Triclabendazole - Dosage, Uses, Warnings, and Side Effects

Overview

Triclabendazole is an oral medication recommended for the management of chronic fascioliasis. It belongs to the class of drugs called anthelmintics and can be used in patients aged six years and older and documented with chronic fascioliasis. Triclabendazole is a benzimidazole derivative and generally a well-tolerated drug. It was previously used in livestock; however, based on historical and published studies regarding its safety and efficacy, it was considered for human use. Triclabendazole was approved by the United States Food and Drug Administration (USFDA) in 2019.

How Does Triclabendazole Work?

Triclabendazole helps manage fascioliasis, an infection caused by the parasite Fasciola hepatica or Fasciola gigantica when humans consume contaminated food, water, or aquatic vegetables. These organisms reside in the bile duct, causing inflammation and epithelial hyperplasia, resulting in biliary obstruction. Rarely, these species can also be found in other organs such as lungs, heart, brain, abdominal wall, muscles, skin, and genitourinary system. Triclabendazole acts on the Fasciola species by inhibiting microtubule formation, affecting protein synthesis, disrupting the mature and immature stages of these parasites, and destroying them.

Indications of Triclabendazole:

Triclabendazole is mainly indicated to treat fascioliasis in patients above six.

Contraindications of Triclabendazole:

Triclabendazole is contraindicated in patients with a history of hypersensitivity to the drug or its components or other benzimidazole derivatives.

Available Doses and Dose Forms:

Triclabendazole is available as 250 mg (milligrams) tablets, taken orally twice daily. The inactive ingredients include lactose monohydrate, magnesium stearate, colloidal silicon dioxide, iron oxide, and methyl-hydroxyethylcellulose. The tablets are functionally scored and can be divided into two halves of 125 mg each.

Warnings and Precautions:

Animal studies have demonstrated that Triclabendazole can cause transient prolongation of the mean QTc interval. Therefore, patients with a known case of QTc interval prolongation or with a history of symptoms similar to those with long QT interval must be frequently monitored.

Adverse Effects of Triclabendazole:

Some of the adverse effects of Triclabendazole include:

• Nausea and vomiting.

• Diarrhea.

• Chest pain and discomfort.

• Urticaria (itchy bumps on the skin).

• Pruritis (itching).

• Cough.

• Abdominal pain.

• Jaundice.

• Hyperhidrosis (excessive sweating).

• Asthenia (abnormal weakness).

• Dyspnea (shortness of breath).

• Vertigo (spinning sensation).

For Patients

What Is Fascioliasis?

Fascioliasis is a rare parasitic infection mainly caused by the microorganisms Fasciola hepatica and Fasciola gigantica (commonly known as liver flukes). It primarily affects the liver and bile passages and is acquired by consuming contaminated food, water plants, or raw watercress. Adult liver flukes release eggs into the hosts' bile ducts, which then pass into the stools. Sheep and cattle are the most commonly affected hosts that defecate in the environment. Therefore, humans living in regions where these animals are prominent are more prone to developing this infection. Some of the symptoms of fascioliasis include nausea, vomiting, abdominal pain, fever, malaise, blockage of the bile ducts, and inflammation of the pancreas.

What Is Triclabendazole?

Triclabendazole is a prescription medicine available in tablet form and used in the treatment of fascioliasis. It belongs to the group of drugs called anthelmintics and is generally well tolerated by patients aged above six years. It is the only drug approved by the FDA for treating fascioliasis, which affects approximately 2.4 million people worldwide.

How Effective Is Triclabendazole?

Triclabendazole is a unique drug among benzimidazoles and has a particular activity against the Fasciola species. Several studies have demonstrated that the cure rate is more than 90 percent for acute stages after administering a single 10 mg/kg (milligram per kilogram) dose of Triclabendazole. Clinical trials have also shown that the drug is remarkably safe as only mild and short-lived adverse events were reported; no severe adverse effects were seen except for upper abdominal pain in some patients, which was treated by oral spasmolytic drugs.

How Should Triclabendazole Be Taken?

Triclabendazole must be taken orally two times a day along with food. Instructions on the prescription label or by the prescribing doctor must be followed exactly. It must be taken at most prescribed. It can be taken as a whole with water or split into two halves. The tablet can also be crushed and mixed with applesauce, but the mixture must be consumed within four hours.

What Are the Side Effects of Triclabendazole?

The side effects of Triclabendazole include:

• Headache.

• Decreased appetite.

• Yellowish discoloration of eyes and skin.

• Itching.

• Nausea and vomiting.

• Fever.

• Dizziness.

• Increased sweating.

• Shortness of breath.

• Stomach pain.

• Diarrhea.

What Must the Patient Inform the Doctor Before Taking Triclabendazole?

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

• Patients must inform the doctor if they have previously experienced any cardiac problems such as irregular heartbeat, variations in electrocardiogram (ECG), or fainting before initiating treatment with Triclabendazole.

• Female patients must inform the doctor if they are pregnant or planning to become pregnant or lactating before taking Triclabendazole.

• Patients must inform the healthcare provider if they are taking medications such as Ciprofloxacin, Flucanozole, Moxifloxacin, Levofloxacin, Ondansetron, Chlorpromazine, Clarithromycin, Phenytoin, Phenobarbital, or any other medicines before taking Triclabendazole. Patients must also inform the prescribing doctor if they take any vitamin or nutritional supplements or over-the-counter medications before starting the treatment.

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

• Triclabendazole can cause prolongation in QTc interval in some patients. Therefore, ECGs are monitored periodically in patients with a history of QT prolongation or similar symptoms or in patients taking medications that may cause prolonged QT interval.

• The doctor must be immediately informed if the patients notice any side effects or experience severe abdominal pain, difficulty breathing, and seizures (sudden uncontrolled unusual electrical activity in the brain) during the treatment with Triclabendazole.

Dietary Considerations: No special dietary precautions are required unless the prescribing doctor recommends them.

Missed Dose: If the patient forgets to take a dose, the missed dose must be taken as soon as possible.

Overdose: If the patient is having any adverse effects, or in case of an overdose or seizures, a healthcare professional must be consulted immediately.

Storage: Triclabendazole must be stored in its original container, tightly closed, at room temperature below 30 degrees Celcius (86 degrees Fahrenheit), away from direct sunlight, heat, moisture, and out of reach of children. Unused or unnecessary medicines must be safely disposed of to ensure that children or pets do not consume them.

For Doctors

Pharmacological Aspects of Triclabendazole

Mechanism of Action:

Triclabendazole is a narrow-spectrum anthelmintic agent with highly specific activity against Fasciola and Paragonimus species. It has minimal action against cestodes, nematodes, and trematodes. Triclabendazole inhibits microtubule formation as the worms' tegument absorbs the drug and its active metabolites. This further prevents protein synthesis and decreases the resting membrane potential. These changes are also associated with decreased motility and inhibition of spermatogenesis, which finally disrupts both the mature and immature stages of Fasciola hepatica organisms.

Pharmacodynamics:

Triclabendazole and its metabolites are highly effective against both the mature and immature worms of Fasciola species. Studies have shown the drug may cause a prolongation in the QT interval. However, the time course and drug exposure-response relationship need to be clearly understood.

Pharmacokinetics:

Following an oral administration of Triclabendazole to patients with fascioliasis at a dose of 10 mg/kg along with approximately 560 calorie meal, the maximum plasma concentration (C max) was 1.16 mmol/L (micromol per liter), and the area under the curve (AUC) was 5.72 mmol/h/L. The peak plasma concentrations of its metabolites sulfoxide and sulfone were 38.6 and 2.29 mmol/L, respectively.

• Absorption: After a single dose oral administration of 10 mg/kg, Triclabendazole to patients with fascioliasis along with a 560-calorie (kcal) meal, the time taken (Tmax) to reach the maximum concentration was around three to four hours. The peak plasma concentration and AUC increased up to three-fold and two-fold when the drug was administered with a 560 kcal meal compared to a fasting state.

• Distribution: The apparent volume of distribution of the sulfoxide metabolite with food was approximately one liter per kilogram (L/kg). The protein binding capacity of Triclabendazole and its metabolites sulfoxide and sulfone in human plasma was 96.7 percent, 98.4 percent, and 98.8 percent, respectively.

• Metabolism: According to in vitro studies, Triclabendazole is primarily metabolized into active metabolite sulfoxide CYP1A2 and other enzymes. This gets further metabolized into active sulfone by CYP2C9 and, to a lesser extent, by CYP1A1, CYP1A2, and other enzymes.

• Excretion: The half-life of Triclabendazole and its metabolites sulfoxide and sulfone are known to be approximately 8, 14, and 11 hours, respectively. The data regarding the excretion of the drug is unknown. However, animal studies have demonstrated that Triclabendazole and its metabolites are mainly excreted via the biliary tract in the feces (up to 90 percent) and urine (less than 10 percent).

Drug Interactions

Some of the drugs that interact with Triclabendazole include:

• Levoketoconazole.

• Piperaquine.

• Sparfloxacin.

• Terfenadine.

• Thioridazine.

• Azithromycin.

• Ciprofloxacin.

• Domperidone.

• Erythromycin.

• Fluconazole.

• Itraconazole.

• Ketoconazole.

• Metronidazole.

• Norfloxacin.

• Ondansetron.

• Phenobarbital.

• Phenytoin.

• Voriconazole.

Clinical Studies

Various clinical trials and case reports conducted over 25 years across a wide range of geographical areas have shown that Triclabendazole has high efficacy in treating all stages and forms of fascioliasis in adults and children. A randomized open-label trial was conducted in patients with acute symptomatic fascioliasis to compare the efficacy of Triclabendazole with oral Artesunate. About 100 patients were randomized to 50 in each treatment group. After three months of treatment, 92 percent of patients treated with Triclabendazole reported no clinical symptoms compared to 76 percent of patients treated with oral Artesunate. Clinical studies conducted in pediatric patients also suggested that the drug is well-tolerated and the same treatment regimen similar to that of adults can be followed in children of more than six years.

Nonclinical Toxicology

• Toxicity: In a 13-week nonclinical study, an oral administration of Triclabendazole at doses up to 39 mg/kg/day (milligram per kilogram per day) demonstrated a transient increase in the QT and QTc intervals during the fifth and ninth weeks. A single dose of 40 or 100 mg/kg also increased the QTc interval. Slight anemia and a minimal increase in reticulocytes and nucleated red blood cells were seen at 39 mg/kg/day doses.

• Mutagenicity: Triclobendazole did not exhibit genotoxic potential in any of the vitro and in vivo genotoxicity assays, including a bacterial reverse mutation assay, micronucleus assay and chromosome aberration assay.

• Impairment of Fertility: During toxicity studies, Triclabendazole administered at a daily dose of 7.3 mg/kg/day for 110 days, including a mating period of 12 days, did not affect the reproductive performance in rats.

Special Considerations

• Pregnancy: No information is available regarding the use of Triclabendazole in pregnant women to determine birth defects, miscarriage, or any adverse effects of the drug on the fetus or the mother. However, animal studies have not demonstrated any significant fetal abnormalities at doses approximately 0.3 to 1.6 times (up to 20 mg/kg) the maximum recommended dose in humans.

• Lactation: Animal studies have detected the presence of Triclabendazole in milk when a single dose of the drug was administered to a lactating animal. However, there is no data to determine the presence of Triclabendazole in human milk. Therefore, the benefits of breastfeeding and the potential adverse effects on the lactating infant must be considered, along with the necessity of the drug for the mother.

• Pediatric Use: Triclabendazole can be recommended for children above six. However, the safety and efficacy of the drug have yet to be established in patients below six years of age.

• Geriatric Use: Patients above 65 years of age were not involved in the clinical studies of Triclabendazole to determine the difference in response compared to younger patients.

• Hepatic and Renal Impairment: Clinical studies of Triclabendazole have not been conducted in patients with hepatic or renal impairment.