Zemuron

Pregnancy Category: C

Lactation: not known if excreted in breast milk; effect on nursing infant not known

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Tell your doctor about all medicines you use, especially:

• an injected antibiotic, such as amikacin, gentamicin, kanamycin, neomycin, paromomycin, streptomycin, tobramycin.

This list is not complete. Other drugs may interact with rocuronium, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

• Produces skeletal muscle relaxation by causing a decreased response to acetylcholine (ACh) at the myoneural (neuromuscular) junction of skeletal muscle.a

• Exhibits high affinity for ACh receptor sites and competitively blocks access of ACh to motor end-plate of myoneural junction; may affect ACh release.1 a

• 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.a

• Appears to have little, if any, histamine-releasing activity.1 a

• It is used to calm muscles during surgery.
• It is used to calm muscles while on a breathing machine.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• A heartbeat that does not feel normal.
• This medicine may irritate the vein. It may burn the skin if the drug leaks from the vein when it is given. Tell your nurse if you have any redness, burning, pain, swelling, or leaking of fluid where the drug is going into your body.

In clinical trials, the most common adverse reactions (2%) are transient hypotension and hypertension.

The following adverse reactions are described, or described in greater detail, in other sections:

• Anaphylaxis [see Warnings and Precautions (5.2)]
• Residual paralysis [see Warnings and Precautions (5.4)]
• Myopathy [see Warnings and Precautions (5.5)]
• Increased pulmonary vascular resistance [see Warnings and Precautions (5.11)]

Clinical Trials Experience

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

Clinical studies in the US (n=1137) and Europe (n=1394) totaled 2531 patients. The patients exposed in the US clinical studies provide the basis for calculation of adverse reaction rates. The following adverse reactions were reported in patients administered Zemuron (all events judged by investigators during the clinical trials to have a possible causal relationship):

Adverse reactions in greater than 1% of patients: None

Adverse reactions in less than 1% of patients (probably related or relationship unknown):

In the European studies, the most commonly reported reactions were transient hypotension (2%) and hypertension (2%); these are in greater frequency than the US studies (0.1% and 0.1%). Changes in heart rate and blood pressure were defined differently from in the US studies in which changes in cardiovascular parameters were not considered as adverse events unless judged by the investigator as unexpected, clinically significant, or thought to be histamine related.

In a clinical study in patients with clinically significant cardiovascular disease undergoing coronary artery bypass graft, hypertension and tachycardia were reported in some patients, but these occurrences were less frequent in patients receiving beta or calcium channel-blocking drugs. In some patients, Zemuron was associated with transient increases (30% or greater) in pulmonary vascular resistance. In another clinical study of patients undergoing abdominal aortic surgery, transient increases (30% or greater) in pulmonary vascular resistance were observed in about 24% of patients receiving Zemuron 0.6 or 0.9 mg/kg.

In pediatric patient studies worldwide (n=704), tachycardia occurred at an incidence of 5.3% (n=37), and it was judged by the investigator as related in 10 cases (1.4%).

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Zemuron. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: In clinical practice, there have been reports of severe allergic reactions (anaphylactic and anaphylactoid reactions and shock) with Zemuron, including some that have been life-threatening and fatal [see Warnings and Precautions (5.2)].

General disorders and administration site conditions: There have been reports of malignant hyperthermia with the use of Zemuron [see Warnings and Precautions (5.6)].

Overdosage with neuromuscular blocking agents may result in neuromuscular block beyond the time needed for surgery and anesthesia. The primary treatment is maintenance of a patent airway, controlled ventilation, and adequate sedation until recovery of normal neuromuscular function is assured. Once evidence of recovery from neuromuscular block is observed, further recovery may be facilitated by administration of an anticholinesterase agent in conjunction with an appropriate anticholinergic agent.

Reversal of Neuromuscular Blockade: Anticholinesterase agents should not be administered prior to the demonstration of some spontaneous recovery from neuromuscular blockade. The use of a nerve stimulator to document recovery is recommended.

Patients should be evaluated for adequate clinical evidence of neuromuscular recovery, e.g., 5-second head lift, adequate phonation, ventilation, and upper airway patency. Ventilation must be supported while patients exhibit any signs of muscle weakness.

Recovery may be delayed in the presence of debilitation, carcinomatosis, and concomitant use of certain drugs which enhance neuromuscular blockade or separately cause respiratory depression. Under such circumstances the management is the same as that of prolonged neuromuscular blockade.

In US clinical studies, a total of 1137 patients received Zemuron, including 176 pediatric, 140 geriatric, 55 obstetric, and 766 other adults. Most patients (90%) were ASA physical status I or II, about 9% were ASA III, and 10 patients (undergoing coronary artery bypass grafting or valvular surgery) were ASA IV. In European clinical studies, a total of 1394 patients received Zemuron, including 52 pediatric, 128 geriatric (65 years or greater), and 1214 other adults.

Adult Patients

Intubation using doses of Zemuron 0.6 to 0.85 mg/kg was evaluated in 203 adults in 11 clinical studies. Excellent to good intubating conditions were generally achieved within 2 minutes and maximum block occurred within 3 minutes in most patients. Doses within this range provide clinical relaxation for a median (range) time of 33 (14-85) minutes under opioid/nitrous oxide/oxygen anesthesia. Larger doses (0.9 and 1.2 mg/kg) were evaluated in 2 studies with 19 and 16 patients under opioid/nitrous oxide/oxygen anesthesia and provided 58 (27-111) and 67 (38-160) minutes of clinical relaxation, respectively.

Cardiovascular Disease: In 1 clinical study, 10 patients with clinically significant cardiovascular disease undergoing coronary artery bypass graft received an initial dose of 0.6 mg/kg Zemuron. Neuromuscular block was maintained during surgery with bolus maintenance doses of 0.3 mg/kg. Following induction, continuous 8 mcg/kg/min infusion of Zemuron produced relaxation sufficient to support mechanical ventilation for 6 to 12 hours in the surgical intensive care unit (SICU) while the patients were recovering from surgery.

Rapid Sequence Intubation: Intubating conditions were assessed in 230 patients in 6 clinical studies where anesthesia was induced with either thiopental (3-6 mg/kg) or propofol (1.5-2.5 mg/kg) in combination with either fentanyl (2-5 mcg/kg) or alfentanil (1 mg). Most of the patients also received a premedication such as midazolam or temazepam. Most patients had intubation attempted within 60 to 90 seconds of administration of Zemuron 0.6 mg/kg or succinylcholine 1 to 1.5 mg/kg. Excellent or good intubating conditions were achieved in 119/120 (99% [95% confidence interval: 95%-99.9%]) patients receiving Zemuron and in 108/110 (98% [94%-99.8%]) patients receiving succinylcholine. The duration of action of Zemuron 0.6 mg/kg is longer than succinylcholine and at this dose is approximately equivalent to the duration of other intermediate-acting neuromuscular blocking drugs.

Obese Patients: Zemuron was dosed according to actual body weight (ABW) in most clinical studies. The administration of Zemuron in the 47 of 330 (14%) patients who were at least 30% or more above their ideal body weight (IBW) was not associated with clinically significant differences in the onset, duration, recovery, or reversal of Zemuron-induced neuromuscular block.

In 1 clinical study in obese patients, Zemuron 0.6 mg/kg was dosed according to ABW (n=12) or IBW (n=11). Obese patients dosed according to IBW had a longer time to maximum block, a shorter median (range) clinical duration of 25 (14-29) minutes, and did not achieve intubating conditions comparable to those dosed based on ABW. These results support the recommendation that obese patients be dosed based on actual body weight [see Dosage and Administration (2.5)].

Obstetric Patients: Zemuron 0.6 mg/kg was administered with thiopental, 3 to 4 mg/kg (n=13) or 4 to 6 mg/kg (n=42), for rapid sequence induction of anesthesia for Cesarean section. No neonate had APGAR scores greater than 7 at 5 minutes. The umbilical venous plasma concentrations were 18% of maternal concentrations at delivery. Intubating conditions were poor or inadequate in 5 of 13 women receiving 3 to 4 mg/kg thiopental when intubation was attempted 60 seconds after drug injection. Therefore, Zemuron is not recommended for rapid sequence induction in Cesarean section patients.

Geriatric Patients

Zemuron was evaluated in 55 geriatric patients (ages 65-80 years) in 6 clinical studies. Doses of 0.6 mg/kg provided excellent to good intubating conditions in a median (range) time of 2.3 (1-8) minutes. Recovery times from 25% to 75% after these doses were not prolonged in geriatric patients compared to other adult patients [see Dosage and Administration (2.5) and Use in Specific Populations (8.5)].

Pediatric Patients

Zemuron 0.45, 0.6, or 1 mg/kg was evaluated under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia for intubation in 326 patients in 2 studies. In 1 of these studies maintenance bolus and infusion requirements were evaluated in 137 patients. In all age groups, doses of 0.6 mg/kg provided time to maximum block in about 1 minute. Across all age groups, median (range) time to reappearance of T3 for doses of 0.6 mg/kg was shortest in the children [36.7 (20.1-65.9) minutes] and longest in infants [59.8 (32.3-87.8) minutes]. For pediatric patients older than 3 months, the time to recovery was shorter after stopping infusion maintenance when compared with bolus maintenance [see Dosage and Administration (2.5) and Use in Specific Populations (8.4)].

Zemuron 0.6 or 0.8 mg/kg was evaluated for intubation in 75 pediatric patients (n=28; age 3-12 months, n=47; age 1-12 years) in 3 studies using halothane (1%-5%) and nitrous oxide (60%-70%) in oxygen. Doses of 0.6 mg/kg provided a median (range) time to maximum block of 1 (0.5-3.3) minute(s). This dose provided a median (range) time of clinical relaxation of 41 (24-68) minutes in 3-month to 1-year-old infants and 26 (17-39) minutes in 1- to 12-year-old pediatric patients [see Dosage and Administration (2.5) and Use in Specific Populations (8.4)].

Obtain information about your patient's medical history, current medications, any history of hypersensitivity to rocuronium bromide or other neuromuscular blocking agents. If applicable, inform your patients that certain medical conditions and medications might influence how Zemuron works.

In addition, inform your patient that severe anaphylactic reactions to neuromuscular blocking agents, including Zemuron, have been reported. Since allergic cross-reactivity has been reported in this class, request information from your patients about previous anaphylactic reactions to other neuromuscular blocking agents.

Manuf. for: Merck Sharp & Dohme Corp., a subsidiary of
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

Manufactured by: Organon (Ireland) Ltd., Swords, Co. Dublin, Ireland, a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ 08889, USA.

For patent information: www.merck.com/product/patent/home.html

Copyright © 1994, 2010 Merck Sharp & Dohme B.V., a subsidiary of Merck & Co., Inc.
All rights reserved.

uspi-mk8085-i-1501r006

PRINCIPAL DISPLAY PANEL - 5 mL Multiple Dose Vial Carton

NDC 0052-0450-15

Injection
Zemuron ®
(rocuronium bromide)

10
mg/mL

Rx only

10 multiple-dose 5 mL vials

For IV use only

Applies to rocuronium: intravenous solution

Along with its needed effects, rocuronium (the active ingredient contained in Zemuron) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking rocuronium:

• Cough
• difficulty with breathing
• dizziness
• fainting
• fast, slow, or irregular heartbeat
• noisy breathing
• swelling at the injection site
• tightness in the chest

• Difficulty with swallowing
• hives, itching, or skin rash
• muscular pain, tenderness, wasting, or weakness
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• unusual tiredness or weakness