Primaxin IM

imipenem and cilastatin sodium

Dosage Form: injection, powder, for suspension
PRIMAXIN® I.M.

(IMIPENEM AND CILASTATIN FOR INJECTABLE SUSPENSION)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of PRIMAXIN I.M.1 and other antibacterial drugs, PRIMAXIN I.M. should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.


For Intramuscular Injection Only

1

Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Copyright © 1985, 1998 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

All rights reserved

Primaxin IM Description

PRIMAXIN I.M. (Imipenem and Cilastatin for Injectable Suspension) is a formulation of imipenem (a thienamycin antibiotic) and cilastatin sodium (the inhibitor of the renal dipeptidase, dehydropeptidase I). PRIMAXIN I.M. is a potent broad spectrum antibacterial agent for intramuscular administration.

Imipenem (N-formimidoylthienamycin monohydrate) is a crystalline derivative of thienamycin, which is produced by Streptomyces cattleya. Its chemical name is [5R-[5α, 6α (R *)]]-6-(1-hydroxyethyl) -3-[[2-[(iminomethyl) amino] ethyl]thio]-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid monohydrate. It is an off-white, nonhygroscopic crystalline compound with a molecular weight of 317.37. It is sparingly soluble in water, and slightly soluble in methanol. Its empirical formula is C12H17N3O4S•H2O, and its structural formula is:

Cilastatin sodium is the sodium salt of a derivatized heptenoic acid. Its chemical name is [R-[R*, S*-(Z)]]-7-[(2-amino-2-carboxyethyl)thio]-2-[[(2,2-dimethylcyclopropyl)carbonyl]amino]-2-heptenoic acid, monosodium salt. It is an off-white to yellowish-white, hygroscopic, amorphous compound with a molecular weight of 380.43. It is very soluble in water and in methanol. Its empirical formula is C16H25N2O5SNa, and its structural formula is:

PRIMAXIN I.M. 500 contains 32 mg of sodium (1.4 mEq) and PRIMAXIN I.M. 750 contains 48 mg of sodium (2.1 mEq). Prepared PRIMAXIN I.M. suspensions are white to light tan in color. Variations of color within this range do not affect the potency of the product.

Primaxin IM - Clinical Pharmacology

Following intramuscular administrations of 500 or 750 mg doses of imipenem-cilastatin sodium in a 1:1 ratio with 1% lidocaine, peak plasma levels of imipenem antimicrobial activity occur within 2 hours and average 10 and 12 μg/mL, respectively. For cilastatin, peak plasma levels average 24 and 33 μg/mL, respectively, and occur within 1 hour. When compared to intravenous administration of imipenem-cilastatin sodium, imipenem is approximately 75% bioavailable following intramuscular administration while cilastatin is approximately 95% bioavailable. The absorption of imipenem from the IM injection site continues for 6 to 8 hours while that for cilastatin is essentially complete within 4 hours. This prolonged absorption of imipenem following the administration of the intramuscular formulation of imipenem-cilastatin sodium results in an effective plasma half-life of imipenem of approximately 2 to 3 hours and plasma levels of the antibiotic which remain above 2 μg/mL for at least 6 or 8 hours, following a 500 mg or 750 mg dose, respectively. This plasma profile for imipenem permits IM administration of the intramuscular formulation of imipenem-cilastatin sodium every 12 hours with no accumulation of cilastatin and only slight accumulation of imipenem.

A comparison of plasma levels of imipenem after a single dose of 500 mg or 750 mg of imipenem-cilastatin sodium (intravenous formulation) administered intravenously or of imipenem-cilastatin sodium (intramuscular formulation) diluted with 1% lidocaine and administered intramuscularly is as follows:

PLASMA CONCENTRATIONS OF IMIPENEM (μg/mL)

* ND: Not Detectable (<0.3 μg/mL)
	500 MG		750 MG
TIME 25 min 1 hr 2 hr 4 hr 6 hr 12 hr	I.V. 45.1 21.6 10.0 2.6 0.6 ND*	I.M. 6.0 9.4 9.9 5.6 2.5 0.5	I.V. 57.0 28.1 12.0 3.4 1.1 ND*	I.M. 6.7 10.0 11.4 7.3 3.8 0.8

Imipenem urine levels remain above 10 μg/mL for the 12-hour dosing interval following the administration of 500 mg or 750 mg doses of the intramuscular formulation of imipenem-cilastatin sodium. Total urinary excretion of imipenem averages 50% while that for cilastatin averages 75% following either dose of the intramuscular formulation of imipenem-cilastatin sodium.

Imipenem, when administered alone, is metabolized in the kidneys by dehydropeptidase I resulting in relatively low levels in urine. Cilastatin sodium, an inhibitor of this enzyme, effectively prevents renal metabolism of imipenem so that when imipenem and cilastatin sodium are given concomitantly, increased levels of imipenem are achieved in the urine. The binding of imipenem to human serum proteins is approximately 20% and that of cilastatin is approximately 40%.

In a clinical study in which a 500-mg dose of the intramuscular formulation of imipenem-cilastatin sodium was administered to healthy subjects, the average peak level of imipenem in interstitial fluid (skin blister fluid) was approximately 5.0 μg/mL within 3.5 hours after administration.

Imipenem-cilastatin sodium is hemodialyzable. However, usefulness of this procedure in the overdosage setting is questionable. (See OVERDOSAGE.)

Microbiology

The bactericidal activity of imipenem results from the inhibition of cell wall synthesis. Its greatest affinity is for penicillin-binding proteins (PBPs) 1A, 1B, 2, 4, 5 and 6 of Escherichia coli , and 1A, 1B, 2, 4 and 5 of Pseudomonas aeruginosa. The lethal effect is related to binding to PBP 2 and PBP 1B.

Imipenem has a high degree of stability in the presence of beta-lactamases, including penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria. It is a potent inhibitor of beta-lactamases from certain gram-negative bacteria which are inherently resistant to many beta-lactam antibiotics, e.g., Pseudomonas aeruginosa, Serratia spp. and Enterobacter spp.

Imipenem has in vitro activity against a wide range of gram-positive and gram-negative organisms. Imipenem has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections treated with the intramuscular formulation of imipenem-cilastatin sodium as described in the INDICATIONS AND USAGE section.

Gram-positive aerobes:

Staphylococcus aureus including penicillinase-producing strains

(NOTE: Methicillin-resistant staphylococci should be reported as resistant to imipenem.)

Group D streptococcus including Enterococcus faecalis

(formerly S. faecalis)

(NOTE: Imipenem is inactive in vitro against Enterococcus faecium [formerly S. faecium].)

Streptococcus pneumoniae

Streptococcus pyogenes (Group A streptococci)

Streptococcus viridans group

Gram-negative aerobes:

Acinetobacter spp., including A. calcoaceticus

Citrobacter spp.

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Klebsiella pneumoniae

Pseudomonas aeruginosa

(NOTE: Imipenem is inactive in vitro against Xanthomonas (Pseudomonas ) maltophilia and P. cepacia.)

Gram-positive anaerobes:

Peptostreptococcus spp.

Gram-negative anaerobes:

Bacteroides spp., including

Bacteroides distasonis

Bacteroides intermedius

(formerly B. melaninogenicus intermedius)

Bacteroides fragilis

Bacteroides thetaiotaomicron

Fusobacterium spp.

Imipenem exhibits in vitro minimal inhibitory concentrations (MICs) of 4 μg/mL or less against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of imipenem in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Gram-positive aerobes:

Bacillus spp.

Listeria monocytogenes

Nocardia spp.

Group C streptococci

Group G streptococci

Gram-negative aerobes:

Aeromonas hydrophila

Alcaligenes spp.

Capnocytophaga spp.

Enterobacter agglomerans

Haemophilus ducreyi

Klebsiella oxytoca

Neisseria gonorrhoeae including penicillinase-producing strains

Pasteurella spp.

Proteus mirabilis

Providencia stuartii

Gram-positive anaerobes:

Clostridium perfringens

Gram-negative anaerobes:

Prevotella bivia

Prevotella disiens

Prevotella melaninogenica

Veillonella spp.

In vitro tests show imipenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa.

Susceptibility Tests:

Dilution techniques:

Use a standardized dilution method{1} (broth, agar, microdilution) or equivalent with imipenem powder. The MIC values obtained should be interpreted according to the following criteria:

MIC (μg/mL)	Interpretation
≤4 8 ≥16	Susceptible Moderately Susceptible Resistant

A report of “susceptible” indicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report of “moderately susceptible” suggests that the organism would be susceptible if high dosage is used or if the infection is confined to tissues and fluids in which high antibiotic levels are attained. A report of “resistant” indicates that achievable concentrations are unlikely to be inhibitory and other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control organisms. Standard imipenem powder should provide the following MIC values:

Organism	MIC (μg/mL)
E. coli ATCC 25922 S. aureus ATCC 29213 E. faecalis ATCC 29212 P. aeruginosa ATCC 27853	0.06-0.25 0.015-0.06 0.5-2.0 1.0-4.0

Diffusion techniques:

Quantitative methods that require measurement of zone diameters give the most precise estimate of antibiotic susceptibility. One such standard procedure{2}, which has been recommended for use with disks to test susceptibility of organisms to imipenem, uses the 10-μg imipenem disk. Interpretation involves the correlation of the diameters obtained in the disk test with the minimum inhibitory concentration (MIC) for imipenem.

Reports from the laboratory giving results of the standard single-disk susceptibility test with a 10-μg imipenem disk should be interpreted according to the following criteria:

Zone Diameter (mm)	Interpretation
≥16 14-15 ≤13	Susceptible Moderately Susceptible Resistant

Standardized procedures require the use of laboratory control organisms. The 10-μg imipenem disk should give the following zone diameters:

Organism	Zone Diameter (mm)
E. coli ATCC 25922 P. aeruginosa ATCC 27853	26-32 20-28

For anaerobic bacteria, the MIC of imipenem can be determined by agar or broth dilution (including microdilution) techniques{3}.

The MIC values obtained should be interpreted according to the following criteria:

MIC (μg/mL)	Interpretation
≤4 8 ≥16	Susceptible Moderately Susceptible Resistant

Indications and Usage for Primaxin IM

PRIMAXIN I.M. is indicated for the treatment of serious infections (listed below) of mild to moderate severity for which intramuscular therapy is appropriate. PRIMAXIN I.M. is not intended for the therapy of severe or life-threatening infections, including bacterial sepsis or endocarditis, or in instances of major physiological impairments such as shock.

PRIMAXIN I.M. is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions listed below:

1. Lower respiratory tract infections, including pneumonia and bronchitis as an exacerbation of COPD (chronic obstructive pulmonary disease), caused by Streptococcus pneumoniae and Haemophilus influenzae.


2. Intra-abdominal infections, including acute gangrenous or perforated appendicitis and appendicitis with peritonitis, caused by Group D streptococcus including Enterococcus faecalis2; Streptococcus viridans group2, Escherichia coli; Klebsiella pneumoniae2; Pseudomonas aeruginosa2; Bacteroides species including B. fragilis, B. distasonis2, B. intermedius2 and B. thetaiotaomicron2; Fusobacterium species and Peptostreptococcu 2 species.


3. Skin and skin structure infections, including abscesses, cellulitis, infected skin ulcers and wound infections caused by Staphylococcus aureus including penicillinase-producing strains; Streptococcus pyogenes2; Group D streptococcus including Enterococcus faecalis; Acinetobacter species2 including A. calcoaceticus2; Citrobacter species2; Escherichia coli; Enterobacter cloacae; Klebsiella pneumoniae2; Pseudomonas aeruginosa 2; and Bacteroides species2 including B. fragilis2.


4. Gynecologic infections, including postpartum endomyometritis, caused by Group D streptococcus including Enterococcus faecalis2; Escherichia coli; Klebsiella pneumoniae2; Bacteroides intermedius2; and Peptostreptococcus species2.

As with other beta-lactam antibiotics, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with PRIMAXIN I.M. During therapy of Pseudomonas aeruginosa infections, periodic susceptibility testing should be done when clinically appropriate.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of PRIMAXIN I.M. and other antibacterial drugs, PRIMAXIN I.M. should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2

Efficacy for this organism in this organ system was studied in fewer than 10 infections.

Contraindications

PRIMAXIN I.M. is contraindicated in patients who have shown hypersensitivity to any component of this product. Due to the use of lidocaine hydrochloride diluent, this product is contraindicated in patients with a known hypersensitivity to local anesthetics of the amide type and in patients with severe shock or heart block. (Refer to the package circular for lidocaine hydrochloride.)

Warnings

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (anaphylactic) REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING THERAPY WITH BETA-LACTAMS. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH ANOTHER BETA-LACTAM. BEFORE INITIATING THERAPY WITH PRIMAXIN® I.M., CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OTHER BETA-LACTAMS, AND OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, PRIMAXIN® SHOULD BE DISCONTINUED. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, MAY ALSO BE ADMINISTERED AS INDICATED.

Seizure Potential

Seizures and other CNS adverse experiences, such as myoclonic activity, have been reported during treatment with PRIMAXIN I.M. (See PRECAUTIONS and ADVERSE REACTIONS.)

Case reports in the literature have shown that co-administration of carbapenems, including imipenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. The concomitant use of imipenem and valproic acid/divalproex sodium is generally not recommended. Anti-bacterials other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of PRIMAXIN I.M. is necessary, supplemental anti-convulsant therapy should be considered (see PRECAUTIONS, Drug Interactions).

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including PRIMAXIN I.M., and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Lidocaine HCl — Refer to the package circular for lidocaine HCl.

Precautions

General

CNS adverse experiences such as myoclonic activity or seizures have been reported with PRIMAXIN I.M. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) who also have compromised renal function. However, there were reports in which there was no recognized or documented underlying CNS disorder. Anticonvulsant therapy should be continued in patients with a known seizure disorder.

As with other antibiotics, prolonged use of PRIMAXIN I.M. may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Prescribing PRIMAXIN I.M. in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Caution should be taken to avoid inadvertent injection into a blood vessel. (See DOSAGE AND ADMINISTRATION.) For additional precautions, refer to the package circular for lidocaine HCl.

Information for Patients

Patients should be counseled to inform their physician if they are taking valproic acid or divalproex sodium. Valproic acid concentrations in the blood may drop below the therapeutic range upon co-administration with PRIMAXIN I.M. If treatment with PRIMAXIN I.M. is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed.

Patients should be counseled that antibacterial drugs including PRIMAXIN I.M. should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When PRIMAXIN I.M. is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by PRIMAXIN I.M. or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Drug Interactions

Since concomitant administration of PRIMAXIN (Imipenem-Cilastatin Sodium) and probenecid results in only minimal increases in plasma levels of imipenem and plasma half-life, it is not recommended that probenecid be given with PRIMAXIN I.M.

PRIMAXIN I.M. should not be mixed with or physically added to other antibiotics. However, PRIMAXIN I.M. may be administered concomitantly with other antibiotics, such as aminoglycosides.

Case reports in the literature have shown that co-administration of carbapenems, including imipenem, to patients receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid (see WARNINGS, Seizure Potential).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term studies in animals have not been performed to evaluate carcinogenic potential of imipenem-cilastatin. Genetic toxicity studies were performed in a variety of bacterial and mammalian tests in vivo and in vitro. The tests used were: V79 mammalian cell mutagenesis assay (imipenem-cilastatin sodium alone and imipenem alone), Ames test (cilastatin sodium alone and imipenem alone), unscheduled DNA synthesis assay (imipenem-cilastatin sodium) and in vivo mouse cytogenetics test (imipenem-cilastatin sodium). None of these tests showed any evidence of genetic alterations.

Reproductive tests in male and female rats were performed with imipenem-cilastatin sodium at intravenous doses up to 80 mg/kg/day and at a subcutaneous dose of 320 mg/kg/day, 2.1 times3 the maximum recommended daily human dose of the intramuscular formulation (on a mg/m2 body surface area basis). Slight decreases in live fetal body weight were restricted to the highest dosage level. No other adverse effects were observed on fertility, reproductive performance, fetal viability, growth, or postnatal development of pups.

3

Based on patient body surface area of 1.6 m2 (weight of 60 kg).

Pregnancy

Teratogenic Effects

Pregnancy Category C:

Teratology studies with cilastatin sodium at doses of 30, 100, and 300 mg/kg/day administered intravenously to rabbits and 40, 200, and 1000 mg/kg/day administered subcutaneously to rats, up to approximately 3.9 and 6.5 times3 the maximum recommended daily human dose (on a mg/m2 body surface area basis) of the intramuscular formulation of PRIMAXIN (25 mg/kg/day) in the two species, respectively, showed no evidence of adverse effects on the fetus. No evidence of teratogenicity was observed in rabbits given imipenem at intravenous doses of 15, 30, or 60 mg/kg/day and rats given imipenem at intravenous doses of 225, 450, or 900 mg/kg/day, up to approximately 0.8 and 5.8 times3 the maximum recommended daily human dose (on a mg/m2 body surface area basis) in the two species, respectively.

Teratology studies with imipenem-cilastatin sodium at intravenous doses of 20 and 80 and a subcutaneous dose of 320 mg/kg/day, approximately equal to (mice) and up to 2.1 times3 (rats) the maximum recommended daily intramuscular human dose (on a mg/m2 body surface area basis) in pregnant rodents during the period of major organogenesis, revealed no evidence of teratogenicity.

Imipenem-cilastatin sodium, when administered to pregnant rabbits subcutaneously at dosages above the usual human dose of the intramuscular formulation (1000-1500 mg/day), caused body weight loss, diarrhea, and maternal deaths. When comparable doses of imipenem-cilastatin sodium were given to non-pregnant rabbits, body weight loss, diarrhea, and deaths were also observed. This intolerance is not unlike that seen with other beta-lactam antibiotics in this species and is probably due to alteration of gut flora.

A teratology study in pregnant cynomolgus monkeys given imipenem-cilastatin sodium at doses of 40 mg/kg/day (bolus intravenous injection) or 160 mg/kg/day (subcutaneous injection) resulted in maternal toxicity including emesis, inappetence, body weight loss, diarrhea, abortion and death in some cases. In contrast, no significant toxicity was observed when non-pregnant cynomolgus monkeys were given doses of imipenem-cilastatin sodium up to 180 mg/kg/day (subcutaneous injection). When doses of imipenem-cilastatin sodium (approximately 100 mg/kg/day or approximately 1.3 times3 the maximum recommended daily human dose of the intramuscular formulation) were administered to pregnant cynomolgus monkeys at an intravenous infusion rate which mimics human clinical use, there was minimal maternal intolerance (occasional emesis), no maternal deaths, no evidence of teratogenicity, but an increase in embryonic loss relative to the control groups.

No adverse effects on the fetus or on lactation were observed when imipenem-cilastatin sodium was administered subcutaneously to rats late in gestation at dosages up to 320 mg/kg/day, 2.1 times the maximum recommended daily human dose (on a mg/m2 body surface area basis).

There are, however, no adequate and well-controlled studies in pregnant women. PRIMAXIN I.M. should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

Nursing Mothers

It is not known whether imipenem-cilastatin sodium or lidocaine HCl (diluent) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PRIMAXIN I.M. is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

Geriatric Use

Clinical studies of PRIMAXIN I.M. did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects; however, clinical studies of PRIMAXIN I.V. in a sufficient number of subjects aged 65 and over have not revealed overall differences in safety or effectiveness between these subjects and younger subjects (refer to the package circular for PRIMAXIN I.V.). Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Dosage adjustment in the case of renal impairment is necessary (see DOSAGE AND ADMINISTRATION, ADULTS WITH IMPAIRED RENAL FUNCTION).

Adverse Reactions

PRIMAXIN I.M.

In 686 patients in multiple dose clinical trials of PRIMAXIN I.M., the following adverse reactions were reported:

Local Adverse Reactions

The most frequent adverse local clinical reaction that was reported as possibly, probably, or definitely related to therapy with PRIMAXIN I.M. was pain at the injection site (1.2%).

Systemic Adverse Reactions

The most frequently reported systemic adverse clinical reactions that were reported as possibly, probably, or definitely related to PRIMAXIN I.M. were nausea (0.6%), diarrhea (0.6%), vomiting (0.3%) and rash (0.4%).

Adverse Laboratory Changes

Adverse laboratory changes without regard to drug relationship that were reported during clinical trials were:

Hemic: decreased hemoglobin and hematocrit, eosinophilia, increased and decreased WBC, increased and decreased platelets, decreased erythrocytes, and increased prothrombin time.

Hepatic: increased AST, ALT, alkaline phosphatase, and bilirubin.

Renal: increased BUN and creatinine.

Urinalysis: presence of red blood cells, white blood cells, casts, and bacteria in the urine.

Potential ADVERSE EFFECTS:

In addition, a variety of adverse effects, not observed in clinical trials with PRIMAXIN I.M., have been reported with intravenous administration of PRIMAXIN I.V. (Imipenem and Cilastatin for Injection). Those listed below are to serve as alerting information to physicians.

Systemic Adverse Reactions

The most frequently reported systemic adverse clinical reactions that were reported as possibly, probably, or definitely related to PRIMAXIN I.V. (Imipenem and Cilastatin for Injection) were fever, hypotension, seizures (see PRECAUTIONS), dizziness, pruritus, urticaria, and somnolence.

Additional adverse systemic clinical reactions reported possibly, probably, or definitely drug related or reported since the drug was marketed are listed within each body system in order of decreasing severity: Gastrointestinal: pseudomembranous colitis (the onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment, see WARNINGS), hemorrhagic colitis, hepatitis (including fulminant hepatitis), hepatic failure, jaundice, gastroenteritis, abdominal pain, glossitis, tongue papillar hypertrophy, staining of the teeth and/or tongue, heartburn, pharyngeal pain, increased salivation; Hematologic: pancytopenia, bone marrow depression, thrombocytopenia, neutropenia, leukopenia, hemolytic anemia; CNS: encephalopathy, tremor, confusion, myoclonus, seizures, paresthesia, vertigo, headache, psychic disturbances including hallucinations; Special Senses: hearing loss, tinnitus, taste perversion; Respiratory: chest discomfort, dyspnea, hyperventilation, thoracic spine pain; Cardiovascular: palpitations, tachycardia; Renal: acute renal failure, oliguria/anuria, polyuria, urine discoloration; Skin: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, angioneurotic edema, flushing, cyanosis, hyperhidrosis, skin texture changes, candidiasis, pruritus vulvae; Body as a whole: polyarthralgia, asthenia/weakness, drug fever.

Adverse Laboratory Changes

Adverse laboratory changes without regard to drug relationship that were reported during clinical trials or reported since the drug was marketed were:

Hepatic: increased LDH; Hemic: positive Coombs test, decreased neutrophils, agranulocytosis, increased monocytes, abnormal prothrombin time, increased lymphocytes, increased basophils; Electrolytes: decreased serum sodium, increased potassium, increased chloride; Urinalysis: presence of urine protein, urine bilirubin, and urine urobilinogen.

Lidocaine HCl— Refer to the package circular for lidocaine HCl.

Overdosage

The acute intravenous toxicity of imipenem-cilastatin sodium in a ratio of 1:1 was studied in mice at doses of 751 to 1359 mg/kg. Following drug administration, ataxia was rapidly produced and clonic convulsions were noted in about 45 minutes. Deaths occurred within 4-56 minutes at all doses.

The acute intravenous toxicity of imipenem-cilastatin sodium was produced within 5-10 minutes in rats at doses of 771 to 1583 mg/kg. In all dosage groups, females had decreased activity, bradypnea and ptosis with clonic convulsions preceding death; in males, ptosis was seen at all dose levels while tremors and clonic convulsions were seen at all but the lowest dose (771 mg/kg). In another rat study, female rats showed ataxia, bradypnea and decreased activity in all but the lowest dose (550 mg/kg); deaths were preceded by clonic convulsions. Male rats showed tremors at all doses and clonic convulsions and ptosis were seen at the two highest doses (1130 and 1734 mg/kg). Deaths occurred between 6 and 88 minutes with doses of 771 to 1734 mg/kg.

In the case of overdosage, discontinue PRIMAXIN I.M., treat symptomatically, and institute supportive measures as required. Imipenem-cilastatin sodium is hemodialyzable. However, usefulness of this procedure in the overdosage setting is questionable.

Primaxin IM Dosage and Administration

PRIMAXIN I.M. is for intramuscular use only.

The dosage recommendations for PRIMAXIN I.M. represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is also present.

Patients with lower respiratory tract infections, skin and skin structure infections, and gynecologic infections of mild to moderate severity may be treated with 500 mg or 750 mg administered every 12 hours depending on the severity of the infection.

Intra-abdominal infection may be treated with 750 mg every 12 hours. [See table below.]

DOSAGE GUIDELINES

Type*/Location of Infection	Severity	Dosage Regimen
* See INDICATIONS AND USAGE section.
Lower respiratory tract Skin and skin structure Gynecologic	Mild/Moderate	500 or 750 mg q 12 h depending on the severity of infection
Intra-abdominal	Mild/Moderate	750 mg q 12 h

Total daily IM dosages greater than 1500 mg per day are not recommended.

The dosage for any particular patient should be based on the location of and severity of the infection, the susceptibility of the infecting pathogen(s), and renal function.

The duration of therapy depends upon the type and severity of the infection. Generally, PRIMAXIN I.M. should be continued for at least two days after the signs and symptoms of infection have resolved. Safety and efficacy of treatment beyond fourteen days have not been established.

PRIMAXIN I.M. should be administered by deep intramuscular injection into a large muscle mass (such as the gluteal muscles or lateral part of the thigh) with a 21 gauge 2” needle. Aspiration is necessary to avoid inadvertent injection into a blood vessel.

ADULTS WITH IMPAIRED RENAL FUNCTION

The safety and efficacy of PRIMAXIN I.M. have not been studied in patients with creatinine clearance of less than 20 mL/min/1.73 m2. Serum creatinine alone may not be a sufficiently accurate measure of renal function. Creatinine clearance (Tcc) may be estimated from the following equation:

Tcc (Males)            =              (wt. in kg) (140–age)

                                           (72) (creatinine in mg/dL)

Tcc (Females)        =             0.85 x above value

PREPARATION FOR ADMINISTRATION

PRIMAXIN I.M. should be prepared for use with 1.0% lidocaine HCl solution4 (without epinephrine). PRIMAXIN I.M. 500 should be prepared with 2 mL and PRIMAXIN I.M. 750 with 3 mL of lidocaine HCl. Agitate to form a suspension, then withdraw and inject the entire contents of vial intramuscularly. The suspension of PRIMAXIN I.M. in lidocaine HCl should be used within one hour after preparation. Note: The IM formulation is not for IV use.

4

Refer to the package circular for lidocaine HCl for detailed information concerning CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS.

COMPATIBILITY AND STABILITY

Before Reconstitution

The dry powder should be stored at a temperature below 25°C (77°F).

Suspensions for IM Administration

Suspensions of PRIMAXIN I.M. are white to light tan in color. Variations of color within this range do not affect the potency of the product.

The suspension of PRIMAXIN I.M. in lidocaine HCl should be used within one hour after preparation.

PRIMAXIN I.M. should not be mixed with or physically added to other antibiotics. However, PRIMAXIN I.M. may be administered concomitantly but at separate sites with other antibiotics, such as aminoglycosides.

How is Primaxin IM Supplied

PRIMAXIN I.M. is supplied as a sterile powder mixture in vials for IM administration as follows:

No. 3582 — 500 mg imipenem equivalent and 500 mg cilastatin equivalent

NDC 0006-3582-75 in trays of 10 vials.

No. 3583 — 750 mg imipenem equivalent and 750 mg cilastatin equivalent

NDC 0006-3583-76 in trays of 10 vials.

REFERENCES

1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically — Fourth Edition. Approved Standard NCCLS Document M7-A4, Vol. 17, No. 2 NCCLS, Villanova, PA, 1997.


2. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests — Sixth Edition. Approved Standard NCCLS Document M2-A6, Vol. 17, No. 1 NCCLS, Villanova, PA, 1997.


3. National Committee for Clinical Laboratory Standards, Method for Antimicrobial Susceptibility Testing of Anaerobic Bacteria — Third Edition. Approved Standard NCCLS Document M11-A3, Vol. 13, No. 26 NCCLS, Villanova, PA, 1993.

Merck Sharp & Dohme Corp., a subsidiary of

MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

Issued February 2010

9882821

This is a representative sample of the packaging. Please see How Supplied section for a complete list of available packaging.


PRINCIPAL DISPLAY PANEL - Single-Dose Vial 500 mg

NDC 0006-3582-75

500

STERILE

PRIMAXIN® I.M.

(IMIPENEM AND CILASTATIN FOR INJECTABLE SUSPENSION)

IMIPENEM 500 mg* *(Anhydrous Equivalent)

CILASTATIN EQUIVALENT 500 mg

CAUTION: SINGLE DOSE VIAL / FOR I.M. USE ONLY

NOT FOR INTRAVENOUS INJECTION

Rx only

500 mg | No. 3582

Merck Sharp & Dohme Corp., a subsidiary of

MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

9960700

For the preparation of Intramuscular Suspension and USUAL ADULT DOSAGE: See accompanying circular.

Store dry material below 25°C.

For intramuscular administration, add 2 mL of 1.0% lidocaine HCl solution (without epinephrine).

Agitate to form a suspension which should be used within one hour after preparation.

Vilazodone

Pronunciation: vil-AZ-oh-done
Generic Name: Vilazodone
Brand Name: Viibryd

Antidepressants may increase the risk of suicidal thoughts or actions in children, teenagers, and young adults. However, depression and certain other mental problems may also increase the risk of suicide. Talk with the patient's doctor to be sure that the benefits of using Vilazodone outweigh the risks.

Families and caregivers must closely watch patients who take Vilazodone. It is important to keep in close contact with the patient's doctor. Tell the doctor right away if the patient has symptoms like worsened depression, suicidal thoughts, or changes in behavior. Discuss any questions with the patient's doctor.

Vilazodone is used for:

Treating depression. It may also be used for other conditions as determined by your doctor.

Vilazodone is an antidepressant. It is thought to work by increasing the activity of one of the brain chemicals (serotonin), which helps elevate mood.

Do NOT use Vilazodone if:

• you are allergic to any ingredient in Vilazodone or to nefazodone


• you are taking rasagiline or tryptophan


• you are taking or have taken linezolid, methylene blue, a monoamine oxidase inhibitor (MAOI) (eg, phenelzine), or St. John's wort within the last 14 days

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

Video: Treatment for Depression

Treatments for depression are getting better everyday and there are things you can start doing right away.

Before using Vilazodone:

Some medical conditions may interact with Vilazodone. 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 low blood volume, low blood pressure, or low blood sodium levels; you are dehydrated; or you are on a low-salt (sodium) diet


• if you or a family member has a history of bipolar disorder (manic-depression) or other mental or mood problems (eg, depression), suicidal thoughts or attempts, alcohol or substance abuse, or if you drink alcohol


• if you have a history of liver problems, kidney problems, bleeding problems, or seizures

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

• Anticoagulants (eg, warfarin), nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, ibuprofen, intranasal ketorolac), or salicylates (eg, aspirin) because the risk of bleeding may be increased


• Antipsychotics (eg, olanzapine, haloperidol), buspirone, fenfluramine or its derivatives (eg, dexfenfluramine), linezolid, MAOIs, (eg, phenelzine), methylene blue, metoclopramide, narcotic (opioid) pain medicines (eg, morphine), phenothiazines (eg, thioridazine), rasagiline, selective serotonin reuptake inhibitors (SSRIs) (eg, fluoxetine), selegiline, serotonin-norepinephrine reuptake inhibitors (SNRIs) (eg, duloxetine, venlafaxine), sibutramine, St. John's wort, tramadol, "triptans" (eg, sumatriptan), or tryptophan because severe side effects, such as a reaction that may include fever, rigid muscles, blood pressure changes, mental changes, confusion, irritability, agitation, delirium, or coma, may occur


• Diuretics (eg, furosemide, hydrochlorothiazide) because the risk of low blood sodium levels may be increased


• Azole antifungals (eg, itraconazole, ketoconazole), HIV protease inhibitors (eg, indinavir, ritonavir), macrolide antibiotics (eg, clarithromycin, erythromycin), nefazodone, or telithromycin because the risk of Vilazodone's side effects may be increased


• Cyproheptadine because it may decrease Vilazodone's effectiveness


• Lithium because the risk of its side effects may be increased by Vilazodone

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

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

• Vilazodone comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Vilazodone refilled.


• Take Vilazodone by mouth with food.


• When starting Vilazodone, your doctor may slowly increase your dose to avoid side effects. Discuss any questions or concerns with your doctor.


• It may take 1 to 4 weeks for Vilazodone to work. Do not stop taking Vilazodone without checking with your doctor.


• Do not suddenly stop taking Vilazodone. You may have an increased risk of side effects. If you need to stop Vilazodone, your doctor will gradually lower your dose.


• If you miss a dose of Vilazodone, 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 Vilazodone.

Important safety information:

• Vilazodone may cause drowsiness, dizziness, or blurred vision. These effects may be worse if you take it with alcohol or certain medicines. Use Vilazodone with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Do not drink alcohol while you are using Vilazodone.


• Check with your doctor before you use medicines that may cause drowsiness (eg, sleep aids, muscle relaxers) while you are using Vilazodone; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness.


• Be sure to keep all doctor appointments while you are taking Vilazodone.


• Children, teenagers, and young adults who take Vilazodone may be at increased risk of suicidal thoughts or actions. Watch all patients who take Vilazodone closely. Contact the doctor at once if new, worsened, or sudden symptoms, such as depressed mood; anxious, restless, or irritable behavior; panic attacks; or any unusual change in mood or behavior, occur. Contact the doctor right away if any signs of suicidal thoughts or actions occur.


• Neuroleptic malignant syndrome (NMS) is a possibly fatal syndrome that can be caused by Vilazodone. Symptoms may include fever; stiff muscles; confusion; abnormal thinking; fast or irregular heartbeat; and sweating. Contact your doctor at once if you have any of these symptoms.


• Serotonin syndrome is a possibly fatal syndrome that can be caused by Vilazodone. Your risk may be greater if you take Vilazodone with certain other medicines (eg, "triptans," MAOIs). Symptoms may include agitation; confusion; hallucinations; coma; fever; fast or irregular heartbeat; tremor; excessive sweating; and nausea, vomiting, or diarrhea. Contact your doctor at once if you have any of these symptoms.


• Tell your doctor or dentist that you take Vilazodone before you receive any medical or dental care, emergency care, or surgery.


• Use Vilazodone with caution in the ELDERLY; they may be more sensitive to its effects, especially low blood sodium levels.


• Vilazodone should not be used in CHILDREN or TEENAGERS; safety and effectiveness in children and teenagers have not been confirmed. Children and teenagers may also be more sensitive to its effects, especially the increased risk of suicidal thoughts or actions.


• PREGNANCY and BREAST-FEEDING: Vilazodone may cause harm to the fetus if taken during the third trimester of pregnancy. If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of taking Vilazodone while you are pregnant. Vilazodone is found in breast milk. If you are or will be breast-feeding while you take Vilazodone, check with your doctor. Discuss any possible risks to your baby.

Do not suddenly stop taking Vilazodone. If you do, you may have WITHDRAWAL symptoms. These may include feeling unwell or unhappy, anxious or irritable, dizzy, confused, or sluggish. You may also have nausea, unusual skin sensations, mood swings, headache, trouble sleeping, or sweating. If you need to stop Vilazodone, your doctor will lower your dose over time.

Possible side effects of Vilazodone:

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:

Decreased sexual desire or ability; diarrhea; dizziness; drowsiness; dry mouth; nausea; vomiting.

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); behavior changes; black, tarry, or bloody stools; bloody or dark urine; blurred vision; decreased coordination; fainting; hallucinations; irregular heartbeat; new or worsening agitation, anxiety, depression, panic attacks, aggressiveness, impulsiveness, irritability, hostility, exaggerated feeling of well-being, restlessness, trouble sleeping, or inability to sit still; seizures; severe or persistent dizziness; suicidal thoughts or actions; symptoms of low blood sodium levels (eg, confusion, severe or persistent headache, trouble concentrating, memory problems, weakness, unsteadiness, sluggishness); tremor; unusual bruising or bleeding; vomit that looks like coffee grounds.

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: Vilazodone 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. Symptoms may include agitation; confusion; disorientation; excessive sweating; fast or irregular heartbeat; fever; hallucinations; loss of consciousness or coma; nausea, vomiting, or diarrhea; restlessness; tiredness or weakness; tremor.

Proper storage of Vilazodone:

Store Vilazodone at 77 degrees F (25 degrees C) in a tight, light-resistant container. Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Vilazodone out of the reach of children and away from pets.

General information:

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


• Vilazodone 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 summary only. It does not contain all information about Vilazodone. 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 Vilazodone resources

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

• vilazodone Advanced Consumer (Micromedex) - Includes Dosage Information


• Viibryd Prescribing Information (FDA)


• Viibryd Consumer Overview

Compare Vilazodone with other medications

• Anxiety
• Depression
• Obsessive Compulsive Disorder

Oculotect

1. Name Of The Medicinal Product

Oculotect 50 mg/ml, eye drops solution in single-dose containers

2. Qualitative And Quantitative Composition

One ml contains 50 mg povidone K25

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Eye drops, solution in single-dose containers

Almost colourless, clear aqueous solution

4. Clinical Particulars

4.1 Therapeutic Indications

Symptomatic treatment of dry eyes.

4.2 Posology And Method Of Administration

One drop into the conjunctival sac of the eye 4 times daily, or as required, depending upon the severity of the condition. The contents of a single-dose container are sufficient for one administration into the left and right eye.

The single-dose containers must be discarded immediately after use. Unused contents must not be stored.

Oculotect eye drops contain a sterile solution until the original closure is broken. The tip of the container should not come into contact with any surface including the eye, as this may cause injury to the eye and contaminate the solution.

4.3 Contraindications

Hypersensitivity to any of the components of the product.

4.4 Special Warnings And Precautions For Use

If irritation of the dry eye persists or worsens, treatment should be discontinued and the patient should consult the physician/ ophthalmologist.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

If the patient instils other medication(s) into the eyes (e.g. for the treatment of glaucoma), there must be an interval of at least 5 minutes between medications. Oculotect should always be instilled last.

4.6 Pregnancy And Lactation

Pregnancy:

There are no data from the use of povidone in pregnant women. Systemic exposure via ocular administration is likely to be negligible.

Animal studies are insufficient with respect to reproductive toxicity. The use of Oculotect eye drops may be considered during pregnancy, if necessary.

Lactation:

It is unknown whether povidone is excreted in human milk. However, no effects on the breastfed newborn/infant are anticipated since the systemic exposure of the breast-feeding woman is negligible. Ocular eye drops can be used during breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

In the event of blurring of vision, patients must refrain from driving vehicles or operating machinery.

4.8 Undesirable Effects

Adverse reactions are ranked under heading of frequency, using the following convention: Very common (

The following adverse events have been reported:

• Immune system disorders

Very rare: Irritation or hypersensitivity reactions

• Eye disorders

Common: Mild transient burning or sticky sensation

Not known: Blurred vision

4.9 Overdose

No case of overdose has been reported.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Ophtalmologicals, artificial tears and other products, ATC code: S01XA20

The product does not contain any active pharmacological compounds. Due to their physical properties, non-irritant water soluble polymers can be used for moistening and lubrication of the ocular surface.

5.2 Pharmacokinetic Properties

Orally administered povidone with a molecular weight of 12,600 is rapidly excreted in the urine, with the major part being excreted within 11 hours.

Following intravenous administration, long-term accumulation of povidone can be avoided by reducing the proportion of povidone of molecular weight higher than 25,000. Because of the relatively large size of the povidone molecule, penetration through the cornea is unlikely.

5.3 Preclinical Safety Data

No toxic effects were observed during or after two years administration of 5 and 10 % PVP K25 (povidone) in to the feed of rats. No data on mutagenicity or teratogenicity are available.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Boric acid

Calcium chloride

Potassium chloride

Magnesium chloride

Sodium chloride

Sodium lactate

Sodium hydroxide for pH adjustment

Water for injections

The product contains no preservative.

6.2 Incompatibilities

High salt concentrations, e.g. of sodium sulphate in cold and of sodium chloride in warm conditions, can result in precipitation of povidone. Depending on the ionic strength of the solution methyl- and propylhydroxybenzoates easily form complexes with povidone.

6.3 Shelf Life

Unopened single-dose container: 2 years

The contents of a single-dose container must be used immediately after first opening.

6.4 Special Precautions For Storage

Do not store above 25°C.

Keep container in the outer carton in order to protect from light.

6.5 Nature And Contents Of Container

The container is a transparent 0.4ml LDPE single-dose container.

Packs of 20, 60 and 120 single-dose containers. Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

The single-dose container itself is not sterile whereas the contents of single-dose containers remain sterile until the original closure is broken.

Oculotect eye drops in single-dose containers must be used immediately once after the container has been opened. The single-dose containers must be discarded after the use. Unused contents must not be stored.

7. Marketing Authorisation Holder

Novartis Pharmaceuticals UK Ltd

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

United Kingdom

8. Marketing Authorisation Number(S)

PL 00101/0611

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 04.12.2001

Date of last renewal: 02.09.2006

10. Date Of Revision Of The Text

23.04.2010

LEGAL CATEGORY

P

nystatin

Generic Name: nystatin (oral) (nye STAH tin)

Brand Names: Bio-Statin, Mycostatin, Mycostatin Pastilles, Nilstat

What is nystatin?

Nystatin is an antifungal medication.

Oral nystatin is used to treat yeast infections of the mouth.

Nystatin may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about nystatin?

Take all of the nystatin that has been prescribed for you even if you begin to feel better. Your symptoms may begin to improve before the infection is completely treated.

What should I discuss with my healthcare provider before taking nystatin?

Nystatin is not absorbed through your stomach. It will not treat fungal infections in any part of your body other than your mouth. Talk to your doctor if you have another type of fungal infection such as athlete's foot, jock itch, ringworm, or a vaginal yeast infection.

Oral nystatin is in the FDA pregnancy category C. This means that it is not known whether nystatin will harm an unborn baby. Do not take this medication without first talking to your doctor if you are pregnant. It is not known whether nystatin will harm a nursing baby. Do not take this medication without first talking to your doctor if you are breast-feeding a baby.

How should I take nystatin?

Take nystatin exactly as directed by your doctor. If you do not understand these instructions, ask your pharmacist, nurse, or doctor to explain them to you.

Take the oral tablets with a full glass of water.

The troches, or pastilles, should be allowed to dissolve in your mouth. Do not chew or swallow them. Suck on one troche at a time until it is completely dissolved.

Shake the suspension well before measuring a dose.

Use a dose-measuring cup, spoon, or dropper to measure the specified dose of the suspension. Swish the suspension around in your mouth, then either spit it out or swallow it, depending upon the instructions given by your doctor.

Take all of the nystatin that has been prescribed for you even if you begin to feel better. Your symptoms may begin to improve before the infection is completely treated. Store the Bio-Statin brand of nystatin tablets and powder and the Mycostatin Pastilles in the refrigerator. Store all other nystatin capsules, tablets, and suspension at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. However, if it is almost time for your next regularly scheduled dose, skip the missed dose and take the next one as directed. Do not take a double dose of this medication unless otherwise directed by your doctor.

What happens if I overdose?

Seek emergency medical attention.

Symptoms of a nystatin overdose include nausea, stomach upset, vomiting, and diarrhea.

What should I avoid while taking nystatin?

There are no restrictions on foods, beverages, or activities during treatment with nystatin unless your doctor directs otherwise.

Nystatin side effects

Stop taking nystatin and seek emergency medical attention if you experience an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives).

Side effects are not likely to occur with nystatin. Continue to take nystatin and talk to your doctor if you experience

• 
  

  nausea or stomach upset,

  
  


• 
  

  vomiting, or

  
  


• 
  

  diarrhea.

  
  

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

Nystatin Dosing Information

Usual Adult Dose for Oral Thrush:

1 to 2 oral lozenges (200,000 to 400,000 units) 4 to 5 times a day or
500,000 units of oral suspension 4 times a day.

Usual Adult Dose for Intestinal Candidiasis:

500,000 to 1,000,000 units orally 3 times a day.

Usual Pediatric Dose for Oral Thrush:

Neonates: 100,000 units of oral suspension 4 times a day.
>1 m >=1 year

What other drugs will affect nystatin?

Since nystatin is not absorbed by your body, drug interactions are not expected. Talk to your doctor and pharmacist before taking other prescription or over-the-counter medicines.

More nystatin resources

• Nystatin Use in Pregnancy & Breastfeeding
• Drug Images
• Nystatin Drug Interactions
• Nystatin Support Group
• 3 Reviews for Nystatin - Add your own review/rating

• nystatin Advanced Consumer (Micromedex) - Includes Dosage Information


• Nystatin Monograph (AHFS DI)


• Nystatin MedFacts Consumer Leaflet (Wolters Kluwer)


• Nystatin Professional Patient Advice (Wolters Kluwer)


• Bio-Statin Powder MedFacts Consumer Leaflet (Wolters Kluwer)


• Mycostatin Prescribing Information (FDA)


• Mycostatin Topical Advanced Consumer (Micromedex) - Includes Dosage Information


• Mycostatin MedFacts Consumer Leaflet (Wolters Kluwer)

Compare nystatin with other medications

• Gastrointestinal Candidiasis
• Oral Thrush

Where can I get more information?

• Your pharmacist has additional information about nystatin written for health professionals that you may read.

Visine LR Drops

Pronunciation: OX-ee-MET-azz-oh-leen
Generic Name: Oxymetazoline
Brand Name: Examples include OcuClear and Visine LR

Visine LR Drops are used for:

Relieving redness in the eye caused by minor irritation.

Visine LR Drops are a decongestant used in the eye. It works by narrowing the blood vessels in the eye, which helps you by relieving irritation.

Do NOT use Visine LR Drops if:

• you are allergic to any ingredient in Visine LR Drops


• you are also taking furazolidone or a monoamine oxidase (MAO) inhibitor (eg, phenelzine)

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

Before using Visine LR Drops:

Some medical conditions may interact with Visine LR 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 glaucoma, high blood pressure, diabetes, or heart or thyroid problems, or are taking medicine for high blood pressure

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

• Tricyclic antidepressants (eg, amitriptyline) because the effectiveness of Visine LR Drops may be decreased


• Cocaine, furazolidone, MAO inhibitors (eg, phenelzine), or tricyclic antidepressants (eg, amitriptyline) because side effects, such as headache, fever, and high blood pressure, may be increased


• Bromocriptine or cocaine because the actions and side effects of these medicines may be increased

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

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

• If you wear contact lenses, remove them before using Visine LR Drops.


• To use Visine LR Drops, wash your hands. Tilt your head back. Using your index finger, pull the lower eyelid away from the eye to form a pouch. Drop the medicine into the pouch and gently close your eyes. Immediately use your finger to apply pressure to the inside corner of the eye and continue to apply pressure for 1 to 2 minutes after using the medicine. Do not blink. Remove excess medicine around your eye with a clean tissue, being careful not to touch your eye. Wash your hands to remove any medicine that may be on them. To prevent germs from entering your medicine, do not touch the applicator tip to any surface, including your eye. Keep the container tightly closed.


• If you miss a dose of Visine LR Drops and are using it regularly, 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 Visine LR Drops.

Important safety information:

• Do not exceed the recommended dose or use Visine LR Drops for longer than 3 days without checking with your doctor. If your symptoms do not improve within 3 days or if they become worse, check with your doctor.


• Visine LR Drops are not recommended for use in CHILDREN younger than 6 years of age. Safety and effectiveness in this age group have not been confirmed.


• PREGNANCY AND BREAST-FEEDING: If you plan on becoming pregnant, discuss with your doctor the benefits and risks of using Visine LR Drops during pregnancy. It is unknown if Visine LR Drops are excreted in breast milk. If you are or will be breast-feeding while you are using Visine LR Drops, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Visine LR 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:

Short period of stinging when the medicine is dropped into the eye.

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); changes in vision; eye pain.

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: Visine LR 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. Visine LR Drops may be harmful if swallowed.

Proper storage of Visine LR Drops:

Store Visine LR Drops at room temperature, between 68 and 77 degrees F (20 and 25 degrees C) in a tightly closed container. Store away from heat and light. Keep Visine LR Drops out of the reach of children and away from pets.

General information:

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


• Visine LR 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 Visine LR 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

Copyright © 2012 Wolters Kluwer Health, Inc.

More Visine LR resources

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

Compare Visine LR with other medications

• Eye Dryness/Redness
• Eye Redness/Itching

Isuprel Mistometer

Generic Name: isoproterenol inhalation (eye so proe TER e nole)

Brand Names: Isuprel Mistometer

What is Isuprel Mistometer (isoproterenol inhalation)?

Isoproterenol is a bronchodilator. It works by relaxing muscles in the airways to improve breathing.

Isoproterenol inhalation is used to treat conditions such as asthma, bronchitis, and emphysema.

Isoproterenol inhalation may also be used for conditions other than those listed in this medication guide.

What is the most important information I should know about Isuprel Mistometer (isoproterenol inhalation)?

It is important to use the isoproterenol inhaler properly, so that the medicine gets into the lungs. Your doctor may want you to use a spacer with the inhaler. Talk to your doctor about proper inhaler use.

Seek medical attention if you notice that you require more than your usual or more than the maximum amount of any asthma medication in a 24-hour period. An increased need for medication could be an early sign of a serious asthma attack.

What should I discuss with my healthcare provider before using Isuprel Mistometer (isoproterenol inhalation)?

Before using this medication, tell your doctor if you have

• 
  

  heart disease or high blood pressure;

  
  


• 
  

  epilepsy or a seizure disorder;

  
  


• 
  

  diabetes;

  
  


• 
  

  an overactive thyroid (hyperthyroidism); or

  
  


• 
  

  liver or kidney disease.

  
  

You may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.

Isoproterenol inhalation is in the FDA pregnancy category C. This means that it is not known whether it will be harmful to an unborn baby. Do not use this medication without first talking to your doctor if you are pregnant or could become pregnant during treatment. It is not known whether isoproterenol passes into breast milk. Do not use isoproterenol inhalation without first talking to your doctor if you are breast-feeding a baby.

How should I use Isuprel Mistometer (isoproterenol inhalation)?

Use isoproterenol inhalation exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

To use the inhaler:

• Shake the inhaler several times and uncap the mouthpiece. Breathe out fully. Put the mouthpiece of the inhaler or spacer into your mouth. Be sure the mouthpiece is above the tongue and past the teeth. Alternatively, place the inhaler mouthpiece (not with spacer attached) several inches in front of your open mouth, if directed to do so by your doctor. Take a deep, slow breath as you push down on the canister. Hold your breath for 10 seconds, then exhale slowly.


• 
  

  If you take more than one dose at a time, wait for at least 1 full minute, then repeat the procedure.

  
  


• 
  

  Keep the inhaler clean and dry. Keep the mouthpiece capped to avoid getting dirt inside it. Clean the inhaler once a day by removing the canister and immersing the mouthpiece in warm water. Allow the parts to dry, then reassemble the inhaler.

  
  

To use the solution for nebulization:

• 
  

  Measure the correct amount of medication with the dropper provided or select the prescribed number of ampules. Transfer the liquid into the medication chamber of the nebulizer. If the medication has a dropper, do not allow the dropper to touch any surface including the hands or the chamber of the nebulizer. Dilute the medication with normal saline if prescribed by your doctor.

  
  


• 
  

  Attach the mouthpiece or face mask to the drug chamber. Then, attach the drug chamber to the compressor. Sit upright, in a comfortable position, and put the mouthpiece into the mouth or put the face mask on, covering the nose and mouth. Breathe slowly and evenly until all of the medicine has been inhaled (usually 5 to 15 minutes). The treatment is complete when no more mist is formed by the nebulizer and the drug chamber is empty.

  
  


• 
  

  Clean the nebulizer after a treatment as directed by the manufacturer.

  
  

If you also use a steroid inhaler, use the isoproterenol inhaler or nebulization solution first to open up the airways, then use the steroid inhaler as directed.

It is important to use the isoproterenol inhaler properly, so that the medicine gets into the lungs. Your doctor may want you to use a spacer with the inhaler. Talk to your doctor about proper inhaler use.

Seek medical attention if you notice that you require more than your usual or more than the maximum amount of any asthma medication in a 24-hour period. An increased need for medication could be an early sign of a serious asthma attack.

Carry the inhaler with you at all times in case of emergencies. Store the solution for nebulization at room temperature. Get a refill before you run out of medicine and before going on vacation.

What happens if I miss a dose?

Use the missed dose as soon as you remember. However, if it is almost time for the next regularly scheduled dose, skip the missed dose and use the next one as directed. Do not use a double dose of this medication.

What happens if I overdose?

Seek emergency medical attention if an overdose is suspected.

Symptoms of an isoproterenol inhalation overdose may include angina or chest pain, irregular heartbeats or a fluttering heart, seizures, tremor, weakness, headache, nausea, and vomiting.

What should I avoid while using Isuprel Mistometer (isoproterenol inhalation)?

Avoid situations that may trigger an asthma attack such as exercising in cold, dry air; smoking; breathing in dust; and exposure to allergens such as pet fur.

Isuprel Mistometer (isoproterenol inhalation) side effects

If you experience any of the following serious side effects, stop using isoproterenol inhalation and seek emergency medical attention or contact your doctor immediately:

• 
  

  an allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives); or

  
  


• 
  

  chest pain or an irregular heartbeat.

  
  

Other, less serious side effects may be more likely to occur. Continue to use isoproterenol inhalation and talk to your doctor if you experience

• 
  

  headache, dizziness, lightheadedness, or insomnia;

  
  


• 
  

  tremor or nervousness;

  
  


• 
  

  sweating;

  
  


• 
  

  nausea, vomiting, or diarrhea; or

  
  


• 
  

  dry mouth.

  
  

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect isoproterenol?

Before using this medication, tell your doctor if you are taking any of the following medicines:

• a beta-blocker such as atenolol (Tenormin), metoprolol (Lopressor, Toprol XL), propranolol (Inderal), and others;


• a tricyclic antidepressant such as amitriptyline (Elavil), doxepin (Sinequan), imipramine (Tofranil), nortriptyline (Pamelor), and others;


• a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate);


• 
  

  another inhaled bronchodilator; or

  
  


• 
  

  caffeine, diet pills, or decongestants.

  
  

You may not be able to use ipratropium inhalation, or you may require a dosage adjustment or special monitoring during treatment.

Drugs other than those listed here may also interact with isoproterenol inhalation or affect your condition. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines, including vitamins, minerals, and herbal products.

More Isuprel Mistometer resources

• Isuprel Mistometer Side Effects (in more detail)
• Isuprel Mistometer Use in Pregnancy & Breastfeeding
• Isuprel Mistometer Drug Interactions
• Isuprel Mistometer Support Group
• 1 Review for Isuprel Mistometer - Add your own review/rating

• Isoproterenol MedFacts Consumer Leaflet (Wolters Kluwer)


• Isoproterenol Professional Patient Advice (Wolters Kluwer)


• Isoproterenol Hydrochloride Monograph (AHFS DI)


• Medihaler-Iso Prescribing Information (FDA)

Compare Isuprel Mistometer with other medications

• Adams-Stokes Syndrome
• Asthma, acute
• AV Heart Block
• Bronchospasm During Anesthesia
• Cardiac Arrhythmia
• COPD, Acute
• Shock

Where can I get more information?

• Your pharmacist has additional information about isoproterenol written for health professionals that you may read.

See also: Isuprel Mistometer side effects (in more detail)