DESCRIPTION:
Atracurium besylate is an intermediate-duration, nondepolarizing, skeletal muscle relaxant for intravenous administration. Atracurium besylate is designated as 2-(2-Carboxyethyl)-1, 2, 3, 4-tetrahydro-6,7-dimethoxy-2-methyl-1-veratrylisoquinolinium benzenesulfonate, pentamethylene ester. It has a molecular weight of 1243.49, and its molecular formula is C65 H82 N2 O18 S2

Atracurium Besylate Injection, is a sterile, non-pyrogenic aqueous solution. Each mL contains 10 mg atracurium besylate. The pH is adjusted to 3.25 to 3.65 with benzenesulfonic acid. Atracurium besylate injection slowly loses potency with time at the rate of approximately 6% per year under refrigeration (5°C). Atracurium besylate injection should be refrigerated at 2° to 8°C (36° to 46°F) to preserve potency.

AVAILABILITY:

Domestic Export Yes Domestic Product insert

INDICATIONS AND USAGE:

Atracurium besylate injection is indicated, as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.

WARNING:

Atracurium should be used only by those skilled in airway management and respiratory support. Equipment and personnel must be immediately available for endotracheal intubation and support of ventilation, including administration of positive pressure oxygen. Adequacy of respiration must be assured through assisted or controlled ventilation. Anticholinesterase reversal agents should be immediately available.

Do not give atracurium besylate by intramuscular administration.

Atracurium besylate injection, which has an acid pH, should not be mixed with alkaline solutions (e.g., barbiturate solutions) in the same syringe or administered simultaneously during intravenous infusion through the same needle. Depending on the resultant pH of such mixtures, atracurium may be inactivated and a free acid may be precipitated.

Atracurium Besylate injection contains benzyl alcohol. In neonates, benzyl alcohol has been associated with an increased incidence of neurological and other complications which are sometimes fatal.

PRECAUTIONS:

Although atracurium is a less potent histamine releaser than d-tubocurarine or metocurine, the possibility of substantial histamine release in sensitive individuals must be considered. Special caution should be exercised in administering atracurium to patients in whom substantial histamine release would be especially hazardous (e.g., patients with clinically significant cardiovascular disease) and in patients with any history (e.g., severe Anaphylactoid reactions or asthma) suggesting a greater risk of histamine release. In these patients, the recommended initial atracurium besylate dose is lower (0.3 to 0.4 mg/kg) than for other patients and should be administered slowly or in divided doses over one minute.

Since atracurium has no clinically significant effects on heart rate in the recommended dosage range, it will not counteract the bradycardia produced by many anesthetic agents or vagal stimulation. As a result, bradycardia during anesthesia may be more common with Atracurium than with other muscle relaxants.

Atracurium may have profound effects in patients with myasthenia gravis, Eaton-Lambert syndrome, or other neuromuscular diseases in which potentiation of nondepolarizing agents has been noted. The use of a peripheral nerve stimulator is especially important for assessing neuromuscular block in these patients. Similar precautions should be taken in patients with severe electrolyte disorders or carcinomatosis.

Multiple factors in anesthesia practice are suspected of triggering malignant hyperthermia (MH), a potentially fatal hypermetabolic state of skeletal muscle. Halogenated anesthetic agents and succinylcholine are recognized as the principal pharmacologic triggering agents in MH susceptible patients; however, since MH can develop in the absence of established triggering agents, the clinician should be prepared to recognize and treat MH in any patient scheduled for general anesthesia. As per literature reviewed Reports of MH have been rare in cases in which atracurium has been used.

DOSAGE AND ADMINISTRATION:

To avoid distress to the patient, atracurium should not be administered before unconsciousness has been induced. Atracurium should not be mixed in the same syringe, or administered simultaneously through the same needle, with alkaline solutions (e.g., barbiturate solutions).

Atracurium besylate should be administered intravenously. DO NOT GIVE ATRACURIUM BESYLATE BY INTRAMUSCULAR ADMINISTRATION. Intramuscular administration of atracurium besylate may result in tissue irritation and there are no clinical data to support this route of administration.

Bolus Doses for Intubation and Maintenance of Neuromuscular Block Adults:

An atracurium besylate dose of 0.4 to 0.5 mg/kg (1.7 to 2.2 times the ED95 ), given as an intravenous bolus injection, is the recommended initial dose for most patients. With this dose, good or excellent conditions for nonemergency intubation can be expected in 2 to 2.5 minutes in most patients, with maximum neuromuscular block achieved approximately 3 to 5 minutes after injection. Clinically required neuromuscular block generally lasts 20 to 35 minutes under balanced anesthesia. Under balanced anesthesia, recovery to 25% of control is achieved approximately 35 to 45 minutes after injection, and recovery is usually 95% complete approximately 60 minutes after injection.

Atracurium is potentiated by isoflurane or enflurane anesthesia. The same initial atracurium besylate dose of 0.4 to 0.5 mg/kg may be used for intubation prior to administration of these inhalation agents; however, if atracurium is first administered under steady-state of isoflurane or enflurane, the initial atracurium besylate dose should be reduced by approximately one-third, i.e., to 0.25 to 0.35 mg/kg, to adjust for the potentiating effects of these anesthetic agents. With halothane, which has only a marginal (approximately 20%) potentiating effect on atracurium, smaller dosage reductions may be considered.

Atracurium besylate doses of 0.08 to 0.10 mg/kg are recommended for maintenance of neuromuscular block during prolonged surgical procedures. The first maintenance dose will generally be required 20 to 45 minutes after the initial atracurium besylate injection, but the need for maintenance doses should be determined by clinical criteria. Because atracurium lacks cumulative effects, maintenance doses may be administered at relatively regular intervals for each patient, ranging approximately from 15 to 25 minutes under balanced anesthesia, slightly longer under isoflurane or enflurane. Higher atracurium doses (up to 0.2 mg/kg) permit maintenance dosing at longer intervals.

Pediatric Patients:

No atracurium dosage adjustments are required for pediatric patients two years of age or older. An atracurium besylate dose of 0.3 to 0.4 mg/kg is recommended as the initial dose for infants (1 month to 2 years of age) under halothane anesthesia. Maintenance doses may be required with slightly greater frequency in infants and children than in adults.

Special Considerations:

An initial atracurium besylate dose of 0.3 to 0.4 mg/kg, given slowly or in divided doses over one minute, is recommended for adults, children, or infants with significant cardiovascular disease and for adults, children, or infants with any history (e.g., severe anaphylactoid reactions or asthma) suggesting a greater risk of histamine release.

Dosage reductions must be considered also in patients with neuromuscular disease, severe electrolyte disorders. In carcinomatosis no specific dosage adjustments can be recommended. No atracurium dosage adjustments are required for patients with renal disease.

An initial atracurium besylate dose of 0.3 to 0.4 mg/kg is recommended for adults following the use of succinylcholine for intubation under balanced anesthesia. Further reductions may be desirable with the use of potent inhalation anesthetics. Insufficient data are available for recommendation of a specific initial atracurium dose for administration following the use of succinylcholine in children and infants.

Use by Continuous Infusion:

Infusion in the Operating Room (OR): After administration of a recommended initial bolus dose of atracurium besylate injection (0.3 to 0.5 mg/kg), a diluted solution of atracurium Besylate can be administered by continuous infusion to adults and pediatric patients aged 2 or more years for maintenance of neuromuscular block during extended surgical procedures.

Infusion of atracurium should be individualized for each patient. The rate of administration should be adjusted according to the patient’s response as determined by peripheral nerve stimulation. Accurate dosing is best achieved using a precision infusion device.

Infusion of atracurium should be initiated only after early evidence of spontaneous recovery from the bolus dose. An initial infusion rate of 9 to 10 mcg/kg/min may be required to rapidly counteract the spontaneous recovery of neuromuscular function. Thereafter, a rate of 5 to 9 mcg/kg/min should be adequate to maintain continuous neuromuscular block in the range of 89% to 99% in most pediatric and adult patients under balanced anesthesia. Occasional patients may require infusion rates as low as 2 mcg/kg/min or as high as 15 mcg/kg/min.

The neuromuscular blocking effect of atracurium administered by infusion is potentiated by enflurane or isoflurane and, to a lesser extent, by halothane. Reduction in the infusion rate of atracurium should, therefore, be considered for patients receiving inhalation anesthesia. The rate of atracurium infusion should be reduced by approximately one-third in the presence of steadystate enflurane or isoflurane anesthesia; smaller reductions should be considered in the presence of halothane.

In patients undergoing cardiopulmonary bypass with induced hypothermia, the rate of infusion of atracurium required to maintain adequate surgical relaxation during hypothermia (25° to 28°C) has been shown to be approximately half the rate required during normothermia.
Spontaneous recovery from neuromuscular block following discontinuation of Atracurium infusion may be expected to proceed at a rate comparable to that following administration of a single bolus dose.

Infusion in the Intensive Care Unit (ICU):

The principles for infusion of atracurium in the OR are also applicable to use in the ICU.

An infusion rate of 11 to 13 mcg/kg/min (range: 4.5 to 29.5) should provide adequate neuromuscular block in adult patients in an ICU. Limited information suggests that infusion rates required for pediatric patients in the ICU may be higher than in adult patients. There may be wide interpatient variability in dosage requirements and these requirements may increase or decrease with time. Following recovery from neuromuscular block, readministration of a bolus dose may be necessary to quickly reestablish neuromuscular block prior to reinstitution of the infusion.

Infusion Rate Tables:

The amount of infusion solution required per minute will depend upon the concentration of atracurium in the infusion solution, the desired dose of atracurium, and the patient’s weight. The following tables provide guidelines for delivery, in mL/hr (equivalent to microdrops/min when 60 microdrops = 1 mL), of atracurium solutions in concentrations of 0.2 mg/mL (20 mg in 100 mL) or 0.5 mg/mL (50 mg in 100 mL) with an infusion pump or a gravity flow device.

Atracurium Besylate Infusion Rates for a Concentration of 0.2 mg/mL

Patient Weight (kg)

Drug Delivery Rate (mcg/kg/min)

5

6

7

8

9

10

11

12

13

Infusion Delivery Rate (ml/hr)

30

45

54

63

72

81

90

99

108

117

35

53

63

74

84

95

105

116

126

137

40

60

72

84

96

108

120

132

144

156

45

68

81

95

108

122

135

149

162

176

50

75

90

105

120

135

150

165

180

195

55

83

99

116

132

149

165

182

198

215

60

90

108

126

144

162

180

198

216

234

65

98

117

137

156

176

195

215

234

254

70

105

126

147

168

189

210

231

252

273

75

113

135

158

180

203

225

248

270

293

80

120

144

168

192

216

240

264

288

312

90

135

162

189

216

243

270

297

324

351

100

150

180

210

240

270

300

330

360

390

Atracurium Besylate Infusion Rates for a Concentration of 0.5 mg/mL

Patient Weight (kg)

Drug Delivery Rate (mcg/kg/min)

5

6

7

8

9

10

11

12

13

Infusion Delivery Rate (ml/hr)

30

18

22

25

29

32

36

40

43

47

35

21

25

29

34

38

42

46

50

55

40

24

29

34

38

43

48

53

58

62

45

27

32

38

43

49

54

59

65

70

50

30

36

42

48

54

60

66

72

78

55

33

40

46

53

59

66

73

79

86

60

36

43

50

58

65

72

79

86

94

65

39

47

55

62

70

78

86

94

101

70

42

50

59

67

76

84

92

101

109

75

45

54

63

72

81

90

99

108

117

80

48

58

67

77

86

96

106

115

125

90

54

65

76

86

97

108

119

130

140

100

60

72

84

96

108

120

132

144

156

PRESENTATION:

Atranir injection is available in 2.5ml and 5ml ampoule