Septrin Paediatric Suspension

1. Name Of The Medicinal Product

Septrin 40 mg/200 mg per 5 ml Paediatric Suspension

2. Qualitative And Quantitative Composition

Each 5 ml contains 200 mg Sulfamethoxazole and 40 mg Trimethoprim

Excipients:

This product contains less than 1 mmol of sodium (23 mg) per dose, and therefore is essentially sodium free.

Also contains 3.25 g sorbitol per 5 ml and less than 100 mg of ethanol per 5 ml.

For a full list of excipients, see Section 6.1

3. Pharmaceutical Form

Suspension

Off white in colour.

4. Clinical Particulars

4.1 Therapeutic Indications

Septrin Paediatric Suspension is indicated for the treatment of the following infections when owing to sensitive organisms (see section 5.1):

Treatment and prevention of Pneumocystis jiroveci (P. carinii) pneumonitis

Treatment and prophylaxis of toxoplasmosis

Treatment of nocardiosis

The following infections may be treated with Septrin where there is bacterial evidence of sensitivity to Septrin and good reason to prefer the combination of antibiotics in Septrin to a single antibiotic:

Acute uncomplicated urinary tract infection

Acute otitis media

Acute exacerbation of chronic bronchitis

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology And Method Of Administration

Method of administration: oral.

It may be preferable to take Septrin with some food or drink to minimise the possibility of gastrointestinal disturbances.

Standard dosage recommendations for acute infections

Children aged 12 years and under:

STANDARD DOSAGE
Age	Paediatric Suspension
6 to 12 years	10 ml every 12 hours
6 months to 5 years	5 ml every 12 hours
6 weeks to 5 months	2.5 ml every 12 hours

This dosage approximates to 6 mg trimethoprim and 30 mg sulfamethoxazole per kilogram body weight per 24 hours.

Treatment should be continued until the patient has been symptom free for two days; the majority will require treatment for at least 5 days. If clinical improvement is not evident after 7 days' therapy, the patient should be reassessed.

As an alternative to Standard Dosage for acute uncomplicated lower urinary tract infections, short-term therapy of 1 to 3 days' duration has been shown to be effective.

Special dosage recommendations

(Standard dosage applies unless otherwise specified)

Pneumocystis jiroveci (P. carinii) pneumonitis:

Treatment: A higher dosage is recommended using 20 mg trimethoprim and 100 mg sulfamethoxazole per kg of body weight per day in two or more divided doses for two weeks. The aim is to obtain peak plasma or serum levels of trimethoprim of greater than or equal to 5 microgram/ml (verified in patients receiving 1-hour infusions of intravenous Septrin). (See 4.8 Undesirable Effects).

Prevention:

The following dose schedules may be used for the duration of the period at risk (see Standard dosage recommendations for acute infections subsection of 4.2):

− Standard dosage taken in two divided doses, seven days per week

− Standard dosage taken in two divided doses, three times per week on alternate days

− Standard dosage taken in two divided doses, three times per week on consecutive days

− Standard dosage taken as a single dose, three times per week on consecutive days

The daily dose given on a treatment day approximates to 150 mg trimethoprim/m²/day and 750 mg sulfamethoxazole/m²/day. The total daily dose should not exceed 320 mg trimethoprim and 1600 mg sulfamethoxazole.

Nocardiosis: There is no consensus on the most appropriate dosage. Adult doses of 6 to 8 tablets daily for up to 3 months have been used (one tablet contains 400 mg sulfamethoxazole and 80 mg trimethoprim).

Toxoplasmosis: There is no consensus on the most appropriate dosage for the treatment or prophylaxis of this condition. The decision should be based on clinical experience. For prophylaxis, however, the dosages suggested for prevention of Pneumocystis jiroveci pneumonitis may be appropriate.

Children aged 12 years and under with renal impairment:

No data are available relating to dosage in children aged 12 years and under with impaired renal function.

Children aged 12 years and under with hepatic impairment:

No data are available relating to dosage in children aged 12 years and under with impaired hepatic function.

4.3 Contraindications

Septrin should not be given to patients with a history of hypersensitivity to sulphonamides, trimethoprim, co-trimoxazole, or any excipients of Septrin.

Contra-indicated in patients showing marked liver parenchymal damage.

Contra-indicated in severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed.

Septrin should not be given to premature babies nor to full-term infants during the first 6 weeks of life except for the treatment/prophylaxis of PCP in infants 4 weeks of age or greater.

4.4 Special Warnings And Precautions For Use

Fatalities, although very rare, have occurred due to severe reactions including Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), fulminant hepatic necrosis, agranulocytosis, aplastic anaemia, other blood dyscrasias and hypersensitivity of the respiratory tract.

Septrin should be discontinued at the first appearance of skin rash. (See 4.8 Undesirable Effects).

Particular care is always advisable when treating elderly patients because, as a group, they are more susceptible to adverse reactions and more likely to suffer serious effects as a result particularly when complicating conditions exist, e.g. impaired kidney and/or liver function and/or concomitant use of other drugs.

An adequate urinary output should be maintained at all times. Evidence of crystalluria in vivo is rare, although sulphonamide crystals have been noted in cooled urine from treated patients. In patients suffering from malnutrition the risk may be increased.

Regular monthly blood counts are advisable when Septrin is given for long periods, or to folate deficient patients or to the elderly, since there exists a possibility of asymptomatic changes in haematological laboratory indices due to lack of available folate. These changes may be reversed by administration of folinic acid (5 to 10 mg/day) without interfering with the antibacterial activity.

In glucose-6-phosphate dehydrogenase (G-6-PD) deficient patients haemolysis may occur.

Septrin should be given with caution to patients with severe allergy or bronchial asthma.

Septrin should not be used in the treatment of streptococcal pharyngitis due to Group A beta-haemolytic streptococci; eradication of these organisms from the oropharynx is less effective than with penicillin.

Trimethoprim has been noted to impair phenylalanine metabolism but this is of no significance in phenylketonuric patients on appropriate dietary restriction.

The administration of Septrin to patients known or suspected to be at risk of acute porphyria should be avoided. Both trimethoprim and sulphonamides (although not specifically sulfamethoxazole) have been associated with clinical exacerbation of porphyria.

Close monitoring of serum potassium and sodium is warranted in patients at risk of hyperkalaemia and hyopnatraemia.

Except under careful supervision Septrin should not be given to patients with serious haematological disorders (see 4.8 Undesirable Effects). Septrin has been given to patients receiving cytotoxic therapy with little or no additional effect on the bone marrow or peripheral blood.

The combination of antibiotics in Septrin should only be used where, in the judgement of the physician, the benefits of treatment outweigh any possible risks; consideration should be given to the use of a single effective antibacterial agent.

Patients with rare hereditary problems of fructose intolerance should not take this medicine. See Section 2 Quantitative and Qualitative Composition.

This medicinal product contains methyl hydroxybenzoate, which may cause allergic reactions (possibly delayed).

This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per 5 ml.

This medicinal product contains less than 1 mmol of sodium (23 mg) per dose, and therefore is essentially sodium free.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Trimethoprim may interfere with the estimation of serum/plasma creatinine when the alkaline picrate reaction is used. This may result in overestimation of serum/plasma creatinine of the order of 10%. The creatinine clearance is reduced: the renal tubular secretion of creatinine is decreased from 23% to 9% whilst the glomerular filtration remains unchanged.

In some situations, concomitant treatment with zidovudine may increase the risk of haematological adverse reactions to co-trimoxazole. If concomitant treatment is necessary, consideration should be given to monitoring of haematological parameters.

Reversible deterioration in renal function has been observed in patients treated with co-trimoxazole and cyclosporin following renal transplantation.

Concurrent use of rifampicin and Septrin results in a shortening of the plasma half-life of trimethoprim after a period of about one week. This is not thought to be of clinical significance.

When trimethoprim is administered simultaneously with drugs that form cations at physiological pH, and are also partly excreted by active renal secretion (e.g. procainamide, amantadine), there is the possibility of competitive inhibition of this process which may lead to an increase in plasma concentration of one or both of the drugs.

In elderly patients concurrently receiving diuretics, mainly thiazides, there appears to be an increased risk of thrombocytopenia with or without purpura.

Occasional reports suggest that patients receiving pyrimethamine at doses in excess of 25 mg weekly may develop megaloblastic anaemia should co-trimoxazole be prescribed concurrently.

Co-trimoxazole has been shown to potentiate the anticoagulant activity of warfarin via stereo-selective inhibition of its metabolism. Sulfamethoxazole may displace warfarin from plasma-albumin protein-binding sites in vitro. Careful control of the anticoagulant therapy during treatment with Septrin is advisable.

Co-trimoxazole prolongs the half-life of phenytoin and if co-administered could result in excessive phenytoin effect. Close monitoring of the patient's condition and serum phenytoin levels are advisable.

Concomitant use of trimethoprim with digoxin has been shown to increase plasma digoxin levels in a proportion of elderly patients.

Co-trimoxazole may increase the free plasma levels of methotrexate.

Trimethoprim interferes with assays for serum methotrexate when dihydrofolate reductase from Lactobacillus casei is used in the assay. No interference occurs if methotrexate is measured by radioimmuno assay.

Administration of trimethoprim/sulfamethoxazole 160mg/800mg (co-trimoxazole) causes a 40% increase in lamivudine exposure because of the trimethoprim component. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole.

Interaction with sulphonylurea hypoglycaemic agents is uncommon but potentiation has been reported.

Caution should be exercised in patients taking any other drugs that can cause hyperkalaemia.

If Septrin is considered appropriate therapy in patients receiving other anti-folate drugs such as methotrexate, a folate supplement should be considered.

4.6 Pregnancy And Lactation

Pregnancy

There are not any adequate data from the use of Septrin in pregnant women. Case-control studies have shown that there may be an association between exposure to folate antagonists and birth defects in humans.

Trimethoprim is a folate antagonist and, in animal studies, both agents have been shown to cause foetal abnormalities (see 5.3 Preclinical Safety Data).

Septrin should not be used in pregnancy, particularly in the first trimester, unless clearly necessary. Folate supplementation should be considered if Septrin is used in pregnancy.

Sulfamethoxazole competes with bilirubin for binding to plasma albumin. As significantly maternally derived drug levels persist for several days in the newborn, there may be a risk of precipitating or exacerbating neonatal hyperbilirubinaemia, with an associated theoretical risk of kernicterus, when Septrin is administered to the mother near the time of delivery. This theoretical risk is particularly relevant in infants at increased risk of hyperbilirubinaemia, such as those who are preterm and those with glucose-6-phosphate dehydrogenase deficiency.

Lactation

The components of Septrin (trimethoprim and sulfamethoxazole) are excreted in breast milk. Administration of Septrin should be avoided in late pregnancy and in lactating mothers where the mother or infant has, or is at particular risk of developing, hyperbilirubinaemia. Additionally, administration of Septrin should be avoided in infants younger than eight weeks in view of the predisposition of young infants to hyperbilirubinaemia.

4.7 Effects On Ability To Drive And Use Machines

There have been no studies to investigate the effect of Septrin on driving performance or the ability to operate machinery. Further a detrimental effect on such activities cannot be predicted from the pharmacology of the drug. Nevertheless the clinical status of the patient and the adverse events profile of Septrin should be borne in mind when considering the patients ability to operate machinery.

4.8 Undesirable Effects

As co-trimoxazole contains trimethoprim and a sulphonamide the type and frequency of adverse reactions associated with such compounds are expected to be consistent with extensive historical experience.

Data from large published clinical trials were used to determine the frequency of very common to rare adverse events. Very rare adverse events were primarily determined from post-marketing experience data and therefore refer to reporting rate rather than a "true" frequency. In addition, adverse events may vary in their incidence depending on the indication.

The following convention has been used for the classification of adverse events in terms of frequency:- Very common

Infections and Infestations

Common: Monilial overgrowth

Blood and lymphatic system disorders

Very rare: Leucopenia, neutropenia, thrombocytopenia, agranulocytosis, megaloblastic anaemia, aplastic anaemia, haemolytic anaemia, methaemoglobinaemia, eosinophilia, purpura, haemolysis in certain susceptible G-6-PD deficient patients

Immune system disorders

Very rare: Serum sickness, anaphylaxis, allergic myocarditis, angioedema, drug fever, allergic vasculitis resembling Henoch-Schoenlein purpura, periarteritis nodosa, systemic lupus erythematosus

Metabolism and nutrition disorders

Very common: Hyperkalaemia

Very rare: Hypoglycaemia, hyponatraemia, anorexia

Psychiatric disorders

Very rare: Depression, hallucinations

Nervous system disorders

Common: Headache

Very rare: Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, dizziness

Aseptic meningitis was rapidly reversible on withdrawal of the drug, but recurred in a number of cases on re-exposure to either co-trimoxazole or to trimethoprim alone.

Respiratory, thoracic and mediastinal disorders

Very rare: Cough, shortness of breath, pulmonary infiltrates

Cough, shortness of breath and pulmonary infiltrates may be early indicators of respiratory hypersensitivity which, while very rare, has been fatal.

Gastrointestinal disorders

Common:	Nausea, diarrhoea
Uncommon:	Vomiting
Very rare:	Glossitis, stomatitis, pseudomembranous colitis, pancreatitis

Eye Disorders

Very rare:

Uveitis

Hepatobiliary disorders

Very rare: Elevation of serum transaminases, elevation of bilirubin levels, cholestatic jaundice, hepatic necrosis

Cholestatic jaundice and hepatic necrosis may be fatal.

Skin and subcutaneous tissue disorders

Common: Skin rashes

Very rare: Photosensitivity, exfoliative dermatitis, fixed drug eruption, erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis)

Lyell's syndrome carries a high mortality.

Musculoskeletal and connective tissue disorders

Very rare: Arthralgia, myalgia

Renal and urinary disorders

Very rare: Impaired renal function (sometimes reported as renal failure), interstitial nephritis

Effects associated with Pneumocystis jiroveci (P. carinii) Pneumonitis (PCP) management

Very rare: Severe hypersensitivity reactions, rash, fever, neutropenia, thrombocytopenia, raised liver enzymes, hyperkalaemia, hyponatraemia, rhabdomyolysis.

At the high dosages used for PCP management severe hypersensitivity reactions have been reported, necessitating cessation of therapy. If signs of bone marrow depression occur, the patient should be given calcium folinate supplementation (5-10 mg/day). Severe hypersensitivity reactions have been reported in PCP patients on re-exposure to co-trimoxazole, sometimes after a dosage interval of a few days. Rhabdomyolysis has been reported in HIV positive patients receiving co-trimoxazole for prophylaxis or treatment of PCP.

4.9 Overdose

Nausea, vomiting, dizziness and confusion are likely signs/symptoms of overdosage. Bone marrow depression has been reported in acute trimethoprim overdosage.

If vomiting has not occurred, induction of vomiting may be desirable. Gastric lavage may be useful, though absorption from the gastrointestinal tract is normally very rapid and complete within approximately two hours. This may not be the case in gross overdosage. Dependant on the status of renal function administration of fluids is recommended if urine output is low.

Both trimethoprim and active sulfamethoxazole are moderately dialysable by haemodialysis. Peritoneal dialysis is not effective.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Combinations of sulfonamides and trimethoprim, incl. derivatives; ATC code: J01EE01

Mode of Action

Septrin is an antibacterial drug composed of two active principles, sulfamethoxazole and trimethoprim. Sulfamethoxazole is a competitive inhibitor of dihydropteroate synthetase enzyme. Sulfamethoxazole competitively inhibits the utilisation of para-aminobenzoic acid (PABA) in the synthesis of dihydrofolate by the bacterial cell resulting in bacteriostasis. Trimethoprim binds to and reversibly inhibits bacterial dihydrofolate reductase (DHFR) and blocks the production of tetrahydrofolate. Depending on the conditions the effect may be bactericidal. Thus trimethoprim and sulfamethoxazole block two consecutive steps in the biosynthesis of purines and therefore nucleic acids essential to many bacteria. This action produces marked potentiation of activity in vitro between the two agents.

Mechanism of resistance

In vitro studies have shown that bacterial resistance can develop more slowly with both sulfamethoxazole and trimethoprim in combination that with either sulfamethoxazole or trimethoprim alone.

Resistance to sulfamethoxazole may occur by different mechanisms. Bacterial mutations cause an increase the concentration of PABA and thereby out-compete with sulfamethoxazole resulting in a reduction of the inhibitory effect on dihydropteroate synthetase enzyme. Another resistance mechanism is plasmid-mediated and results from production of an altered dihydropteroate synthetase enzyme, with reduced affinity for sulfamethoxazole compared to the wild-type enzyme.

Resistance to trimethoprim occurs through a plasmid-mediated mutation which results in production of an altered dihydrofolate reductase enzyme having a reduced affinity for trimethoprim compared to the wild-type enzyme.

Trimethoprim binds to plasmodial DHFR but less tightly than to bacterial enzyme. Its affinity for mammalian DHFR is some 50,000 times less than for the corresponding bacterial enzyme.

Many common pathogenic bacteria are susceptible in vitro to trimethoprim and sulfamethoxazole at concentrations well below those reached in blood, tissue fluids and urine after the administration of recommended doses. In common with other antibiotics, however, in vitro activity does not necessarily imply that clinical efficacy has been demonstrated and it must be noted that satisfactory susceptibility testing is achieved only with recommended media free from inhibitory substances, especially thymidine and thymine.

Breakpoints

EUCAST

Enterobacteriaceae: S

S. maltophilia: S

Acinetobacter: S

Staphylococcus: S

Enterococcus: S

Streptococcus ABCG: S

Streptococcus pneumoniae: S

Hemophilus influenza: S

Moraxella catarrhalis: S

Psuedomonas aeruginosa and other non-enterobacteriaceae: S

S = susceptible, R = resistant. *These are CLSI breakpoints since no EUCAST breakpoints are currently available for these organisms.

Trimethoprim: sulfamethoxazole in the ratio 1:19. Breakpoints are expressed as trimethoprim concentration.

Antibacterial Spectrum

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. This information gives only an approximate guidance on probabilities whether microorganisms will be susceptible to trimethoprim/sulfamethoxazole or not.

Trimethoprim/sulfamethoxazole susceptibility against a number of bacteria are shown in the table below:

Commonly susceptible species:

Gram-positive aerobes: Staphylococcus aureus Staphylococcus saprophyticus Streptococcus pyogenes

Gram-negative aerobes: Enterobacter cloacae Haemophilus influenzae Klebsiella oxytoca Moraxella catarrhalis Salmonella spp. Stenotrophomonas maltophilia Yersinia spp.

Species for which acquired resistance may be a problem:

Gram-positive aerobes: Enterococcus faecalis Enterococcus faecium Nocardia spp. Staphylococcus epidermidis Streptococcus pneumoniae

Gram-negative aerobes: Citrobacter spp. Enterobacter aerogenes Escherichia coli Klebsiella pneumoniae Klebsiella pneumonia Proteus mirabilis Proteus vulgaris Providencia spp. Serratia marcesans

Inherently resistant organisms:

Gram-negative aerobes: Pseudomonas aeruginosa Shigella spp. Vibrio cholera

5.2 Pharmacokinetic Properties

After oral administration trimethoprim and sulfamethoxazole are rapidly and nearly completely absorbed. The presence of food does not appear to delay absorption. Peak levels in the blood occur between one and four hours after ingestion and the level attained is dose related. Effective levels persist in the blood for up to 24 hours after a therapeutic dose. Steady state levels in adults are reached after dosing for 2-3 days. Neither component has an appreciable effect on the concentrations achieved in the blood by the other.

Trimethoprim is a weak base with a pKa of 7.4. It is lipophilic. Tissue levels of trimethoprim are generally higher than corresponding plasma levels, the lungs and kidneys showing especially high concentrations. Trimethoprim concentrations exceed those in plasma in the case of bile, prostatic fluid and tissue, saliva, sputum and vaginal secretions. Levels in the aqueous humor, breast milk, cerebrospinal fluid, middle ear fluid, synovial fluid and tissue (intestinal) fluid are adequate for antibacterial activity. Trimethoprim passes into amniotic fluid and foetal tissues reaching concentrations approximating those of maternal serum.

Approximately 50% of trimethoprim in the plasma is protein bound. The half-life in man is in the range 8.6 to 17 hours in the presence of normal renal function. It is increased by a factor of 1.5 to 3.0 when the creatinine clearance is less than 10 ml/minute. There appears to be no significant difference in the elderly compared with young patients.

The principal route of excretion of trimethoprim is renal and approximately 50% of the dose is excreted in the urine within 24 hours as unchanged drug. Several metabolites have been identified in the urine. Urinary concentrations of trimethoprim vary widely.

Sulfamethoxazole is a weak acid with a pKa of 6.0. The concentration of active sulfamethoxazole in a variety of body fluids is of the order of 20 to 50% of the plasma concentration.

Approximately 66% of sulfamethoxazole in the plasma is protein bound and the principal route of excretion of sulfamethoxazole is renal. The half-life in man is approximately 9 to 11 hours in the presence of normal renal function. There is no change in the half-life of active sulfamethoxazole with a reduction in renal function but there is prolongation of the half-life of the major, acetylated metabolite when the creatinine clearance is below 25 ml/minute.

The principle route of excretion of sulphamethoxazole is renal; between 15% and 30% of the dose recovered in the urine is in the active form. In elderly patients there is a reduced renal clearance of sulfamethoxazole.

5.3 Preclinical Safety Data

Reproductive toxicology:

At doses in excess of recommended human therapeutic dose, trimethoprim and sulfamethoxazole have been reported to cause cleft palate and other foetal abnormalities in rats, findings typical of a folate antagonist. Effects with trimethoprim were preventable by administration of dietary folate. In rabbits, foetal loss was seen at doses of trimethoprim in excess of human therapeutic doses.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sorbitol solution 70% (non crystallising) (E420 ii)

Glycerol (E422)

Dispersible Cellulose (E460)

Sodium Carmellose

Polysorbate 80 (E433)

Methyl Hydroxybenzoate (E218)

Sodium Benzoate (E211)

Saccharin Sodium (E954)

Ethanol (96%)

Flavour, Banana 81.605P

Flavour, Vanilla 407

Purified Water to 5 ml

6.2 Incompatibilities

None Known

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Store below 25^o C

Protect from light

6.5 Nature And Contents Of Container

Amber glass bottles with metal roll-on closures.

Pack size: 100 and 30 ml

A double-ended 5mL/2.5mL measuring spoon is included.

Paper/Aluminium foil/ionomer resin sachet

Pack size: 5ml

6.6 Special Precautions For Disposal And Other Handling

Trimethoprim interferes with assays for serum methotrexate when dihydrofolate reductase from Lactobacillus casei is used in the assay. No interference occurs if methotrexate is measured by radioimmuno assay.

Trimethoprim may interfere with the estimation of serum/plasma creatinine when the alkaline picrate reaction is used. This may result in overestimation of serum/plasma creatinine of the order of 10%. Functional inhibition of the renal tubular secretion of creatinine may produce a spurious fall in the estimated rate of creatinine clearance.

7. Marketing Authorisation Holder

The Wellcome Foundation Ltd

Glaxo Wellcome House

Berkeley Avenue

Greenford,

Middlesex, UB6 0NN

Trading as:

GlaxoSmithKline UK

Stockley Park West

Uxbridge

Middlesex UB11 1BT

8. Marketing Authorisation Number(S)

PL 00003/5222R

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 09 January 1972

Date of last of renewal: 17 October 2006

10. Date Of Revision Of The Text

21 July 2009

Liver Abscess Medications

There are currently no drugs listed for "Liver Abscess".

Definition of Liver Abscess: A pus-filled cavity within the liver.

Learn more about Liver Abscess

Micromedex Care Notes:

• Liver Abscess

Medical Encyclopedia:

• Amebic liver abscess
• Pyogenic liver abscess

Drug List:

Salbutamol 100 microgram per actuation pressurised inhalation, suspension

1. Name Of The Medicinal Product

Sabumalin 100 mcg/dose Inhaler

2. Qualitative And Quantitative Composition

One metered dose contains 120 micrograms salbutamol sulphate (equivalent to 100 micrograms salbutamol).

The delivered dose through the mouthpiece is 108 micrograms salbutamol sulphate (equivalent to 90 micrograms salbutamol).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Pressurised inhalation, suspension

Pressurised aluminium canister closed with a metering valve containing a white suspension, inserted into a plastic actuator.

4. Clinical Particulars

4.1 Therapeutic Indications

Symptomatic treatment of reversible bronchoconstriction due to bronchial asthma and chronic obstructive pulmonary disease (COPD) including chronic bronchitis and emphysema.

Prophylaxis of exercise and allergen induced asthma.

Salbutamol is particularly useful for the relief of symptoms of asthma, providing it does not delay the introduction and regular use of inhaled corticosteroid therapy.

4.2 Posology And Method Of Administration

Salbutamol is intended for inhalation only.

The aim should be individual dosage.

Adults and children from 12 years of age

Relief of attacks: 1-2 inhalations as required.

Maximum dosage: 8 inhalations per day.

To prevent allergen- or exercise-induced symptoms, two inhalations should be taken 10-15 minutes before challenge.

Children below 12 years of age

Relief of attacks: 1 inhalation as required.

Maximum dosage: approx. 8 doses per day.

To prevent allergen- or exercise-induced symptoms, one inhalation, or two if necessary, should be taken 10-15 minutes before challenge.

Handling

A faulty inhalation technique with pressurised inhalers is very common. It is therefore important that the patient be instructed in the correct inhalation technique. The patient's inhalation technique should be checked at visits.

Salbutamol may be used with a Vortex^® or AeroChamber^® Plus spacer device by children and patients who find it difficult to synchronise aerosol actuation with inspiration.

For instructions on the use of the Vortex^® or AeroChamber^® Plus spacer device please refer to the information leaflets of the spacer devices.

Priming/Re-priming the device

Before Salbutamol is used for the first time, or if it has not been used for 7 days or more, it is important to check that the spray is functioning. The protective cap should be removed, the inhaler be shaken and sprayed twice into the air.

Instructions for use

The inhalation should be performed sitting or standing, wherever possible.

1. The protective cap should be removed. The inside and outside should be checked to make sure that the mouthpiece is clean.

2. The inhaler should be shaken thoroughly for a couple of seconds before use.

3. The inhaler should be held upright with the bottom of the container upwards.

The thumb should be put on the base, below the mouthpiece. The patient should breathe out as far as is comfortable, but he should not breathe into the mouthpiece.

4. The mouthpiece should be placed in the mouth between the teeth and the lips should be closed around it without biting it.

5. Just after starting to breathe in through the mouth, the patient should press down the canister to release a puff while still breathing in steadily and deeply.

6. The breath should be held, the inhaler taken from the mouth and the finger from the top of the inhaler. The breath should be held for a few seconds, or as long as is comfortable.

7. If another puff is required, the inhaler should be kept upright and the patient should wait about half a minute before repeating steps 2 to 6.

8. After use ,the mouthpiece should always be covered to keep out dust and fluff. The mouthpiece cover should be replaced firmly and snapped into position.

Cleaning

To prevent the inhaler blocking up, it is important to clean it at least once a week, following the instructions below. If the inhaler does block up, the same cleaning instructions should be followed.

To clean the inhaler:

1. The metal canister should be pulled out of the plastic case of the inhaler and the mouthpiece cover should be removed.

2. The plastic case and the mouthpiece cover should be rinsed in warm water. If a build up of medicine is noticed around the mouthpiece,the patient should not attempt to unblock it with a sharp object, such as a pin. A mild detergent may be added to the water, then the mouthpiece should be rinsed thoroughly with clean water before drying. The metal canister should not be put into water.

3. The plastic case and the mouthpiece cover should be left to dry in a warm place. Excessive heat should be avoided.

4. The canister and mouthpiece cover should be replaced.

Inhaler content:

The inhaler should be shaken to check the remaining amount of medicine in it. Salbutamol should not be used if you no liquid can be detected in the inhaler while shaking.

Cold temperature use:

If the inhaler has been stored beneath 0 °C, it has to be warmed in the hands of the patient for 2 minutes, be shaken and sprayed twice into the air before use.

4.3 Contraindications

Hypersensitivity to salbutamol or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Treatment of asthma normally follows a gradually adjusted programme, and the patient's response to therapy must be monitored clinically and with lung function tests. An increased use of beta-2 agonist indicates deterioration of the asthma and the need for reassessment of the treatment.

Bronchodilators should not be the only or main treatment in patients with persistent asthma.

In the following cases Salbutamol should only be used with caution and if strictly indicated:

- serious cardiac disorders, in particular recent myocardial infarction

- coronary heart disease, hypertrophic obstructive cardiomyopathy and tachyarrhythmia

- severe and untreated hypertension

- aneurysm

- diabetes which is difficult to control

- pheochromocytoma

- uncontrolled hyperthyroidism

- untreated hypokalaemia.

There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischaemia associated with salbutamol. Patients with underlying severe heart disease (e.g. ischaemic heart disease, tachyarrhythmia or severe heart failure) who are receiving salbutamol for respiratory disease, should be warned to seek medical advice if they experience chest pain or other symptoms of worsening heart disease.

Hypokalaemia can be potentiated in cases of concomitant treatment with xanthine derivatives, steroids or diuretics, and in hypoxia. The serum potassium level should therefore be monitored in risk patients, especially in the treatment of acute severe asthma with high doses of Salbutamol.

When initiating treatment with Salbutamol in diabetics, extra checks of blood glucose levels are recommended, as beta₂-agonists increase the risk of hyperglycaemia.

Non-selective beta-adrenoreceptor blockers can completely inhibit the effect of salbutamol. In patients with asthma administration of β-receptor blocking drugs is associated with a risk of severe bronchoconstriction. Therefore, Salbutamol and non-selective β-receptor blocking drugs should not usually be prescribed together (see section 4.5).

Sudden and progressive deterioration of asthma control is potentially life-threatening. If the effect of Salbutamol becomes less effective, the patient should be warned to seek medical advice, as repeated inhalations must not delay the initiation of other important therapy. Treatment with increased doses of corticosteroids should be considered.

As with other inhalation therapy, paradoxical bronchospasm may occur, with increased wheezing immediately after administration. Should this occur, the preparation should be immediately discontinued and replaced by alternative treatment.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Hypokalaemia may be potentiated in cases of concomitant treatment with xanthine derivatives, steroids or diuretics (see section 4.4).

Salbutamol and non-selective β-receptor blocking drugs should not usually be prescribed together. In patients with asthma administration of β-receptor blocking drugs is associated with a risk of severe bronchoconstriction.

When administering halogenated anaesthetics, e.g. halothane, methoxyflurane or enflurane, to patients treated with salbutamol an increased risk of severe dysrhythmia and hypotension must be expected. If anaesthesia with halogenated anaesthetics is planned, care should be taken to ensure that salbutamol is not used for at least 6 hours before initiation of the anaesthesia.

Monoamine oxidase inhibitors and tricyclic antidepressants may increase the risk of cardiovascular side-effects

Salbutamol induced hypokalemia may increase susceptibility to digoxin induced arrhythmias

4.6 Pregnancy And Lactation

Pregnancy

Studies in animals have shown reproductive toxicity. Safety in pregnant women has not been established. Salbutamol should not be used during pregnancy unless clearly necessary.

Lactation

As salbutamol is probably secreted in breast milk, its use in nursing mothers requires careful consideration. It is not known whether salbutamol has a harmful effect on the neonate, and so its use should be restricted to situations where it is felt that the expected benefit to the mother is likely to outweigh any potential risk to the neonate.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

Undesirable effects are classified according to organ system and frequency. The frequency range is defined as very common (

Very common, common and uncommon undesirable effects have been obtained from clinical trials. Very rare undesirable effects have been obtained from spontaneous post-marketing reports.

Organ system	Undesirable effects	Frequency
Immune system disorders	Hypersensitivity reactions incl. angioedema, urticaria, bronchospasm, hypotension, collapse	Very rare
Metabolism and nutrition disorders	Hypokalaemia	Rare
Nervous system disorders	Tremor, headache. Hyperactivity, sleep disturbances, hyperexcitability, hallucinations	Common Very rare
Cardiac disorders	Tachycardia Palpitations Cardiac arrhythmia (e.g. atrial fibrillation, supraventricular tachycardia and extrasystoles), myocardial ischaemia	Common Uncommon Very rare
Vascular disorders	Peripheral vasodilatation	Rare
Respiratory, thoracic and mediastinal disorders	Paradoxical bronchospasm	Very rare
Gastrointestinal disorders	Irritation in mouth and throat	Uncommon
Musculoskeletal and connective tissue disorders	Muscle cramps	Common

Undesirable effects typical of beta₂-agonists, such as skeletal muscle tremor and palpitations, can occur especially at the beginning of treatment, and are often dose-dependent.

As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with an alternative presentation or a different fast-acting inhaled bronchodilator. Salbutamol should be discontinued immediately, the patient assessed, and, if necessary, alternative therapy instituted

4.9 Overdose

Symptoms of an overdose

In case of overdose, the adverse reactions already named may appear very rapidly and possibly to an increased extent.

Typical symptoms are:

tachycardia, palpitations, arrhythmias, agitation, dyssomnia, chest pain and severe tremor, particularly affecting hands, but also the whole body.

Gastrointestinal complaints including nausea can occur, particularly after oral intoxication.

Psychotic reactions have uncommonly been observed after excessive salbutamol doses.

In association with overdose of salbutamol, displacements of potassium into the intracellular space may occur with the consequence of hypokalaemia as well as hyperglycaemia.

Therapeutic measures in case of an overdose

Treatment of overdoses with beta-sympathomimetics is mainly symptomatic. The following measures can be recommended:

- Gastric lavage should be considered if large quantities of the medicinal product have been swallowed inadvertently. Activated charcoal and laxatives may have a positive influence on undesired absorption.

- Cardiac symptoms may be treated with a cardioselective beta-blocker, but an elevated risk that bronchospasticity occurs in patients with bronchial asthma is to be borne in mind.

- ECG monitoring is indicated for cardiac supervision.

- In case or more pronounced hypotension, volume substitution (e.g. plasma substitutes) are recommended.

The development of hypokalaemia must be expected, hence appropriate monitoring of the electrolyte balance and, if necessary, substitutions are to be recommended while heeding a possible preceding treatment with other medicinal products that can induce hypokalaemia, hyperlipidemia, ketonemia.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Drugs for obstructive airway diseases, selective beta-2-adrenoreceptor agonists.

ATC code: R03AC02

Salbutamol is an adrenergic beta-receptor stimulant with a selective effect on the beta₂- receptors of the bronchi, which produces bronchodilatation. The bronchodilator effect occurs within a few minutes after inhalation and reaches its maximum after 30-60 minutes. It generally lasts at least 4 hours. With inhalation the bronchodilator effect is not related to the serum concentration.

Adrenergic beta₂-stimulants have also been shown to increase the reduced mucociliary clearance that occurs in obstructive pulmonary disease, and thus facilitate the coughing up of viscous secretion.

The active substance in Salbutamol is micronised salbutamol sulphate suspended in liquid non-freon-based propellant (norflurane), which does not adversely affect the earth's ozone layer.

5.2 Pharmacokinetic Properties

Salbutamol administered intravenously has a half life of 4 to 6 hours and is cleared partly renally and partly by metabolism to the inactive 4'-O-sulphate (phenolic sulphate) which is also excreted primarily in the urine. The faeces are a minor route of excretion.

After administration by the inhaled route between 10 and 20% of the dose reaches the lower airways. The remainder is retained in the delivery system or is deposited in the oropharynx from where it is swallowed. The fraction deposited in the airways is absorbed into the pulmonary tissues and circulation, but is not metabolised by the lung. On reaching the systemic circulation it becomes accessible to hepatic metabolism and is excreted, primarily in the urine, as unchanged drug and as the phenolic sulphate.

The swallowed portion of an inhaled dose is absorbed from the gastrointestinal tract and undergoes considerable first-pass metabolism to the phenolic sulphate. Both unchanged drug and conjugate are excreted primarily in the urine. Most of a dose of salbutamol given intravenously, orally or by inhalation is excreted within 72 hours. Salbutamol is bound to plasma proteins to the extent of 10%.

5.3 Preclinical Safety Data

Preclinical data revealed no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. The observed effects in the preclinical studies were related to the beta-adrenergic activity of salbutamol.

In common with other potent selective β2-receptor agonists, salbutamol has been shown to be teratogenic in mice when given subcutaneously. In a reproductive study, 9.3% of fetuses were found to have cleft palate at 2.5mg/kg, 4 times the maximum human oral dose. In rats, treatment at the levels of 0.5, 2.32, 10.75 and 50mg/kg/day orally throughout pregnancy resulted in no significant fetal abnormalities. The only toxic effect was an increase in neonatal mortality at the highest dose level as the result of lack of maternal care. Reproductive studies in the rabbit at doses of 50mg/kg/day orally (i.e. 78 times the maximum human oral dose) have shown fetuses with treatment related changes; these included open eyelids (ablepharia), secondary palate clefts (palatoschisis), changes in ossification of the frontal bones of the cranium (cranioschisis) and limb flexure.

The non-CFC propellant, HFA 134a, has been shown to have no toxic effect at very high vapour concentrations, far in excess of those likely to be experienced by patients, in a wide range of animal species exposed daily for periods of two years.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Norflurane (HFA 134a)

Anhydrous Ethanol

Oleic acid

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 30 °C.

Salbutamol should be stored horizontal or in an inverted position, with the mouthpiece pointing downwards.

The canister contains a pressurised liquid. Do not expose to temperatures higher than 50° C, even for a short period of time.

Protect from heat, direct sunlight and frost!

Do not pierce the container, even when empty.

6.5 Nature And Contents Of Container

Aluminium containers with metering valve polypropylene actuator

Packs containing

200 metered actuations (equivalent to 8.5 g pressurised inhalation, suspension)

2 x 200 metered actuations (equivalent to 2 x 8.5 g pressurised inhalation, suspension)

3 x 200 metered actuations (equivalent to 3 x 8.5 g pressurised inhalation, suspension)

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements. See section 4.2 for patient instructions.

7. Marketing Authorisation Holder

Sandoz Ltd

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8. Marketing Authorisation Number(S)

PL 04416/0785

9. Date Of First Authorisation/Renewal Of The Authorisation

17/06/2009

10. Date Of Revision Of The Text

11/2010

Menotropins

Pronunciation: MEN-oh-troh-pinz
Generic Name: Menotropins
Brand Name: Menopur

Menotropins is used for:

Treating infertility in women. Menotropins is generally used as part of an Assisted Reproduction Technology (ART) program. It may also be used to treat certain conditions as determined by your doctor.

Menotropins is combination of hormones. It works by stimulating the ovaries to produce eggs. Human chorionic gonadotropin (hCG) is then given to cause ovulation (release of an egg). It also stimulates sperm production in men with certain types of infertility.

Do NOT use Menotropins if:

• you are allergic to any ingredient in Menotropins


• you have an abnormal growth in the brain (eg, pituitary gland tumor) or reproductive system


• you are pregnant, or have an enlarged ovary or ovarian failure


• you have undiagnosed abnormal uterine bleeding


• you have uncontrolled thyroid or adrenal gland problems

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

Before using Menotropins:

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

• if you 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 liver or kidney problems, thyroid or adrenal gland problems, or bleeding problems (eg, hemorrhage)

Some MEDICINES MAY INTERACT with Menotropins. However, no specific interactions with Menotropins are known at this time. Tell your health care provider if you are taking any other medicines.

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

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

• Menotropins is usually administered as an injection under the skin (subcutaneously) at your doctor's office, hospital, or clinic. If you are using Menotropins at home, carefully follow the injection procedures taught to you by your health care provider.


• If Menotropins contains particles or is discolored, or if the vial is cracked or damaged in any way, do not use it.


• Wash your hands thoroughly with soap and water before preparing for an injection.


• To use Menotropins, draw up diluent into a syringe. Add the diluent to the powder by slowly pushing in the plunger of the syringe. Mix the solution by slowly rotating the container. Do not shake.


• Draw up the solution for injection. Use a different syringe or needle for the injection. Needles with higher gauge (25 g or higher) are smaller and less painful to the patient. Be sure all air bubbles are tapped out of the syringe.


• Wipe the site with an alcohol swab and then insert the syringe through the skin at the appropriate injection site (usually the upper thigh or buttocks). While holding the syringe in place, pull back on the plunger of the syringe to be sure the needle is not in a vein.


• If the syringe begins to fill with blood, the needle is in a vein. If this happens, remove the needle from the skin, throw the syringe away, and start the procedure again using new materials (eg, medicine, syringes).


• After giving the injection, cover the site with a small bandage if necessary.


• If you miss a dose of Menotropins, contact your doctor for instructions.

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

Important safety information:

• Menotropins may cause dizziness. Do not drive, operate machinery, or do anything else that could be dangerous until you know how you react to Menotropins. Using Menotropins alone, with certain other medicines, or with alcohol may lessen your ability to drive or to perform other potentially dangerous tasks.


• Do not reuse needles, syringes, or other materials. Dispose of properly after use. Ask your doctor, nurse, or pharmacist to explain local regulations for selecting an appropriate container and properly disposing of the container when full.


• Using Menotropins may result in a pregnancy with multiple fetuses (eg, twins). Discuss this possibility with your doctor.


• You will be given a thorough evaluation before using Menotropins. Pregnancy must be ruled out before you use Menotropins.


• LAB TESTS, including hormone levels and pregnancy tests, may be required to monitor your progress. Be sure to keep all doctor and lab appointments.


• Use Menotropins with caution in the ELDERLY because they may be more sensitive to its effects.


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


• PREGNANCY and BREAST-FEEDING: Do not use Menotropins if you are or become pregnant. If you suspect that you could be pregnant, contact your doctor. It is unknown if Menotropins is excreted in breast milk. If you are or will be breast-feeding while you are using Menotropins, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Menotropins:

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:

Abdominal pain; back pain; breast enlargement; chills; dizziness; fever; flu-like symptoms; flushing; general body discomfort; headache; menstrual changes; muscle or joint pain; pain or rash at the injection 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); abdominal bloating; changes in speech or vision; chest pain; decreased urination; diarrhea; fast heartbeat; nausea; one-sided weakness; severe abdominal pain; severe headache; shortness of breath; sudden leg pain; vomiting; weakness; weight gain; yellowing of the skin or eyes.

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: Menotropins 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 Menotropins:

Before mixing, store Menotropins refrigerated or at room temperature, 37 to 77 degrees F (3 to 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Use immediately after mixing. Discard any unused medicine. Keep Menotropins, as well as needles and syringes, out of the reach of children and away from pets.

General information:

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


• Menotropins 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 Menotropins. 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 Menotropins resources

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

Compare Menotropins with other medications

• Female Infertility
• Follicle Stimulation
• Ovulation Induction

Atracurium Besylate

Class: Neuromuscular Blocking Agents
VA Class: MS200
Chemical Name: 2,2′- [1,5-Pentanediylbis [oxy(3-oxo-3,1-propanediyl)]]bis[1-[(3,4-dimethoxyphenyl)methyl] -1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinolinium] dibenzenesulfonate
Molecular Formula: C₆₅H₈₂N₂O₁₈S₂
CAS Number: 64228-81-5
Brands: Tracrium

• 
  

  Should be administered only under supervision of qualified clinicians experienced in the administration of neuromuscular blocking agent therapy.¹

  
  

Introduction

Nondepolarizing neuromuscular blocking agent.¹

Uses for Atracurium Besylate

Skeletal Muscle Relaxation

Production of skeletal muscle relaxation during surgery after general anesthesia has been induced.^{1 2}

Facilitation of endotracheal intubation;^{1 2} however, succinylcholine generally is preferred in emergency situations where rapid intubation is required.^{17 58 80 83 84 86 91 94} A single dose should not be used in place of succinylcholine for rapid sequence induction of anesthesia (“crash intubation”).²

Treatment to increase pulmonary compliance during assisted or controlled respiration after general anesthesia has been induced.^{1 2}

Has been used for facilitation of mechanical ventilation in intensive care settings.^{1 133 134 135 167}

Atracurium Besylate Dosage and Administration

General

• 
  

  Adjust dosage carefully according to individual requirements and response.¹

  
  


• 
  

  Assess neuromuscular blockade and recovery in patients undergoing anesthesia; a peripheral nerve stimulator is recommended to accurately monitor the degree of muscle relaxation and to minimize the possibility of overdosage.¹

  
  


• 
  

  To avoid patient distress, administer only after unconsciousness has been induced.¹

  
  

Facilitation of Endotracheal Intubation

• 
  

  Endotracheal intubation for nonemergency surgical procedures generally can be performed within 2–2.5 minutes following administration.^{1 2} (See Onset and also Duration under Pharmacokinetics.)

  
  

Maintenance of Neuromuscular Blockade

• 
  

  Repeated administration of maintenance doses does not have a cumulative effect on duration of neuromuscular blockade,^{1 2 9 24 42 43} provided recovery from blockade is allowed to begin prior to administering maintenance doses.¹

  
  


• 
  

  Rate of spontaneous recovery from neuromuscular blockade following discontinuance of maintenance infusion usually is comparable to that following administration of a single IV injection.¹ (See Onset and also Duration under Pharmacokinetics.)

  
  

Reversal of Neuromuscular Blockade

• 
  

  To reverse neuromuscular blockade, administer a cholinesterase inhibitor (e.g., neostigmine, pyridostigmine, edrophonium), usually in conjunction with an antimuscarinic (e.g., atropine, glycopyrrolate) to block adverse muscarinic effects of the cholinesterase inhibitor.^{1 9 16 17 18 19 21 23 24 26}

  
  


• 
  

  Under balanced anesthesia, reversal generally can be attempted about 20–35 minutes after the initial dose or 10–30 minutes after the last maintenance dose, when recovery of muscle twitch has started.¹

  
  


• 
  

  Complete reversal generally is achieved within 8–10 minutes after administration of the cholinesterase inhibitor and antimuscarinic.¹

  
  

Administration

Administer IV only; do not administer IM.^{1 2}

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer initial (intubating) dose by rapid IV injection;^{1 2 HID} administer maintenance dosage for prolonged surgical procedures by intermittent IV injection^{1 2} or continuous IV infusion.^{1 3 57 60 90 118 119}

Consult specialized references for specific procedures and techniques of administration.

Do not mix in the same syringe or administer through the same needle as an alkaline solution.¹

Dilution

For continuous IV infusion, dilute atracurium besylate injection to the desired concentration (usually 0.2 or 0.5 mg/mL) in 5% dextrose, 5% dextrose and 0.9% sodium chloride, or 0.9% sodium chloride injection.¹ Use within 24 hours.¹

Dosage

Available as atracuium besylate; dosage expressed in terms of the salt.¹

Pediatric Patients

Skeletal Muscle Relaxation

Initial (Intubating) Dosage

IV

Infants and children 1 month to 2 years of age: 0.3–0.4 mg/kg when used concomitantly with halothane anesthesia.^{1 132 169 170 171} (See Onset and also Duration under Pharmacokinetics.)

Children >2 years of age should receive dosages recommended for adults.¹ (See Adults under Dosage and Administration.)

Insufficient data for recommendation of a specific initial dose of atracurium besylate in infants and children following administration of succinylcholine.¹³²

Maintenance Dosage

Intermittent IV Injection

Infants and children may require more frequent doses than adults.^{1 2 132}

Children >2 years of age should receive doses recommended for adults.¹ (See Adults under Dosage and Administration.)

Continuous IV Infusion

Not recommended in children <2 years of age.^{1 169 170 171}

Children >2 years of age should receive dosages recommended for adults.¹ (See Adults under Dosage and Administration.)

Adults

Skeletal Muscle Relaxation

Initial (Intubating) Dosage

IV

0.4–0.5 mg/kg.^{1 2} (See Onset and also Duration under Pharmacokinetics.)

Reduce initial dosage by about 33% (i.e., to 0.25–0.35 mg/kg) if steady-state anesthesia has been induced with enflurane or isoflurane.^{1 2 37 169 170 171} (See Specific Drugs under Interactions.)

Consider reducing initial dosage by about 20% if steady-state anesthesia has been induced with halothane.^{1 2 86} (See Specific Drugs under Interactions.)

If administering following succinylcholine, reduce dosage to 0.3–0.4 mg/kg.^{1 2 86} Reduce dosage further (e.g., to 0.2–0.3 mg/kg) when inhalation anesthetics are also administered concomitantly.^{1 2 86} (See Specific Drugs under Interactions.)

Maintenance Dosage

Intermittent IV Injection

0.08–0.1 mg/kg, administered as necessary.^{1 2} (See Onset and also Duration under Pharmacokinetics.)

Administer first maintenance dose generally 20–45 minutes after the initial dose in patients undergoing balanced anesthesia.^{1 2}

Administer repeat maintenance doses at relatively regular intervals (i.e., from 15–25 minutes in patients undergoing balanced anesthesia).^{1 2} Administration at longer intervals may be possible if higher maintenance doses (i.e., up to 0.2 mg/kg) are used or if used with enflurane or isoflurane.^{1 2}

Continuous IV Infusion

Initially, 9–10 mcg/kg per minute may be necessary to rapidly counteract spontaneous recovery from neuromuscular blockade.^{1 3 57 118} 5–9 mcg/kg per minute generally maintains 89–99% neuromuscular blockade in patients receiving balanced anesthesia; however, adequate blockade may occur with infusion rates of 2–15 mcg/kg per minute.¹

Initiate continuous IV infusion only after early spontaneous recovery from IV dose is evident.¹

Reduce infusion rate by about 33% if steady-state anesthesia has been induced with enflurane or isoflurane.¹ (See Specific Drugs under Interactions.)

Consider a smaller reduction in the infusion rate if steady-state anesthesia has been induced with halothane.¹ (See Specific Drugs under Interactions.)

Special Populations

Renal Impairment

Dosage adjustments not required.^{1 2 169 170 171}

Burn Patients

Substantially increased doses may be required due to development of resistance.^{1 143 144 145 146 147} (See Burn Patients under Cautions.)

Cardiopulmonary Bypass Patients with Induced Hypothermia

Infusion rate required to maintain adequate surgical relaxation during hypothermia (i.e., 25–28°C) is approximately 50% of the infusion rate necessary in normothermic patients.^{1 57 79}

Intensive Care Settings

Average infusion rates of 11–13 mcg/kg per minute (range: 4.5–29.5 mcg/kg per minute) have been used in adults; infusion rates may be higher in pediatric patients.¹ Dosage requirements may increase or decrease with time.¹⁶⁸ (See Intensive Care Settings under Cautions.)

Patients with Myasthenia Gravis

Administer at low initial doses and with careful monitoring in well-controlled patients whose usual therapy is continued up to the time of surgery.^{114 115 116 130}

Patients with Cardiovascular Disease

Initial dose of 0.3–0.4 mg/kg administered slowly or in fractional doses over 1 minute.^{1 2 132 169 170 171} (See Cardiovascular Effects under Cautions.)

Other Populations

Patients with an increased risk of histamine release (e.g., history of severe anaphylactoid reactions or asthma): Initial dose of 0.3–0.4 mg/kg administered slowly or in fractional doses over 1 minute.^{1 2 132 169 170 171}

Patients in whom potentiation of neuromuscular blockade or difficulties with reversal of blockade may occur (e.g., neuromuscular disease, severe electrolyte disturbances, carcinomatosis): Consider dosage reduction.^{1 2} However, no clinical experience to date in these patients, and no specific doses are recommended.^{1 2} (See Neuromuscular Disease and also Electrolyte Disturbances under Cautions.)

Cautions for Atracurium Besylate

Contraindications

• 
  

  Known hypersensitivity to atracurium besylate or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Respiratory Effects

Potential for severely compromised respiratory function and respiratory paralysis.^{80 81 82 83 86}

Should be used only by individuals experienced in the use of neuromuscular blocking agents and in the maintenance of an adequate airway and respiratory support.¹ Facilities and personnel necessary for intubation, administration of oxygen, and assisted or controlled respiration should be immediately available.¹

IV cholinesterase inhibitor (e.g., neostigmine, pyridostigmine, edrophonium) should be readily available.^{1 80 89} (See Reversal of Neuromuscular Blockade under Dosage and Administration.)

Use with caution in patients with pulmonary impairment or respiratory depression.^b

Sensitivity Reactions

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic or anaphylactoid reactions, reported.¹

Use with caution and at lower initial doses in patients with a history of severe anaphylactoid reactions.^{1 2}

General Precautions

Neuromuscular Disease

Possible exaggerated neuromuscular blockade in patients with neuromuscular disease (e.g., myasthenia gravis, Eaton-Lambert syndrome).^{1 2 114 115 116}

Monitor degree of neuromuscular blockade with a peripheral nerve stimulator; consider dosage reduction.^{1 2 114 115 116}

Burn Patients

Resistance to therapy^{1 143 144 145 147 148} can develop in burn patients, particularly those with burns over 25–30% or more of body surface area.^{143 144 145 146 147 148 149}

Resistance generally becomes apparent ≥1 week after the burn,^{143 144 145 146 147 148 149} peaks ≥2 weeks after the burn,^{144 145 146 148} persists for several months or longer,^{144 146} and decreases gradually with healing.^{143 144 146 148}

Consider possible need for substantially increased doses.^{1 143 144 145 146 147} (See Distribution: Special Populations, under Pharmacokinetics.)

Histamine Release

Possible substantial histamine release.^{1 2}

Use with caution and at lower initial doses in patients in whom substantial histamine release would be particularly hazardous (e.g., those with clinically important cardiovascular disease) and in patients with any history suggesting a greater risk of histamine release (e.g., history of severe anaphylactoid reactions or asthma).^{1 2}

Safety in patients with asthma not established.¹

Cardiovascular Effects

Exhibits minimal effects on heart rate;^{4 9 12 13 14 31 36 41 67} therefore, will not counteract the bradycardia induced by many anesthetic agents or by vagal stimulation.^{1 2}

Use with caution and at lower initial doses in patients with clinically important cardiovascular disease because of potential for substantial histamine release.^{1 2}

Intensive Care Setting

Possible prolonged paralysis and/or muscle weakness or atrophy.^b

Continuous monitoring of neuromuscular transmission recommended during neuromuscular blocking agent therapy in intensive care setting.¹⁶⁸ Do not administer additional doses before there is a definite response to nerve stimulation tests.¹⁶⁸ If no response is elicited, discontinue administration until a response returns.¹⁶⁸

Seizures reported rarely in patients with predisposing factors (e.g., head trauma, cerebral edema, hypoxic encephalopathy, viral encephalitis, uremia) receiving continuous IV infusions for facilitation of mechanical ventilation in intensive care settings.¹⁶⁸

Electrolyte Disturbances

Monitor the degree of neuromuscular blockade with a peripheral nerve stimulator and consider dosage reduction in patients with severe electrolyte disturbances (i.e., hypermagnesemia, hypokalemia, hypocalcemia).^{1 2 86}

Malignant Hyperthermia

Malignant hyperthermia is rarely associated with use of neuromuscular blocking agents and/or potent inhalation anesthetics.^{1 137 139 141 b} Be vigilant for its possible development and prepared for its management in any patient undergoing general anesthesia.^{1 141}

Carcinomatosis

Monitor the degree of neuromuscular blockade with a peripheral nerve stimulator and consider dosage reduction.^{1 2 86}

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether atracurium is distributed into milk.¹ Caution advised if used in nursing women.¹

Pediatric Use

Safety and efficacy not established in children <1 month of age.¹³²

Large amounts of benzyl alcohol (i.e., 100–400 mg/kg daily) have been associated with toxicity in neonates;^{1 161 162 163 164 165 166} each mL of atracurium besylate injection in multiple-dose vials contains 9 mg of benzyl alcohol.¹

Geriatric Use

Use with caution.^b However, no substantial differences in safety, efficacy, or dosage requirements relative to younger adults.¹

Hepatic Impairment

Use with caution.^b

Renal Impairment

Use with caution.^b

Common Adverse Effects

Skin flush.¹

Interactions for Atracurium Besylate

Specific Drugs

Drug	Interaction	Comments
Anesthetics, general (enflurane, halothane, isoflurane)	Increased potency and prolonged duration of neuromuscular blockade1 10 24 31 35	Reduced atracurium dosage recommended1 (See Dosage under Dosage and Administration)
Anticonvulsants (carbamazepine, phenytoin)	Decreased duration and/or degree of neuromuscular blockadeb	Close monitoring recommended; adjust atracurium dose accordinglyb
Anti-infectives (aminoglycosides, bacitracin, clindamycin, lincomycin, polymyxins, tetracyclines)	Possible increased neuromuscular blockade1 b
Lithium	Possible increased neuromuscular blockade1
Magnesium salts	Possible increased neuromuscular blockade1 b	Use with caution1 b
Neuromuscular blocking agents, nondepolarizing	Possible increased or decreased neuromuscular blockade1 169 170 171
Procainamide	Possible increased neuromuscular blockade1
Quinidine	Possible increased neuromuscular blockade1
Succinylcholine	Variable effects (increased128 129 or decreased117 neuromuscular blockade) reported1	Administer atracurium in reduced dosage and only after patient has recovered from succinylcholine-induced neuromuscular blockade1

Atracurium Besylate Pharmacokinetics

Absorption

Bioavailability

Poorly absorbed from the GI tract.^b

Onset

Time to maximum neuromuscular blockade decreases as the dose increases.^{1 22 24 39}

Following IV administration of 0.4–0.5 mg/kg, maximum neuromuscular blockade generally occurs within 3–5 minutes^{1 2} (range: 1.7–10 minutes).^{5 22 26 27 35 40}

Duration

Duration of maximum neuromuscular blockade increases as the dose increases.^{1 22 24 35 39}

Duration of neuromuscular blockade induced by 0.4–0.5 mg/kg under balanced anesthesia is about 20–35 minutes.^{1 2 17 35 86} Recovery generally is 25 and 95% complete approximately 35–45 and 60–70 minutes, respectively, after the injection.^{1 86 169 170 171}

Regardless of the dose, recovery from the maximum effect of neuromuscular blockade is 95% complete in approximately 30 minutes¹ (range: 12–75.7 minutes)^{2 6 22 24 26 31 39 100} under balanced anesthesia and approximately 40 minutes¹ (range: 6–104 minutes)^{5 6 24 27 34 100} under anesthesia with enflurane, isoflurane, or halothane.

Rate of recovery from neuromuscular blockade is more rapid in children than adults.^{41 88 92}

Alkalosis may enhance recovery.^{3 54}

Special Populations

Hepatic dysfunction does not substantially alter duration of and rate of recovery from neuromuscular blockade.^{19 40 49 103 104 105 106 131}

In patients with renal failure, onset may be slightly delayed;^{40 103 105} however, renal dysfunction does not substantially alter duration of and rate of recovery from neuromuscular blockade.^{19 40 49 103 104 105 106 131}

In patients undergoing cardiopulmonary bypass surgery under induced hypothermia, duration of blockade may be prolonged.^{57 79 97}

Distribution

Extent

Distributed into extracellular fluid;^{2 85} rapidly reaches site of action at motor end-plate of myoneural junction.^b

Crosses the placenta in small amounts.^{1 2 61 107}

Plasma Protein Binding

82%.^{45 46}

Special Populations

In burn patients, possible increased protein binding (possibly to α₁-acid glycoprotein) with subsequent decreases in the free fraction of circulating drug.^{143 144 145 147}

Elimination

Metabolism

Rapidly metabolized via Hofmann elimination and nonspecific enzymatic ester hydrolysis; the liver does not appear to play a major role.^{1 9 31}

Elimination Route

Excreted principally in urine and also in feces via biliary elimination.^{1 2 3 9 22 31 54 108 109 160}

Half-life

Biphasic; terminal elimination half-life is approximately 20 minutes.^{1 2 47 48 49 50 104}

Stability

Storage

Parenteral

Injection

2–8°C; do not freeze.^{1 2}

Use within 14 days once removed from refrigeration, regardless of whether injection was subsequently rerefrigerated.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Unstable in the presence of acids and bases.² May be incompatible with alkaline solutions (e.g., barbiturate solutions).¹

Solution Compatibility^HID

Compatible for 24 hours at 5 or 25°C;^HID use within 24 hours when diluted with dextrose 5% in water or sodium chloride 0.9% injection.¹

Compatible
Dextrose 5% in sodium chloride 0.9%
Incompatible
Ringer’s injection, lactated
Variable
Dextrose 5% in water
Sodium chloride 0.9%

Drug Compatibility

Admixture CompatibilityHID

Compatible
Bretylium tosylate
Cimetidine HCl
Ciprofloxacin
Dobutamine HCl
Dopamine HCl
Esmolol HCl
Gentamicin sulfate
Isoproterenol HCl
Lidocaine HCl
Morphine sulfate
Potassium chloride
Procainamide HCl
Vancomycin HCl
Incompatible
Aminophylline
Cefazolin sodium
Heparin sodium
Quinidine gluconate
Ranitidine HCl
Sodium nitroprusside

Y-Site CompatibilityHID

Compatible
Amiodarone HCl
Cefazolin
Cefuroxime sodium
Cimetidine HCl
Co-trimoxazole
Dobutamine HCl
Dopamine HCl
Epinephrine HCl
Esmolol HCl
Etomidate
Fenoldopam mesylate
Fentanyl citrate
Gentamicin sulfate
Heparin sodium
Hetastarch in lactated electrolyte injection (Hextend)
Hydrocortisone sodium succinate
Isoproterenol HCl
Lorazepam
Midazolam HCl
Milrinone lactate
Morphine sulfate
Nitroglycerin
Ranitidine HCl
Sodium nitroprusside
Vancomycin HCl
Incompatible
Diazepam
Propofol
Thiopental sodium

ActionsActions

• 
  

  Produces skeletal muscle relaxation by causing a decreased response to acetylcholine (ACh) at the myoneural (neuromuscular) junction of skeletal muscle.^{1 b}

  
  


• 
  

  Exhibits high affinity for ACh receptor sites and competitively blocks access of ACh to motor end-plate of myoneural junction; may affect ACh release.^b

  
  


• 
  

  Blocks the effects of both the small quantities of ACh that maintain muscle tone and the large quantities of ACh that produce voluntary skeletal muscle contraction; does not alter the resting electrical potential of the motor end-plate or cause muscular contractions.^b

  
  


• 
  

  Exhibits minimal cardiovascular effects.^{2 5 6 7 8 9 12 13 14 15 20 22 24 25 26 27 28 88 93}

  
  

Advice to Patients

• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease, neuromuscular disease).¹

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Atracurium Besylate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for IV use	10 mg/mL*	Atracurium Besylate Injection (preservative-free in single-use vials or with benzyl alcohol 0.9% in multiple-dose vials)	Baxter, Bedford, Hospira, Mayne, Sicor
			Tracrium (preservative-free in single-use vials or with benzyl alcohol 0.9% in multiple-dose vials)	Abbott

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Abbott Laboratories. Tracrium (atracurium besylate) injection prescribing information. North Chicago, IL; 2000 Mar.

2. Burroughs Wellcome Co. Tracrium pharmacist product information. Research Triangle Park, NC; 1983 Dec.

3. Collins GE. (Burroughs Wellcome Co, Research Triangle Park, NC): Personal communication; 1984 Mar 22.

4. Lee C, Yang E, Katz RL. Clinical neuromuscular pharmacology of BW 33A. Anesth Analg. 1982; 61:199-200.

5. Goudsouzian NG, Liu LMP, Coté CJ et al. Safety and efficacy of atracurium in adolescents and children anesthetized with halothane. Anesthesiology. 1983; 59:459-62. [IDIS 178106] [PubMed 6688932]

6. Rupp SM, Fahey MR, Miller RD. Neuromuscular and cardiovascular effects of atracurium during nitrous oxide-fentanyl and nitrous oxide-isoflurane anaesthesia. Br J Anaesth. 1983; 55(Suppl 1): 67-70S. [IDIS 172717] [PubMed 6688020]

7. Brandom BW, Woelfel SK, Cook DR et al. Clinical pharmacology of atracurium in infants. Anesthesiology. 1983; 59:A440.

8. Hunt TM, Hughes R, Payne JP. Preliminary studies with atracurium in anaesthetized man. Br J Anaesth. 1980; 52:238-9P.

9. Basta SJ, Ali HH, Savarese JJ et al. Clinical pharmacology of atracurium besylate (BW 33A): a new non-depolarizing muscle relaxant. Anesth Analg. 1982; 61:723-9. [IDIS 157360] [PubMed 6213181]

10. Savarese JJ, Basta SJ, Ali HH et al. Neuromuscular and cardiovascular effects of BW 33A (atracurium) in patients under halothane anesthesia. Anesthesiology. 1982; 57:A262.

11. Basta SJ, Savarese JJ, Ali HH et al. Histamine-releasing potencies of atracurium besylate (BW 33A), metocurine, and d-tubocurarine. Anesthesiology. 1982; 57:A261.

12. Barnes PK, Thomas VJE, Boyd I et al. Comparison of the effects of atracurium and tubocurarine on heart rate and arterial pressure in anaesthetized man. Br J Anaesth. 1983; 55(Suppl 1):91-4S.

13. Basta SJ, Savarese JJ, Ali HH et al. Histamine-releasing potencies of atracurium, dimethyl tubocurarine and tubocurarine. Br J Anaesth. 1983; 55(Suppl 1):105-6S. [IDIS 172726] [PubMed 6338892]

14. Pokar H, Brandt L. Haemodynamic effects of atracurium in patients after cardiac surgery. Br J Anaesth. 1983; 55(Suppl 1):139S. [IDIS 172736] [PubMed 6688010]

15. Hughes R, Payne JP. Clinical assessment of atracurium using the single twitch and tetanic responses of the adductor pollicis muscles. Br J Anaesth. 1983; 55(Suppl 1):47-52S.

16. Baird WLM, Kerr WJ. Reversal of atracurium with edrophonium. Br J Anaesth. 1983; 55(Suppl 1):63-6S.

17. Foldes FF, Nagashima H, Boros M et al. Muscular relaxation with atracurium, vecuronium and duador under balanced anesthesia. Br J Anaesth. 1983; 55:(Suppl 1):97-103S. [IDIS 172725] [PubMed 6190489]

18. Rowlands DE. Atracurium in clinical anaesthesia. Br J Anaesth. 1983; 55(Suppl 1):125-8S. [IDIS 165994] [PubMed 6131682]

19. Hunter JM, Jones RS, Utting JE. Atracurium in renal failure. Br J Anaesth. 1983; 55(Suppl 1):129S. [IDIS 172733] [PubMed 6688007]

20. Philbin DM, Machaj VR, Tomichek RC et al. Haemodynamic effects of bolus injections of atracurium in patients with coronary artery disease. Br J Anaesth. 1983; 55(Suppl 1):131-4S. [IDIS 172734] [PubMed 6131683]

21. Goudsouzian NG, Liu LMP, Gionfriddo M et al. The dose response effect of atracurium in infants. Anesth Analg. 1984; 63:223.

22. Hilgenberg JC. Comparison of the pharmacology of vecuronium and atracurium with that of other currently available muscle relaxants. Anesth Analg. 1983; 62:524-31. [IDIS 170170] [PubMed 6132564]

23. Anon. Atracurium. Lancet. 1983; 1:394-5. [PubMed 6130383]

24. Payne JP, Hughes R. Evaluation of atracurium in anaesthetized man. Br J Anaesth. 1981; 53:45-54. [IDIS 129791] [PubMed 7459185]

25. Fragen RJ, Robertson EN, Booij LHDJ et al. A comparison of vecuronium and atracurium in man. Anesthesiology. 1982; 57:A253.

26. Katz RL, Stirt J, Murray AL et al. Neuromuscular effects of atracurium in man. Anesth Analg. 1982; 61:730-4. [IDIS 157361] [PubMed 6285767]

27. Stirt JA, Murray AL, Katz RL et al. Atracurium during halothane anesthesia in humans. Anesth Analg. 1983; 62:207-10. [IDIS 166904] [PubMed 6687515]

28. Robertson EN, Booij LHDJ, Fragen RJ et al. Clinical comparison of atracurium and vecuronium (ORG NC 45). Br J Anaesth. 1983; 55:125-9. [IDIS 165994] [PubMed 6131682]

29. Rosewarne FA. Vecuronium and atracurium. Br J Anaesth. 1983; 55:1042. [IDIS 176811] [PubMed 6138052]

30. Robertson EN, Booij LHDJ, Crul JF. Vecuronium and atracurium. Br J Anaesth. 1983; 55:1043. [IDIS 176812] [PubMed 6626407]

31. Ali HH, Savarese JJ, Basta SJ et al. Clinical pharmacology of atracurium: a new intermediate acting nondepolarizing relaxant. Semin Anesth. 1982; 1:57-62.

32. Scott RPF, Goat VA. Atracurium: its speed of onset. A comparison with suxamethonium. Br J Anaesth. 1982; 54:909-11. [IDIS 157910] [PubMed 7115602]

33. Brandom BW, Woelfel SK, Cook DR et al. Relative potency of atracurium in children during halothane, isoflurane, or thiopental-fentanyl anesthesia. Anesthesiology. 1983; 59:A442.

34. Goudsouzian NG, Liu LMP, Coté CJ et al. Clinical pharmacology of atracurium (BW 33A) in adolescents anesthetized with halothane. Anesthesiology. 1982; 57:A414.

35. Sokoll MD, Gergis SD, Mehta M et al. Safety and efficacy of atracurium (BW 33A) in surgical patients receiving balanced or isoflurane anesthesia. Anesthesiology. 1983; 58:450-5. [IDIS 170743] [PubMed 6340561]

36. Nguyen HD, Nagashima H, Kaplan R et al. Relaxation with BW33A under neurolept and enflurane anesthesia. Anesthesiology. 1982; 57:A277.

37. Ramsey FM, White PA, Stullken EH et al. Enflurane potentiation of neuromuscular blockade by atracurium. Anesthesiology. 1982; 57:A255.

38. Cook DR, Rudd GD, Brandom BW. Clinical pharmacology of atracurium (BW33A) in pediatric patients. Anesthesiology. 1982; 57:A415.

39. Hughes R, Hunt TM, Payne JP. Recovery from neuromuscular blockade by atracurium. Br J Anaesth. 1980; 52:634P.

40. Hunter JM, Jones RS, Utting JE. Use of atracuriu