Sugammadex Injection - Mechanism of Action, Indications, Dosage, and Adverse Drug Reactions

Overview:

Sugammadex has become an essential tool for anesthesiologists and surgical teams, allowing for more precise control of muscle relaxation and faster recovery for patients undergoing surgery. Its development and approval have significantly impacted the practice of anesthesia and surgery. In 2015, the United States Food and Drug Administration (FDA) approved Sugammadex for use in the United States. It had already been approved in several other countries before this.

The introduction of Sugammadex has improved patient safety and recovery in surgical and anesthesia settings by allowing for more precise control of muscle relaxation during procedures. While Sugammadex has been widely adopted, ongoing research may continue to refine its usage and expand its applications. This article delves into the mechanisms and clinical significance of Sugammadex, shedding light on its evolution and the pivotal role it plays in enhancing the precision and safety of surgeries.

Drug Group:

Sugammadex belongs to the drug group known as neuromuscular blocking agents (NMBAs) reversal agents. Neuromuscular blocking agents are a group of medications used during surgery to induce muscle paralysis, primarily for facilitating intubation and maintaining a relaxed state during the procedure. They block the transmission of nerve impulses to muscles, resulting in temporary paralysis.

Available Doses and Dosage Forms

Available doses and forms:

• In a single-dose vial for bolus injection, there is a concentration of 200 mg (milligrams) per two mL (milliliter) (100 milligrams per milliliter).

• In a single-dose vial for bolus injection, there is a concentration of 500 mg (milligrams) per five mL (milliliter) (100 milligrams per milliliter).

For Patients:

What Is Neuromuscular Blockade Reversal?

Neuromuscular blockade reversal is a medical procedure employed to counteract the impact of neuromuscular blocking agents (NMBAs), which are drugs that induce muscle relaxation. NMBAs are commonly used during surgical procedures to facilitate endotracheal intubation (a procedure involving placing a tube into the windpipe to support breathing in medical emergencies), improve surgical conditions, and assist with mechanical ventilation (a life-supporting intervention that assists or replaces spontaneous breathing). These agents block nerve signal transmission at the neuromuscular junction, leading to temporary paralysis of skeletal muscles.

How Does Sugammadex Injection Work?

Sugammadex injection works by encapsulating and inactivating neuromuscular blocking agents in the body. NMBAs are drugs used during surgical procedures to induce muscle relaxation. These agents block nerve signal transmission at the neuromuscular junction, causing temporary muscle paralysis. After surgery, it is crucial to reverse this muscle paralysis to allow the patient to regain normal muscle function.

Sugammadex operates through the following steps:

• Binding to NMBAs: When Sugammadex is administered, it selectively binds to the NMBAs, such as Rocuronium or Vecuronium, in the bloodstream. This binding forms a complex, effectively trapping the NMBA molecules.

• Inactivation and Removal: The encapsulated NMBAs are rendered inactive and unable to exert the paralyzing effects on muscles. Sugammadex then facilitates rapidly removing this complex from the body through the kidneys.

• Restoration of Muscle Function: As the NMBAs are eliminated, the patient's muscle function is quickly restored, allowing for natural respiration and movement.

This process is swift and effective, providing a reliable means of reversing neuromuscular blockade. Sugammadex has become a valuable tool in surgical and anesthesia settings, offering advantages in rapid reversal and a reduced risk of side effects compared to traditional reversal agents like Neostigmine. The precise mechanism of action of Sugammadex sets it apart as an innovative and essential medication in the field of anesthesia and surgery.

How Effective Is Sugammadex Injection?

Sugammadex is highly effective in rapidly reversing the effects of certain muscle relaxants used in anesthesia, such as Rocuronium and Vecuronium. It helps patients regain muscle function and resume breathing after surgery. Its effectiveness is well-established when administered correctly by healthcare professionals. It has contributed to improved patient safety and postoperative outcomes.

What Are the Things to Inform the Doctor Before Taking Sugammadex Injection?

Informing the healthcare provider is crucial if any of these conditions are present:

• Bleeding disorders.

• Kidney disease.

• Slow heartbeat.

• Unusual or allergic reactions to Sugammadex, other medications, foods, dyes, or preservatives.

• Pregnancy or the intent to become pregnant.

• Current breastfeeding status.

How Is Sugammadex Injection Administered?

Sugammadex injection guidelines are as follows:

Administered by Trained Healthcare Providers:

• Sugammadex injection is an intravenous medication for neuromuscular blockade reversal.

• It should be administered by healthcare professionals familiar with neuromuscular blocking agents (NMBAs) and neuromuscular block reversal agents.

• Dosing and timing should be based on careful monitoring of twitch responses and spontaneous recovery.

Administration Procedure:

• Administer Sugammadex injection as a single intravenous bolus injection.

• The bolus injection should take approximately ten seconds and be delivered through an existing intravenous line.

• It is important to note that in clinical trials, Sugammadex injection has been administered exclusively as a single bolus injection.

Patient Monitoring:

• Monitor patients after Sugammadex injection administration until complete recovery of neuromuscular function.

• Ensure proper ventilation and maintain a patent airway during this period.

• Assess satisfactory recovery by evaluating skeletal muscle tone, respiratory measurements, and the response to peripheral nerve stimulation.

Dosage Independence from the Anesthetic Regimen:

• The recommended dose of Sugammadex injection does not depend on the specific anesthetic regimen.

Recommended Dosing for Sugammadex Injection:

For Rocuronium and Vecuronium:

• Administer a four mg/kg (milligrams per kilogram) Sugammadex injection dose if spontaneous recovery reaches one to two post-tetanic counts (PTC), counts following tetanic stimulation, and there are no twitch responses to train-of-four (TOF), a technique to assess neuromuscular blockade stimulation following Rocuronium- or Vecuronium-induced neuromuscular blockade.

• A two mg/kg Sugammadex injection dose is recommended if spontaneous recovery progresses to the reappearance of the second twitch (T2) in response to TOF stimulation following neuromuscular blockade induced by Rocuronium or Vecuronium.

For Rocuronium Only:

• In cases where there is a clinical need to rapidly reverse neuromuscular blockade (approximately three minutes) after administering a single dose of 1.2 mg/kg of Rocuronium, a 16 mg/kg Sugammadex injection is recommended. Please note that the efficacy of the 16 mg/kg of Sugammadex following Vecuronium administration has yet to be studied.

Body Weight-Based Dosage:

• The dosage of Sugammadex injection is based on the patient's body weight.

What Are the Side Effects of Sugammadex Injection?

Side Effects Requiring Immediate Reporting to the Healthcare Provider:

• Signs of an allergic reaction (skin rash, itching, hives, swelling of the face, lips, or tongue).

• Symptoms of low blood pressure or a slow heartbeat (breathing difficulties, chest pain, dizziness, feeling faint, falling, unusual weakness, extreme fatigue).

Side Effects That Typically Do Not Necessitate Immediate Medical Attention (Consult the Healthcare Provider if They Persist or Are Troublesome):

• Feelings of anxiety.

• Headache.

• Muscle pain.

• Nausea.

• Discomfort at the injection site.

• Abdominal pain.

• Vomiting.

Dietary Considerations:

None

Missed Dose:

If a dose of Sugammadex is missed during a medical procedure, healthcare providers will manage its administration to ensure the patient's safety and reverse muscle relaxation. Patients should refrain from self-administering the medication and should consult the medical team for guidance.

Overdose:

During premarketing clinical trials, an accidental overdose of 40 mg/kg (milligrams per kilogram) of Sugammadex was reported, but it did not result in significant effects. Using a high-flux filter, sugammadex can be eliminated through hemodialysis (a blood-cleansing procedure for individuals with kidney failure). However, a low-flux filter is not effective for this purpose. Clinical studies indicate that a high-flux filter can reduce Sugammadex concentrations in plasma by approximately 70 percent after a three to six-hour dialysis session.

Storage and Handling:

Sugammadex injection is a clear, colorless, slightly yellow-brown, non-pyrogenic aqueous solution for intravenous infusion. It is available in the following formats:

• Sugammadex two mL single-dose vials containing 200 mg Sugammadex (100 mg/mL), packaged in a box of 10.

• Sugammadex five mL single-dose vials containing 500 mg Sugammadex (100 mg/mL), packaged in a box of 10.

The product packaging is free of natural rubber latex. According to USP-controlled room temperature guidelines, storage should be at 25 degrees Celsius (77 degrees Fahrenheit), with permissible excursions between 15 and 30 degrees Celsius (59 and 86 degrees Fahrenheit). Protect the product from light, and if not protected from light, use the vial within five days.

For Doctors:

Indication: Sugammadex injection has received approval for reversing neuromuscular blockade caused by Rocuronium bromide and Vecuronium bromide in adult patients undergoing surgical procedures.

Dose: Sugammadex injection can reverse various degrees of neuromuscular blockade induced by Rocuronium or Vecuronium.

When It Comes to Rocuronium and Vecuronium:

• A recommended dose of four mg/kg Sugammadex injection is advised when the spontaneous recovery of the twitch response has reached one to two post-tetanic counts (PTC) and there are no twitch responses during train-of-four (TOF) stimulation following Rocuronium- or Vecuronium-induced neuromuscular blockade.

• A recommended dose of two mg/kg Sugammadex injection is suggested when spontaneous recovery has progressed to the reappearance of the second twitch (T2) in response to TOF stimulation after Rocuronium- or Vecuronium-induced neuromuscular blockade.

For Rocuronium Specifically:

• A dose of 16 mg/kg Sugammadex injection is recommended if there is a clinical requirement to promptly reverse neuromuscular blockade, typically around three minutes after the administration of a single 1.2 mg/kg dose of Rocuronium. It is important to note that the effectiveness of the 16 mg/kg dose of Sugammadex injection following Vecuronium administration has yet to be studied.

Dosing Considerations:

In Patients with Renal Impairment: Sugammadex is significantly excreted by the kidneys. Exposure increases with impairment, with up to 17-fold higher exposure in severe cases. Low concentrations of Sugammadex persist for at least 48 hours in cases of severe renal impairment. Clearance and half-life are progressively affected, leading to higher exposure.

In the Geriatric Population: Age has a limited impact on Sugammadex pharmacokinetics.

Regarding Sex and Race: No significant pharmacokinetic differences are observed between males and females.

Drug Compatibility:

Sugammadex injection may be injected into an intravenous line alongside the following intravenous solutions:

• 0.9 percent sodium chloride.

• Five percent dextrose.

• 0.45 percent sodium chloride and 2.5 percent dextrose.

• Five percent dextrose in 0.9 percent sodium chloride.

• Isolyte P with 5 percent dextrose.

• Ringer’s lactate solution.

• Ringer’s solution.

Ensure that the infusion line is adequately flushed (with 0.9 percent sodium chloride) between Sugammadex injection administration and other medications. Do not mix Sugammadex injection with products other than those mentioned. It is physically incompatible with Verapamil, Ondansetron, and Ranitidine. Always visually inspect parenteral drug products for particulate matter and discoloration before administering if the solution and container allow it.

What Are the Pharmacological Aspects of Sugammadex Injection?

Pharmacodynamics

Sugammadex injection has been tested at different doses in response to Rocuronium and Vecuronium-induced muscle block. There is a clear relationship between the dose of Sugammadex injection and its effectiveness in reversing the block.

Sugammadex injection may contain a small amount (up to seven percent) of a related substance called the mono OH derivative. Studies show that this derivative is almost as effective as Sugammadex in reversing muscle block caused by Rocuronium or Vecuronium, although it has a slightly lower affinity.

While Sugammadex injection works best with drugs like Rocuronium and Vecuronium, it can also affect levels of other substances with a similar structure in the body, such as certain hormones and contraceptives. Regarding heart rhythm, even at twice the recommended dose, Sugammadex injections do not affect the QTc interval.

Mechanism

Sugammadex injection is a modified gamma cyclodextrin that creates a complex with the neuromuscular blocking agents Rocuronium and Vecuronium. This complex reduces the availability of these agents to bind to nicotinic cholinergic receptors at the neuromuscular junction, leading to the reversal of neuromuscular blockade induced by Rocuronium and Vecuronium.

Pharmacokinetics

Pharmacokinetic parameters consider both bound and unbound Sugammadex. Clearance and distribution volumes are assumed to be the same for both forms.

Distribution and Volume:

• Sugammadex has a volume distribution of 11 to 14 liters in adults with normal kidney function.

• It does not bind to plasma proteins or red blood cells.

• Linear kinetics are observed when administered in doses ranging from one to 16 mg/kg.

• In nonclinical studies, Sugammadex is retained in bones and teeth.

Metabolism and Elimination:

• It is not metabolized; renal elimination accounts for over 90 percent of excretion.

• Minimal excretion occurs in feces or expired air (less than 0.02 percent of the dose).

• Administration of Sugammadex injections increases renal elimination of Rocuronium in healthy volunteers.

Toxicity:

Regarding Potential Cancer Risks: Long-term animal studies examining the carcinogenicity of Sugammadex have not been conducted.

Regarding Mutagenesis (The Potential to Cause Genetic Mutations): Sugammadex and its mono OH-derivative tested negative in various assays, including bacterial reverse mutation tests, chromosomal aberration tests, and micronucleus assays in mice and rats.

Concerning Effects on Fertility: In a study involving rats, daily treatment with Sugammadex at different doses did not adversely affect fertility or early embryonic development.

Clinical Studies:

In a comparative study:

Reversal of Moderate Blockade (Reappearance of T2):

• 189 patients underwent surgical procedures under general anesthesia with Rocuronium or Vecuronium-induced neuromuscular blockade.

• They were randomly given two mg/kg Sugammadex injections or 50 mcg/kg (micrograms per kilogram) Neostigmine after the reappearance of T2.

• Sugammadex injection facilitated a faster return of the T4/T1 ratio to 0.9 compared to neostigmine, with a significant time difference.

Reversal of Deep Blockade (One to Two PTCs):

• 157 patients had surgical procedures under general anesthesia with Rocuronium or Vecuronium-induced neuromuscular blockade.

• At one to two post-tetanic counts (PTCs), they received four mg/kg Sugammadex injection or 70 mcg/kg Neostigmine after the last dose of Rocuronium or Vecuronium.

• The return of the T4/T1 ratio to 0.9 varied by four mg/kg but was comparable to the T2 reversal study, showing effectiveness.

Reversal of Rocuronium 1.2 mg/kg (Three Minutes Later):

• 110 patients underwent surgical procedures requiring short neuromuscular relaxation.

• They received Sugammadex injections at 16 mg/kg for Rocuronium reversal, and recovery was compared to spontaneous recovery from succinylcholine.

• Rocuronium/Sugammadex injection combination yielded a faster recovery to T1 of 10 percent of baseline compared to Succinylcholine alone.

These studies demonstrate the efficacy of Sugammadex injection in reversing neuromuscular blockade induced by various agents at different depths, highlighting its advantages over Neostigmine and spontaneous recovery.

What Are the Contraindications of Sugammadex Injection?

Sugammadex injections should not be used in individuals with a confirmed hypersensitivity to Sugammadex or its constituent components. Hypersensitivity responses observed have ranged from isolated skin reactions to severe systemic reactions, including anaphylaxis and anaphylactic shock, and they have been reported in patients who had not previously been exposed to Sugammadex.

Warnings and Precautions:

The associated warnings and precautions are:

• Anaphylaxis and Hypersensitivity: Clinicians should be alert to potential drug hypersensitivity, including anaphylaxis, while using Sugammadex injections. It has been associated with anaphylactic reactions, especially in patients receiving higher doses. Symptoms may include skin reactions, severe hypotension, and respiratory complications.

• Severe Bradycardia Warning: Sugammadex use has been associated with severe bradycardia, sometimes resulting in cardiac arrest. Monitor patients closely for hemodynamic changes during and after neuromuscular blockade reversal. Administer Atropine if significant bradycardia is observed.

• Respiratory Monitoring: Ensure continuous ventilatory support until patients regain independent breathing and a clear airway. Even after reversing neuromuscular blockade, remain vigilant for potential respiratory depression from other medications, which may require continued ventilatory assistance. If persistent neuromuscular blockade occurs post-Sugammadex injections or upon extubation, take the necessary steps for proper ventilation.

• Prolonged Neuromuscular Blockade Risk: A few patients showed a delayed response to Sugammadex injection administration in trials. Vigilantly monitor ventilation until recovery is assured.

• Waiting for Neuromuscular Blockade Re-Administration After Sugammadex Injections Reversal: To re-administer steroidal neuromuscular blocking agents after Sugammadex injection reversal, observe these waiting times: After Sugammadex injection reversal, allow a minimum waiting time. Recommended waiting times and doses for re-administering Rocuronium or Vecuronium after Sugammadex injection reversal (up to four mg/kg): five minutes for 1.2 mg/kg Rocuronium.

Four hours for 0.6 mg/kg Rocuronium or 0.1 mg/kg Vecuronium. If the patient is given 1.2 mg/kg Rocuronium within 30 minutes after Sugammadex injection reversal, the initiation of neuromuscular blockade may experience a delay of up to four minutes. Its duration may be shortened by up to 15 minutes.

For patients with mild or moderate impairment (renal), the recommended waiting time before reusing 0.6 mg/kg Rocuronium or 0.1 mg/kg Vecuronium after reversing with up to four mg/kg Sugammadex injections is 24 hours. Consider a 1.2 mg/kg Rocuronium dose if needed sooner for a new neuromuscular blockade. When re-administering Rocuronium or administering Vecuronium after reversing Rocuronium with 16 mg/kg Sugammadex injections, a 24-hour waiting period is suggested. If neuromuscular blockade is needed before the suggested waiting time has elapsed, consider using a nonsteroidal neuromuscular blocking agent. The onset of a depolarizing neuromuscular blocking agent might be slower than expected due to potential receptor occupancy.

• Interactions Potentially Affecting Drug Efficacy: The use of Sugammadex injections may reduce the effectiveness of certain drugs, like hormonal contraceptives, by lowering plasma concentrations. In such cases, consider re-administering the affected drug, using an equivalent alternative (preferably from a different chemical class), or employing non-pharmacological interventions as needed.

• Risk of Neuromuscular Blockade Recurrence Due to Displacement Interactions: A recurrence of neuromuscular blockade can occur due to the displacement of Rocuronium or Vecuronium by other drugs when Sugammadex injections are administered. In these situations, mechanical ventilation may be required for the patient. If a drug causing displacement is administered via infusion, consider discontinuing its use. The risk of displacement reactions is highest during a period equivalent to three times the half-life of Sugammadex injections.

• Risk of Neuromuscular Blockade Recurrence with Insufficient Dosing: Using doses of Sugammadex injections lower than the recommended amount may increase the risk of recurrent neuromuscular blockade after initial reversal and is not advisable.

• Risk of Neuromuscular Blockade Recurrence Due to the Use of Blockade-Potentiating Drugs: When drugs that enhance neuromuscular blockade are employed in the post-operative phase, special attention should be given to the potential for neuromuscular blockade recurrence. If a recurrence of neuromuscular blockade is observed, the patient may require mechanical ventilation.

• Coagulation and Bleeding Risk: Sugammadex doses up to 16 mg/kg caused transient increases in coagulation parameters (aPTT and PT/INR) by up to 25 percent in healthy volunteers. In patients having major orthopedic surgery with concomitant heparin treatment, Sugammadex injections at four mg/kg led to 5.5 percent and three percent increases in aPTT and PT/INR, respectively, within the hour. Clinical trials showed no significant differences between Sugammadex injection and usual care in blood loss, anemia incidence, or bleeding events. In vitro experiments demonstrated increased aPTT and PT/INR when Sugammadex was combined with various anticoagulants. Caution should be exercised to monitor coagulation parameters in patients with coagulopathies, therapeutic anticoagulation, or other thromboprophylaxis drugs alongside 16 mg/kg Sugammadex.

• Renal Impairment: Avoid administering Sugammadex injections to individuals with severe renal impairment or undergoing dialysis.

• Light Anesthesia: Reversing neuromuscular blockade during anesthesia may occasionally result in signs of light anesthesia. Reversal After Rocuronium or Vecuronium in the ICU (intensive care unit), Sugammadex injection have not been studied for reversing Rocuronium or Vecuronium in the ICU.

• Reversal of Other Neuromuscular Blocking Agents: Do not use Sugammadex injection to reverse nonsteroidal neuromuscular blocking agents like Succinylcholine or Benzylisoquinoline compounds. Sugammadex injection should not be used to reverse neuromuscular blockade induced by steroidal neuromuscular blocking agents other than Rocuronium or Vecuronium.

What Are the Drug Interactions of Sugammadex Injection?

Drug Interactions Affecting Sugammadex Injection Efficacy

• Toremifene: In the case of Toremifene, which has a relatively strong binding affinity for Sugammadex and may result in higher Sugammadex levels in the bloodstream, there is a possibility of Vecuronium or Rocuronium being displaced from their complex with Sugammadex injection. This could lead to a delayed recovery of the train-of-four (TOF) ratio, reaching 0.9 in patients who receive toremifene on the same day as their surgery.

• Drug Interaction Affecting Hormonal Contraceptives' Efficacy: Laboratory studies have shown that Sugammadex injection may bind to progestogen, potentially reducing exposure to progestogen. When a patient takes a Sugammadex injection on the same day as an oral contraceptive, it is considered equivalent to missing one or more doses of the contraceptive containing estrogen or progesterone. Therefore, in such cases, the patient needs to use an additional non-hormonal contraceptive method or backup contraception (like condoms and spermicides) for the following seven days. The same additional contraceptive measures should be taken when non-oral hormonal contraceptives are used alongside Sugammadex injections.

• Interference with Lab Tests: Sugammadex injection might interfere with serum progesterone measurement. This interference was observed at 100 mcg/mL plasma concentrations, which could be present for up to 30 minutes following a 16 mg/kg Sugammadex injection dose.

Specific Considerations:

1. Pregnancy

Risk Summary: No data about Sugammadex injection use during pregnancy exists. In animal studies, doses up to six to eight times the recommended human dose (MRHD) showed no teratogenicity. Still, they did cause incomplete fetal bone development and decreased fetal weight in rabbits at eight times MRHD. Sugammadex exposure during pre and postnatal development led to early postnatal loss, potentially linked to maternal behavior, at MRHD and higher exposure levels. In the general population, the typical risk of major birth defects is about two to five percent, and the risk of miscarriage is approximately 15 to 20 percent.

Data: In animal studies, rats and rabbits showed no treatment-related maternal or fetal changes in embryofetal development studies. However, rabbits exposed to Sugammadex at eight times MRHD experienced incomplete bone development and reduced fetal weight. Pre and postnatal exposure to Sugammadex in rats was correlated with early postnatal loss, potentially associated with maternal behavior.

2. Lactation

Risk Summary: Sugammadex was detected in rat milk, but it had no adverse effects on rat pups' survival, body weight, or physical and behavioral development when rat mothers were exposed to the drug.

Data: In a study involving rat mothers, Sugammadex in milk was approximately equal to plasma levels, with no observed adverse effects on their pups' development.

3. Females and Males of Reproductive Potential

Contraception: After Sugammadex injection administration, hormonal contraceptives may be less effective for a week. Women of reproductive age using hormonal contraceptives should use additional non-hormonal contraception for seven days after receiving a Sugammadex injection.

4. Pediatric Use

The safety and efficacy of Sugammadex injections in pediatric patients have not been established. In juvenile animal studies, higher Sugammadex concentrations and some effects on bone and teeth were observed, such as reduced bone length and disturbances in enamel formation.

5. Geriatric Use

Sugammadex injection was well-tolerated by geriatric patients, and no dose adjustment is required.

6. Renal Impairment

Sugammadex injection is not recommended for patients with severe kidney problems because there is not enough safety data available and there is increased exposure.

7. Hepatic Impairment

Specific trials in patients with hepatic impairment have not been conducted. Use caution when giving Sugammadex injections to patients with liver issues along with blood clotting problems or significant swelling.

8. Cardiac Patients

Cardiac patients showed similar recovery times after Sugammadex injection administration compared to other trials. No dosage adjustment is necessary.

9. Pulmonary Patients

Pulmonary patients exhibited similar recovery times to those in other trials. No dosage adjustment is necessary.