Teriflunomide

Teriflunomide is a Disease-Modifying agent belonging to the pharmacological class of Immunomodulatory agents.

Teriflunomide has been approved to relieve symptoms and also for the treatment and maintenance of Relapsing multiple sclerosis.

Absorption of teriflunomide occurs through oral administration, leading to peak plasma concentrations within an average timeframe of 1 to 4 hours. The volume of distribution following a single intravenous dose is 11 L. This compound exhibits a high degree of plasma protein binding, with over 99% of teriflunomide bound to these proteins. In terms of metabolism, the primary metabolic pathway involves hydrolysis to generate minor metabolites. Additional minor pathways include oxidation, N-acetylation, and sulfate conjugation. It's noteworthy that teriflunomide is not subjected to metabolism by CYP450 or flavin monoamine oxidase enzymes. In terms of elimination, teriflunomide is primarily excreted in an unchanged form through bile, with approximately 37.5% being eliminated in feces and 22.6% in urine.

The common side effects of Teriflunomide include Rash on the skin with red or purple coloring, along with blistering and shedding, Difficulties with breathing, Changes in the sensation of your hands or feet that are distinct from your M.S. symptoms, Skin discomfort, Having hives, A sense of burning in your eyes, Pain in the upper abdomen, A throat that feels sore, Chills, A cough, which might be new or worsening and could be accompanied by fever, Nausea, Loss of appetite, Body aches, Feeling exhausted, Trouble with breathing.

Teriflunomide is available in the form of Tablets.

Teriflunomide is approved in Germany, Japan, Malaysia, India, the U.K.,and China.

Teriflunomide, belonging to the pharmacological class of Immunomodulatory agents. , acts as an Disease-Modifying agent .

The precise mechanism through which teriflunomide operates in multiple sclerosis remains uncertain. However, it is established that teriflunomide hinders pyrimidine synthesis by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase. This action might play a role in its immunomodulatory impact on multiple sclerosis.

Teriflunomide has been approved to relieve symptoms and also for the treatment and maintenance of Relapsing multiple sclerosis.

Teriflunomide is found to be available in the form of Tablets.

Teriflunomide can be used in the following treatment:

• Relapsing multiple sclerosis

Teriflunomide can help to relieve symptoms and also for the treatment and maintenance of Relapsing multiple sclerosis.

Teriflunomide is approved for use in the following clinical indications:

• Relapsing multiple sclerosis

• Relapsing multiple sclerosis: It's important to mention that in populations at high risk or in countries with a significant tuberculosis burden, it's recommended to conduct screenings for latent infections such as hepatitis and tuberculosis before starting treatment. For patients who test positive for latent infections, seeking advice from infectious disease specialists or relevant experts, such as liver specialists, about treatment options is advisable before beginning therapy (Reference).
• Dosage: The oral dosage for relapsing multiple sclerosis is either 7 mg or 14 mg taken once daily.

Teriflunomide is available in the following dosage forms and strengths:

• Tablets : 7mg, 14mg

Tablets

• Dosage Adjustments in Kidney Patients:

There are found to be no dosage adjustments in the manufacturer's labeling for mild to moderate or severe impairment.

• Dosage Adjustments in Hepatic Impairment Patients:

There are found to be no dosage adjustments in the manufacturer's labeling for mild to moderate impairments.

• Dosage Adjustments in Pediatric Patients:

No specific dosage adjustments has been found in the product monograph.

Grapefruit and Grapefruit Juice:

Grapefruit and grapefruit juice contain compounds that can interfere with drug metabolism in the liver, potentially leading to higher drug concentrations in the blood. Since teriflunomide is metabolized by the liver, it's best to avoid grapefruit products while on this medication.

Folate-Rich Foods:

Teriflunomide may interfere with the way the body uses folate, an essential B-vitamin. While there is no strict dietary restriction, consider consuming foods rich in folate (such as leafy greens, beans, and citrus fruits) to help support your body's folate levels. You might also discuss with your healthcare provider whether folate supplements are advisable.

High-Fat Meals:

High-fat meals may affect the absorption of certain medications, including teriflunomide. While there isn't a specific restriction, consuming a balanced diet that includes moderate amounts of healthy fats may be beneficial.

Herbal Supplements and Alternative Remedies:

Certain herbal supplements and alternative remedies might interact with teriflunomide or impact its effectiveness. Always consult your healthcare provider before incorporating new supplements or remedies into your diet.

Salt-Restricted Diet:

Teriflunomide itself doesn't necessarily warrant a salt-restricted diet. However, if you're on a salt-restricted diet due to other health conditions (such as high blood pressure), continue following your healthcare provider's recommendations.

Balanced and Nutrient-Rich Diet:

While there are no strict dietary restrictions with teriflunomide, maintaining a balanced and nutrient-rich diet can contribute to overall health and well-being. Ensure you're consuming a variety of fruits, vegetables, whole grains, lean proteins, and healthy fats.

Hydration:

Staying hydrated is important for overall health and can support your body's metabolism and elimination processes. Drinking an adequate amount of water is generally advisable, but there are no specific hydration restrictions related to teriflunomide.

Molecule Teriflunomide may be contraindicated in the following conditions:

● Individuals known to have hypersensitivity to teriflunomide, leflunomide (the precursor compound), or any nonmedicinal ingredients in the formulation.

● Those currently undergoing treatment with leflunomide.

● Co-administration of teriflunomide with leflunomide is strictly contraindicated.

● Individuals with severe hepatic impairment .

● Pregnant women or women of childbearing potential not using reliable contraception . Teriflunomide has the potential to cause harm to a developing fetus, necessitating pregnancy confirmation before treatment initiation.

● Individuals with immunodeficiency conditions (e.g., AIDS).

● Those with compromised bone marrow function or significant cases of anemia, leucopenia, neutropenia, or thrombocytopenia.

● Individuals currently experiencing serious active infections.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows :

• Hepatotoxicity

Severe Liver Injury Risk: Rare Instances of Severe Liver Injury have been reported in post-marketing experiences. The combined use of Teriflunomide with other potentially hepatotoxic drugs may heighten the risk of severe liver damage. Transaminase and bilirubin levels should be obtained within 6 months before starting Teriflunomide. Monitoring of ALT levels should occur at least monthly during the initial six months of Teriflunomide treatment. Discontinue Teriflunomide and employ an accelerated elimination process with cholestyramine or charcoal if drug-induced liver injury is suspected. Teriflunomide is not suitable for patients with severe hepatic impairment. Caution should be exercised with patients who have pre-existing liver disease due to a higher likelihood of elevated serum transaminases with Teriflunomide use.

• Risk of Teratogenicity

Potential for Birth Defects: Based on animal findings, Teriflunomide could induce major birth defects if taken during pregnancy. Pregnancy confirmation is essential before initiating Teriflunomide. Pregnant women or women of childbearing potential not using reliable contraception should avoid Teriflunomide. Pregnant women should not receive Teriflunomide treatment, and pregnancy should be prevented while on Teriflunomide or until after an accelerated elimination procedure post-treatment. Careful consideration of the risks and benefits is essential .

• General

Accelerated Elimination Procedure: Teriflunomide is slowly eliminated from the plasma. An accelerated elimination procedure can be used after discontinuation of Teriflunomide to reduce plasma concentrations rapidly. Two methods are suggested: administration of cholestyramine or oral activated charcoal powder. These procedures significantly decrease teriflunomide plasma concentrations. Caution should be taken as this may lead to a gradual return of disease activity, particularly if the patient was positively responding to Teriflunomide therapy.

• Cardiovascular

Blood Pressure Effects: Slight increases in systolic and diastolic blood pressure have been observed. Regular blood pressure checks are recommended before and during Teriflunomide treatment.

• Hematologic

Blood Cell Count Changes: Placebo-controlled trials indicate reductions in white blood cell and platelet counts, particularly in the first 6 weeks of Teriflunomide use. Patients with pre-existing anemia, leucopenia, thrombocytopenia, or impaired bone marrow function face an increased risk of hematological issues.

• Hepatic/Pancreatic

Liver Function Abnormalities: Instances of liver function abnormalities have been noted, including severe liver injury. Patients with pre-existing liver conditions should exercise caution with Teriflunomide. Liver enzyme levels should be monitored, and Teriflunomide discontinued if serum transaminase levels increase significantly.

• Immune

Infections and Immune Response: Teriflunomide treatment may lead to increased susceptibility to infections. Screen for active infections before treatment. Serious infections have been reported in post-marketing experiences. Use caution and monitor for infections during Teriflunomide treatment.

• Neurologic

Peripheral Neuropathy: Peripheral neuropathy, such as polyneuropathy or mononeuropathy, is more frequent in patients taking Teriflunomide than those on placebo. Risk factors include age over 60, neurotoxic medications, and diabetes. Consider discontinuation of Teriflunomide if peripheral neuropathy symptoms arise.

• Respiratory

Lung Disease: Cases of interstitial lung disease (ILD) have occurred, leading to acute interstitial pneumonitis. Suspicion of ILD should prompt discontinuation and further investigation.

• Sexual Function / Reproduction

Pregnancy and Fertility: Teriflunomide is contraindicated in pregnant or potentially pregnant women. Special care must be taken to ensure reliable contraception. Pregnancy confirmation is necessary before Teriflunomide initiation. Men wishing to father a child should discontinue Teriflunomide and undergo an accelerated elimination procedure.

• Skin

Skin Reactions: Stevens-Johnson syndrome and toxic epidermal necrolysis cases have been reported post-marketing. Ulcerative stomatitis should lead to Teriflunomide discontinuation. Severe skin reactions necessitate Teriflunomide discontinuation and an accelerated elimination procedure.

There are no specific alcohol-related warnings associated with the use of Teriflunomide mentioned in the provided information. However, it's important to note that combining alcohol with medications, including Teriflunomide, can sometimes have unpredictable effects.

Research involving animals has demonstrated the presence of teriflunomide in breast milk. The presence of this drug in human milk has not been established. Given that numerous medications find their way into human milk and due to the possibility of significant adverse effects on breastfeeding infants stemming from Teriflunomide, a choice must be made whether to cease breastfeeding or halt drug usage. This decision should consider the drug's significance to the mother.

Pregnancy category : Not assigned

Teriflunomide should not be used by pregnant women or women of childbearing age who are not employing dependable contraception methods. Comprehensive and well-controlled investigations involving pregnant women have not been conducted for Teriflunomide.

However, based on findings from studies involving animals, the administration of Teriflunomide to pregnant women may raise the likelihood of fetal death or the occurrence of teratogenic impacts . Women capable of bearing children must not commence Teriflunomide treatment until the absence of pregnancy has been confirmed, and it has been ascertained that they are practicing reliable contraception. Before initiating Teriflunomide therapy, patients must receive comprehensive counseling regarding the potential serious risks to the developing fetus.

Grapefruit and Grapefruit Juice: Consumption of grapefruit or grapefruit juice should be avoided while taking teriflunomide, as it may increase the levels of the drug in the body and potentially lead to adverse effects.

Alcohol: Due to the potential for additive hepatotoxic effects, alcohol consumption should be avoided during treatment with teriflunomide.

Vitamin Supplements: Before taking any vitamin supplements or dietary products, it's advisable to consult with a healthcare professional, as some supplements may interact with teriflunomide or impact its effectiveness.

Folate and Folic Acid: Teriflunomide's mechanism of action involves inhibition of dihydroorotate dehydrogenase, which is involved in pyrimidine synthesis. This can affect the synthesis of DNA and RNA. Because folic acid is important for DNA and RNA synthesis, maintaining adequate folate levels through diet or supplementation could be considered.

Calcium and Vitamin D: Maintaining bone health is important, especially considering the potential risk of decreased bone density associated with some medications for multiple sclerosis. Adequate calcium and vitamin D intake, either through diet or supplements, may be advised in consultation with a healthcare provider.

Drug-Food Interactions: Some foods or dietary components might interact with teriflunomide or other medications you're taking. It's recommended to discuss your diet with your healthcare provider to ensure there are no potential interactions.

Balanced Diet: Maintaining a well-balanced and nutritious diet can support overall health and well-being, which is particularly important for individuals with multiple sclerosis who may have specific nutritional needs.

The adverse reactions related to Teriflunomide can be categorized as follows:

Common

• Increased levels of liver enzymes
• Diarrhea
• Hair thinning or hair loss
• Nausea
• Headache
• Elevated blood pressure
• Upper respiratory tract infections
• Back pain
• Pain in extremities (arms and legs)

Less Common

• Reduced white blood cell count
• Elevated blood pressure
• Insomnia
• Tingling or numbness in hands or feet
• Skin rash or itching
• Stomach discomfort
• Muscle weakness
• Memory problems
• Weight loss

Rare

• Severe skin reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis
• Severe liver problems
• Pancreatitis (inflammation of the pancreas)
• Lung problems
• Serious infections
• Blood disorders
• Allergic reactions
• Vision problems
• Mood changes or depression

The clinically relevant drug interactions of Teriflunomide is briefly summarized here:

Impact of Teriflunomide on CYP2C8 Substrates

Teriflunomide functions as an inhibitor of CYP2C8 in real-world scenarios. In individuals undergoing Teriflunomide treatment, drugs metabolized by CYP2C8 (such as paclitaxel, pioglitazone, repaglinide, rosiglitazone) might exhibit increased exposure. It's essential to monitor these patients closely and adjust the dosage of concomitant drugs metabolized by CYP2C8 as necessary .

Influence of Teriflunomide on Warfarin

When coadministered with warfarin, vigilant tracking of the international normalized ratio (INR) becomes crucial since Teriflunomide could potentially lower peak INR by approximately 25%.

Teriflunomide's Effect on Oral Contraceptives

Teriflunomide could lead to elevated systemic exposures of ethinylestradiol and levonorgestrel. It's advisable to contemplate the type or dosage of contraceptives used in combination with Teriflunomide.

Teriflunomide's Impact on CYP1A2 Substrates

Teriflunomide might function as a mild inducer of CYP1A2 in practical circumstances. In patients on Teriflunomide therapy, the exposure to drugs metabolized by CYP1A2 (like alosetron, duloxetine, theophylline, tizanidine) could decrease. It's important to closely monitor such patients and adjust the dosage of concomitant drugs metabolized by CYP1A2 as needed .

Influence of Teriflunomide on Organic Anion Transporter 3 (OAT3) Substrates

Teriflunomide's activity could inhibit OAT3 in practical settings. For individuals taking Teriflunomide, drugs considered as OAT3 substrates (such as cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine) might experience heightened exposure. Close monitoring and dosage adjustments for concomitant drugs classified as OAT3 substrates are crucial .

Effect of Teriflunomide on BCRP and Organic Anion Transporting Polypeptide B1 and B3 (OATP1B1/1B3) Substrates

Teriflunomide could inhibit BCRP and OATP1B1/1B3 in actual scenarios. Patients using Teriflunomide should not exceed a daily dose of 10 mg for rosuvastatin. For other BCRP substrates (like mitoxantrone) and drugs in the OATP family (such as methotrexate, rifampin), especially HMG-Co reductase inhibitors, special attention is advised.

The following are the side effects involving Teriflunomide:

• Rash on the skin with red or purple coloring, along with blistering and shedding
• Difficulties with breathing
• Changes in the sensation of your hands or feet that are distinct from your M.S. symptoms
• Skin discomfort
• Having hives
• A sense of burning in your eyes
• Pain in the upper abdomen
• A throat that feels sore
• Chills
• A cough, which might be new or worsening and could be accompanied by fever
• Nausea
• Loss of appetite
• Body aches
• Feeling exhausted
• Trouble with breathing
• Swelling in your face, lips, tongue, or throat
• A new or enhanced cough, which may or may not come with a fever
• Fever
• Vomiting
• Feeling fatigued
• Dark urine
• Yellowing of your skin or eyes, known as jaundice

The use of Teriflunomide should be prudent in the following group of special populations:

Pregnancy:

Pregnancy category : Not assigned

Teriflunomide should not be used by pregnant women or women of childbearing age who are not employing dependable contraception methods. Comprehensive and well-controlled investigations involving pregnant women have not been conducted for Teriflunomide.

However, based on findings from studies involving animals, the administration of Teriflunomide to pregnant women may raise the likelihood of fetal death or the occurrence of teratogenic impacts . Women capable of bearing children must not commence Teriflunomide treatment until the absence of pregnancy has been confirmed, and it has been ascertained that they are practicing reliable contraception. Before initiating Teriflunomide therapy, patients must receive comprehensive counseling regarding the potential serious risks to the developing fetus.

Lactation

Research involving animals has demonstrated the presence of teriflunomide in breast milk. The presence of this drug in human milk has not been established. Given that numerous medications find their way into human milk and due to the possibility of significant adverse effects on breastfeeding infants stemming from Teriflunomide, a choice must be made whether to cease breastfeeding or halt drug usage. This decision should consider the drug's significance to the mother.

Pediatric

The safety and effectiveness of Teriflunomide in children with multiple sclerosis who are under 18 years old have not been assessed. Teriflunomide is not recommended for use in individuals under the age of 18.

Geriatric Use

Patients aged 65 years and older were not part of the clinical trials for Teriflunomide. Therefore, when considering the use of Teriflunomide in individuals aged 65 and above, caution is recommended. This is because there is a higher likelihood of having other concurrent medical conditions and using additional medications. Patients aged 65 years and older were not encompassed in the clinical investigations of Teriflunomide. Therefore, exercising prudence is advisable when administering Teriflunomide to individuals in this age group. Physicians opting to provide treatment to geriatric patients should take into account that using Teriflunomide, given the heightened occurrence of additional concurrent medical conditions and coexisting medication regimens, demands cautious consideration and potentially requires enhanced monitoring or more frequent assessments.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Teriflunomide.

No instances of symptomatic overdose or intoxication with teriflunomide in humans have been reported. Healthy subjects demonstrated good tolerance to teriflunomide at a daily dose of 70 mg for a duration of up to 14 days.

In the event of a significant overdose or toxicity, the use of cholestyramine or activated charcoal is advised to expedite the elimination process.

Pharmacodynamics:

Teriflunomide serves as an immunomodulating agent that reduces the quantity of active lymphocytes within the central nervous system (CNS), leading to outcomes that are both anti-inflammatory and antiproliferative in nature.

Pharmacokinetics:

● Absorption:

The time it takes for teriflunomide to reach its highest plasma concentrations spans from 1 to 4 hours following oral intake.

● Impact of Food:

Food consumption does not lead to any significant effects on teriflunomide's pharmacokinetics.

● Distribution:

Teriflunomide displays strong affinity for plasma proteins, with over 99% of the compound being bound. It primarily resides within the plasma. Following a singular intravenous (IV) administration, its volume of distribution amounts to 11 liters.

● Metabolism:

Teriflunomide undergoes a moderate level of metabolism and predominantly remains as the predominant circulating component in plasma. The principal route of biotransformation involves hydrolysis, with oxidation playing a minor role. Supplementary metabolic pathways encompass oxidation, N-acetylation, and sulfate conjugation.

● Excretion:

Teriflunomide's elimination process involves primarily excretion through the gastrointestinal tract, potentially via the bile in its original form, and potentially via direct secretion. Renal excretion constitutes a significant elimination route for teriflunomide's metabolites. Over a 21-day span, 60.1% of the administered dosage exits the body via feces (37.5%) and urine (22.6%). After an expedited elimination procedure incorporating cholestyramine, an additional 23.1% is recovered, predominantly in feces. The overall clearance of teriflunomide from the body after a solitary IV administration measures at 30.5 mL/h.

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