Naloxegol - Indication, Dosage, and Side Effects

Overview

Naloxegol is a drug indicated for the management of opioid-induced constipation (difficulty in bowel movement caused by opioids) in adult patients undergoing noncancer pain or chronic pain associated with cancer or its treatment and who do not need frequent opioid dose escalation. Naloxegol was approved by the United States Food and Drug Administration (USFDA) on September 16, 2014, and by the European Medicines Agency (EMA) on December 8, 2014. All laxative drugs must be discontinued before starting the treatment with Naloxegol. If the opioid medications are stopped, then Naloxogol must also be discontinued.

How Does Naloxegol Work?

Naloxegol is derived from Naloxone, a substance well known for blocking the action of opioids. It belongs to a class of medications called peripherally acting opioid receptor antagonists and is used for treating constipation due to chronic opioid use for noncancer pain. Naloxegol attaches to a specific opioid receptor called the mu-opioid receptor and inhibits the opioids from binding to these receptors. Therefore, by blocking these receptors in the gut, Naloxegol reduces constipation caused by opioids but does not interfere with its pain-relieving effects.

Indications of Naloxegol

Naloxegol is recommended for treating opioid-induced constipation in adult patients who have chronic non-cancer pain or chronic pain before cancer or its treatment and who are not on frequent opioid dose escalation.

Contraindications of Naloxegol

• Naloxegol is contraindicated in patients with a history of severe hypersensitivity reactions (severe allergies) to Naloxogol or its ingredients.

• Naloxegol is also contraindicated in patients with a history of or suspected gastrointestinal obstruction (block in the gastrointestinal tract) or those at an increased risk of recurrent obstruction because of the drug's potential for gastrointestinal perforation (hole in the gastrointestinal tract).

• It is not recommended in combination with drugs such as Ketoconazole, Clarithromycin, and other CYP3A4 inhibitor agents, as it can increase exposure to Naloxegol and precipitate opioid withdrawal symptoms.

• Naloxegol is not recommended for pregnant females, lactating women, children, or patients with severe hepatic disorders.

Available Doses and Dose Forms

• Naloxegol is recommended at 25 mg (milligrams) daily in the morning. If this is not tolerated by some patients, the dose is reduced to 12.5 mg once daily.

• The initial dose for patients with renal disorders is 12.5 mg once daily. If it is well tolerated but the symptoms prevail, the dose may be increased to 25 mg once a day, considering the risk of adverse reactions with the high-dose exposure.

• Naloxegol can interact with drugs such as Erythromycin, Diltiazem, Verapamil, etc. If concomitant use cannot be avoided, the Naloxegol dose is reduced to 12.5 mg, and the patient is regularly monitored for any adverse reactions.

Warnings and Precautions

• Opioid withdrawal symptoms can occur in patients treated with Naloxegol, which include chills, diarrhea, anxiety, irritability, hyperhidrosis (excessive sweating), yawning, and abdominal pain. Patients with disruptions in the blood-brain barrier are at a high risk of reduced analgesia or opioid withdrawal. Therefore, considering the risk-benefit profile, patients must be frequently monitored during the treatment.

• Diarrhea and severe abdominal pain have been reported in some patients within a few days of taking 25 mg doses of Naloxegol. Hence, patients must be monitored for such symptoms during the treatment, and Naloxegol may be discontinued if severe symptoms are observed. If appropriate, a 12.5 mg dose of Naloxegol may be initiated later.

• Gastrointestinal perforation may occur during treatment with peripherally acting opioid antagonists in patients with gastrointestinal tract disorders. Therefore, the overall risk-benefit profile must be considered, patients must be monitored frequently, and the drug must be discontinued if symptoms such as severe abdominal pain are observed.

Adverse Effects of Naloxegol

Some of the adverse effects of Naloxegol include:

• Severe stomach pain.

• Diarrhea.

• Skin rash.

• Swelling of the face, lips, tongue, throat, hands, and feet.

• Nausea and vomiting.

• Anxiety.

• Irritability.

• Chills.

• Sweating.

• Headache.

For Patients

What Is Opioid-Induced Constipation?

Constipation is when bowel movements are tough and less frequent, causing difficulty passing stools. Opioid-induced constipation (OIC) occurs due to the effects of opioids (pain-relief medicines) on the digestive system. Opioids are known to prevent gastric emptying and peristalsis (movement of food) in the gastrointestinal tract, which causes increased absorption of fluids and delayed absorption of medicines. It occurs in approximately 40 to 60 percent of patients without cancer receiving opioids. OIC can present immediately or gradually after a few days of opioid therapy. Associated symptoms include nausea, vomiting, abdominal pain, bloating sensations, and excessive strain while passing stools. Increasing fluid intake, consuming foods rich in dietary fiber, and engaging in physical exercise are the initial treatment options for OIC. Medications are started if these methods are ineffective. Methylnaltrexone, Lubiprostone, Naloxegol, Naldemedine, and Alvimopan are some of the drugs that treat opioid-induced constipation.

What Is Naloxegol?

Naloxegol is a prescription medicine used to treat opioid-induced constipation in adult patients with chronic non-cancer pain. It is mostly used for patients for whom medicines called laxatives are not effective. Naloxegol works by blocking the effects of opioids, helping in stool movement, and protecting the intestine, thus reducing constipation caused by opioids. The instructions prescribed by the doctor must be followed exactly, and the dose of Naloxegol must not be altered.

How Effective Is Naloxegol?

Naloxegol is prescribed for the treatment of OIC in patients with an inadequate response to laxatives. Studies have shown that Naloxegol is effective in such patients, as the treatment received a good response. Patients either received 25 mg or 12.5 mg of the drug for 12 weeks. The results observed after the treatment were that the drug was well tolerated, an improvement was noted in spontaneous bowel movements per week and stool consistency, and a reduction in the symptoms.

How Should Naloxegol Be Taken?

Naloxegol must be taken orally with water once daily, around the same time daily. It must be taken at least one hour before or two hours after the first meal. The tablet must not be split or chewed, but if the patient cannot swallow it, it can be crushed to a powder and mixed with four ounces of water (120 milliliters) and consumed immediately. The remaining mixture contents must also be consumed by refilling the glass with four ounces of water. Naloxegol can also be administered to patients who cannot consume the drug orally through a nasogastric tube.

What Are the Side Effects of Naloxegol?

The side effects of Naloxegol include:

• Nausea and vomiting.

• Headache.

• Stomach pain.

• Gas, bloating sensation.

• Diarrhea.

• Indigestion.

• Trouble breathing.

• Black or tarry stools.

What Must the Patient Inform the Doctor Before Taking Naloxegol?

• Before starting treatment, patients must tell the doctor if they are allergic to Naloxegol, its components, or any other medications.

• Patients must inform the doctor if they take Clarithromycin, Ketoconazole, Itraconazole, or other drugs before taking Naloxegol.

• Before beginning treatment, patients must tell the doctor if they have or previously experienced a block in the intestine, stomach ulcers, Crohn’s disease (chronic inflammatory bowel disorder), kidney or liver disease, or any other gastrointestinal issues.

• Before beginning treatment with Naloxegol, patients must inform the doctor if they take any vitamins or herbal supplements, including St.John’s wort, over-the-counter (OTC) drugs, or other medications.

• Female patients must tell the doctor if they are pregnant, planning pregnancy, or breastfeeding before taking Naloxegol.

What Are the Precautionary Measures to Be Followed While Taking Naloxegol?

• All laxative medicines must be discontinued before starting Naloxegol.

• Naloxegol must be discontinued if treatment with opioids is stopped.

• Patients must inform the doctor if they experience any serious adverse effects during the treatment or cannot tolerate Naloxegol.

• If Naloxegol is administered via a nasogastric tube, all instructions must be followed exactly as the doctor prescribes.

• Patients must inform the doctor if no improvement is observed even after taking Naloxegol for three days.

• Naloxegol must not be taken by individuals other than those prescribed without the doctor’s consent, even if they experience the same symptoms.

Dietary Considerations

Consuming grapefruit or its juice must be avoided while taking Naloxegol. No other dietary considerations are required unless instructed by the prescribing doctor.

Missed Dose

The missed dose of Naloxegol must be taken as soon as remembered; however, if it is almost time for the next dose, the missed dose can be skipped, and the regular dosing schedule can be continued.

Overdose

Patients or caregivers should consult the doctor immediately in the event of an overdose or if severe adverse effects are observed.

Storage

Naloxegol tablets must be stored in their original packaging between 20 and 25 degrees Celsius (68 and 77 degrees Fahrenheit) away from excess heat and moisture.

For Doctors

Pharmacological Aspects of Naloxegol

Mechanism of Action

Naloxegol is a derivative of Naloxone and a peripherally acting opioid antagonist that binds to the mu-opioid receptor. At recommended dose levels, it acts on the gastrointestinal tissues and reduces the constipating effects of opioids. Naloxegol has a lower passive permeability compared to Naloxone and an increased efflux across the blood-brain barrier as it is related to P-gp substrate properties. However, at the recommended doses, the central nervous system (CNS) penetration of Naloxegol is negligible, thus limiting its interference with centrally mediated opioid analgesic effects.

Pharmacodynamics

Opioid use slows down the gastrointestinal motility and transit. As Naloxegol possesses antagonistic properties, it inhibits opioid-induced gastrointestinal delay and transit time.

Pharmacokinetics

• Absorption: After an oral administration, Naloxegol gets absorbed with a peak concentration in less than two hours. In many subjects, a secondary plasma concentration was noted 0.4 to three hours after the first peak concentration. The peak plasma concentration (Cmax) and area under the curve increased dose-proportionally. When used as a crushed tablet with water or administered through a nasogastric tube, the systemic concentrations were comparable to the Naloxegol tablet, and the time taken to achieve maximum concentration (Tmax) was around 0.75 to 1.5 hours.

• Distribution: Naloxegol has a low plasma protein binding capacity, and the mean apparent volume of distribution ranges from 968 L to 2140 L (liters).

• Metabolism: Naloxegol is primarily metabolized by the CYP3A4 enzyme, and around six metabolites were identified in the plasma, urine, and feces. The activity of the metabolites has not been determined at the opioid receptor.

• Excretion: After an oral administration of Naloxegol (radiolabeled), about 68 percent was recovered in the feces, and 16 percent was recovered in the urine. Around 16 percent of the radioactivity was noted unchanged in feces, and the remaining was attributed to metabolites. The half-life of Naloxegol ranged from six to 11 hours.

Drug Interactions

Some of the drugs that interact with Naloxegol include:

• Clarithromycin.

• Chloramphenicol.

• Dexamethasone.

• Enzalutamide.

• Idelalisib.

• Itraconazole.

• Mifepristone.

• Phenytoin.

• Rifampin.

• Erythromycin.

• Fluconazole.

• Lidocaine.

• Methylnaltrexone.

• Metronidazole.

• Naloxone.

• Sertraline.

• Verapamil.

Clinical Studies

Two double-blind, randomized, placebo-controlled studies were conducted to evaluate the safety and efficacy of Naloxegol in patients with opioid-induced constipation and non-cancer-associated pain. A total of 652 and 700 patients were included in Study 1 and Study 2, respectively, and were randomized to receive 25 or 12.5 mg of Naloxegol or a placebo once daily for 12 weeks. The mean age of the patients was 52 years, with back pain, arthritis, and joint pain being the most prominent indications of opioids. After the treatment period, both studies demonstrated statistically significant higher response rates and sustained improvements in opioid-induced constipation symptoms with 25 mg and 12.5 mg of Naloxegol in comparison to a placebo.

Nonclinical Toxicology

• Carcinogenesis: Animal studies demonstrated that Naloxegol was not carcinogenic at doses up to 100 mg/kg/day in male mice and 160 mg/kg/day (milligram per kilogram per day) in female mice.

• Mutagenesis: Naloxegol was found to be non-genotoxic in the in vitro bacterial reverse mutation (Ames) assay or in vivo mouse micronucleus assay.

• Impairment of Fertility: Naloxegol did not affect reproductive performance or fertility in male and female rats at doses up to 1000 mg/kg/day.

Specific Considerations

• Pregnancy: Naloxegol can precipitate opioid withdrawal symptoms in pregnant women and the fetus, and there is very limited data available regarding the use of Naloxegol in pregnant women; hence, it is not recommended in pregnancy.

• Lactation: Naloxegol is contraindicated during lactation, as no data are available regarding the drug's presence in breast milk or its adverse effects on milk production, the breastfed infant, or the lactating mother.

• Pediatric Use: Naloxegol is not recommended for children, as the safety and effectiveness of the drug are not established in this population.

• Geriatric Use: No significant differences were observed during the clinical studies of Naloxegol in elderly patients compared to younger adults.

• Hepatic and Renal Impairment: Dose modification is not required in patients with mild renal impairment, and a lower dose of 12.5 mg of Naloxegol is recommended in patients with moderate or severe renal disorders. Naloxegol must be avoided in patients with severe liver impairment; however, dose modification is not necessary in patients with mild or moderate hepatic impairment.