses for a long time you may develop symptoms of salicylism, these include: dizziness, ringing or buzzing in the ear, deafness, sweating, feeling or being sick, headache and confusion.

If you are concerned about any side-effects or have any other unusual effects, tell your doctor immediately and seek advice.

How to store

Keep out of the reach and sight of children.

Store the tablets below 25°C in a dry place.

Do not use Aspirin tablets after the expiry date stated on the label/carton/bottle. The expiry date refers to the last day of that month.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further information

What Aspirin tablets contain

• The active substance (the ingredient that makes the tablets work) is 300mg aspirin (also known as acetylsalicylic acid).


• The other ingredients are maize starch, purified talc (E553).

What Aspirin tablets look like and contents of the pack

Aspirin are white, uncoated tablets.

Pack sizes are 100 tablets.

Marketing Authorisation Holder and manufacturer

Actavis

Barnstaple

EX32 8NS

UK

This leaflet was last revised in January 2008

Iodosorb Gel

Pronunciation: ka-DEX-oh-mer EYE-oh-din
Generic Name: Cadexomer Iodine
Brand Name: Iodosorb

Iodosorb Gel is used for:

Cleansing and protecting wounds and sores (eg, wet ulcers, venous stasis ulcers, pressure sores, infected surgical wounds). It may also be used for other conditions as determined by your doctor

Iodosorb Gel is an antibacterial and absorbent agent. It works by absorbing fluid and bacteria from the surface of the wound, which helps it to heal.

Do NOT use Iodosorb Gel if:

• you are allergic to any ingredient in Iodosorb Gel, including iodine


• you have Hashimoto thyroiditis, or a history of Grave disease or nontoxic nodular goiter


• you are pregnant or breast-feeding

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

Before using Iodosorb Gel:

Some medical conditions may interact with Iodosorb Gel. 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 thyroid or kidney problems

Some MEDICINES MAY INTERACT with Iodosorb Gel. However, no specific interactions with Iodosorb Gel are known at this time.

This may not be a complete list of all interactions that may occur. Ask your health care provider if Iodosorb Gel 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 Iodosorb Gel:

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

• An additional patient leaflet is available with Iodosorb Gel. Talk to your pharmacist if you have questions about this information.


• Wash your hands before and after using Iodosorb Gel, unless your hands are a part of the treated area.


• Clean the wound and surrounding area with a gentle stream of sterile water, saline, or other wound cleansing solution. Do not dry the area.


• Spread a thin layer (up to inch) of Iodosorb Gel on dry, sterile gauze. Use enough medicine to completely cover the wound. With gloved hands, place the prepared gauze onto the wound.


• If you are treating a venous stasis ulcer, use a compression bandage as directed by your doctor.


• Change the gauze dressing when the medicine changes from brown to yellow/gray or as directed by your doctor.


• To change the dressing, peel the gauze away from the wound and cleanse the area. Gently blot away excess fluid and leave the surface slightly moist. Prepare the gauze as before and reapply.


• If you miss a dose of Iodosorb Gel, use it as soon as you remember. Continue to use Iodosorb Gel as directed by your doctor.

Ask your health care provider any questions you may have about how to use Iodosorb Gel.

Important safety information:

• Iodosorb Gel is for external use only. Do not get Iodosorb Gel in your eyes, nose, or mouth. If you get Iodosorb Gel in your eyes, rinse immediately with cool water.


• Iodosorb Gel is not effective in cleaning dry wounds.


• The wound may appear larger during the first few days of treatment, due to decreased swelling.


• Do not use more of Iodosorb Gel than prescribed.


• Do not use Iodosorb Gel for longer than 3 months without checking with your doctor.


• Iodosorb Gel may interfere with certain lab tests, including thyroid function tests. Be sure your doctor and lab personnel know you are using Iodosorb Gel.


• Use Iodosorb Gel with extreme caution in CHILDREN. Safety and effectiveness have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Do not use Iodosorb Gel if you are pregnant. If you think you may be pregnant, contact your doctor immediately. Iodosorb Gel is excreted in breast milk. Do not breast-feed while taking Iodosorb Gel.

Possible side effects of Iodosorb Gel:

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 irritation, pain, redness, or swelling at the application site.

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

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

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: Iodosorb 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 Iodosorb Gel:

Store Iodosorb Gel at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Keep Iodosorb Gel out of the reach of children and away from pets

General information:

• If you have any questions about Iodosorb Gel, please talk with your doctor, pharmacist, or other health care provider.


• Iodosorb Gel is 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 Iodosorb Gel. 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

Copyright © 2012 Wolters Kluwer Health, Inc.

More Iodosorb resources

• Iodosorb Side Effects (in more detail)
• Iodosorb Use in Pregnancy & Breastfeeding
• Iodosorb Support Group
• 0 Reviews · Be the first to review/rate this drug