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Tofacitinib - Uses, Side Effects, Dosage, Administration, Warning, and Precautions

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Tofacitinib is used to treat rheumatoid arthritis, ulcerative colitis, and ankylosing spondylitis. The article describes the drug in detail.

Medically reviewed by

Dr. Muhammad Zohaib Siddiq

Published At May 8, 2023
Reviewed AtFebruary 8, 2024

Overview:

Tofacitinib is a JAK or Janus kinase inhibitor used to treat rheumatoid arthritis, ulcerative colitis, and ankylosing spondylitis. Janus kinases are a group of enzymes that help in signaling pathways affecting immune cell function and hematopoiesis. It has been approved by the Food and Drug Administration or FDA for the treatment of moderate to severe rheumatoid arthritis, which does not respond properly to Methotrexate or in people who cannot tolerate Methotrexate. Apart from rheumatoid arthritis, Tofacitinib has also been used in the prevention of organ transplant rejection and is being studied for its use in psoriasis treatment.

How Does Tofacitinib Work?

Rheumatoid arthritis is a condition in which there is dysregulation of pro-inflammatory cytokines such as (interleukins) IL7, IL15, IL21, IL6, IFN-alpha, and IFN-beta. Cytokines are responsible for inflammation in the tissues and joint damage caused by stimulating the activation of the body's immune cells through the Janus kinase signaling pathway. Tofacitinib is a Janus kinase inhibitor that prevents the body from responding to cytokine signals. Tofacitinib prevents the phosphorylation and activation of Signal Transducers and Activators of Transcription (STATs) by inhibiting the Janus kinase pathway. This JAK-STAT signaling pathway is involved in the cellular transcription of immune cell function and hematopoiesis. Tofacitinib works by inhibiting the JAK-STAT pathway, therefore, reducing inflammation.

What Are the Uses of Tofacitinib?

Tofacitinib is used to treat the following conditions:

Limitations:

Tofacitinib, combined with biological disease-modifying anti-rheumatic drugs or immunosuppressants like Azathioprine and Cyclosporine, is not recommended.

Dosage Restrictions:

1. Route of Administration- Oral.

2. Dosage Strengths-

  • 5 mg.

  • 10 mg.

  • 11 mg.

3. Dosage Forms-

  • 5 mg - White, round, immediate-release film-coated tablets.

  • 10 mg - Blue, round, immediate-release film-coated tablets.

  • 11 mg - Pink, oval, extended-release film-coated tablets with a hole on one end.

Special Considerations:

The following may be some of the special considerations of Tofacitinib:

  • Pregnancy: The data available for the use of Tofacitinib in pregnant women is insufficient to establish the risk of major birth defects, miscarriage, or any maternal or fetal side effects. Rheumatoid arthritis is associated with pregnancy risks to the mother and fetus. In certain studies, feticide and teratogenic effects were seen in pregnant rats and rabbits receiving Tofacitinib.

  • Breastfeeding: No data is available on the presence of Tofacitinib in human milk, its effects on the infant, or milk production. Tofacitinib is present in the milk of lactating rats. Keeping in mind the severe adverse reactions seen in adults treated with Tofacitinib, such as the increased risk of serious infections, the patients are advised not to breastfeed during treatment and at least 18 hours after the last dose of Tofacitinib.

  • Females of Reproductive Potential: Tofacitinib has been associated with adverse embryo-fetal findings and reduced fertility in females of reproductive age. However, there is not much data to prove how these animal findings relate to females of reproductive age treated with Tofacitinib. Therefore, pregnancy planning and prevention are recommended for females of reproductive potential.

  • Pediatric Usage: The safety and efficacy of Tofacitinib have not been assessed in pediatric populations.

  • Geriatric Usage: The infection rate is high in the elderly population, so they should be treated cautiously.

  • Use in Diabetics: People with diabetes have an increased incidence of catching infections; hence they should be treated with caution.

  • Moderate To Severe Renal Impairment: Individuals with moderate to severe renal impairment have been found to have a higher concentration of Tofacitinib in their blood. Therefore dosage adjustment is recommended in such individuals.

  • Hepatic Impairment: Tofacitinib is not recommended if the patient suffers from severe hepatic impairment. Dose adjustment is required in moderate hepatic impairment.

Warnings and Contraindications:

No contraindications.

What Are the Warnings and Precautions of the Drug?

  • Serious Infections - Serious and fatal bacterial, mycobacterial, invasive fungal, viral, or other infections have been seen in people receiving Tofacitinib. The most common infections reported with Tofacitinib include cellulitis, pneumonia, herpes zoster, diverticulitis, urinary tract infection, and appendicitis. Tuberculosis and other mycobacterial infections, pneumocystosis, cryptococcosis, histoplasmosis, esophageal candidiasis, herpes zoster, Cytomegalovirus infections, BK virus infection, and listeriosis have been found with the drug.

  • Malignancies - The risks and benefits of the use of Tofacitinib treatment before starting the therapy in patients with malignancy, except for a successfully treated non-melanoma skin cancer, should be considered. Malignancies were reported in clinical studies of Tofacitinib.

  • Gastrointestinal Perforations - Reports of gastrointestinal perforation have been found in clinical studies with Tofacitinib. Gastrointestinal Perforations should be used with caution in patients with an increased risk for gastrointestinal perforation.

  • Lymphocyte Abnormalities - Treatment with Tofacitinib was associated with initial lymphocytosis within one month of exposure, followed by a slight decrease in the mean absolute lymphocyte counts.

  • Anemia - Avoid treatment with Tofacitinib in people with a low hemoglobin level. Tofacitinib should be interrupted in people with hemoglobin levels less than eight g/dL or if their hemoglobin level drops greater than two g/dL during treatment.

  • Increased Liver Enzymes - People undergoing treatment with Tofacitinib have increased liver enzymes.

  • Increased Cholesterol Levels - Treatment with Tofacitinib has been associated with dose-dependent increases in cholesterol levels, including total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol.

  • Vaccinations - The use of live vaccines should be avoided with Tofacitinib.

For Patients:

What Is Rheumatoid Arthritis?

Rheumatoid arthritis is a chronic inflammatory disease that affects many joints of the body. The immune system attacks its cells, including the joints. In severe cases, it also attacks the internal organs. As a result, rheumatoid arthritis affects the joints causing pain and swelling. Over some time, rheumatoid arthritis can cause bone erosion and joint deformity. There is no cure for rheumatoid arthritis; physiotherapy and medication can help slow the progression of the disease. Most of them can be managed with a class of medications called anti-rheumatic drugs.

Why Is Tofacitinib Prescribed for Rheumatoid Arthritis?

  • Tofacitinib is either used alone or in combination with other medicines to treat rheumatoid arthritis (a disease in which the body attacks its joints leading to pain, swelling, and function loss) in individuals who cannot take or do not respond to any tumor necrosis factor inhibitor medicines. It is also used to treat people with psoriatic arthritis (a condition with joint pain and scaly skin).

  • Tofacitinib is also used to treat ulcerative colitis (a condition that causes swelling and ulcerations in the colon lining).

  • It is used in the treatment of polyarticular juvenile idiopathic arthritis, a type of childhood arthritis affecting five or more joints during the first six months, causing pain, swelling, and function loss, in kids two years and older. Tofacitinib belongs to a class of medicines known as Janus kinase (JAK) inhibitors, which work by impairing the activity of the immune system.

Facts One Should Know About Tofacitinib:

How Should One Take Tofacitinib?

  • Tofacitinib is available as a tablet, an oral solution (liquid), and an extended-release (long-acting) tablet.

  • It should be taken orally.

  • The tablet should be taken twice daily with or without food, and the extended-release tablet should be taken daily once with or without food. Tofacitinib should be taken at the same time daily.

  • Follow the directions on the prescription carefully, and ask the doctor about any part that needs to be understood.

  • Tofacitinib should be taken exactly as directed by the doctor.

  • Take it as prescribed by the doctor.

  • Do not chew, split, chew, or crush the tablets, and swallow them whole.

  • Use the syringe that comes with the drug solution to measure the dose.

  • Talk to the doctor to know how to measure the dose of the Tofacitinib solution.

  • Read the instructions carefully.

  • In case of side effects, the dose should be decreased or stopped.

What Should One Discuss With the Doctor Before Beginning Tofacitinib?

  • Inform the doctor if one is allergic to Tofacitinib, its ingredients, or any other medications.

  • Inform the doctor about any other medications, vitamins, and nutritional supplements that one is taking. Mention the medications such as certain antifungal medications such as Fluconazole, Itraconazole, and Ketoconazole; Aspirin and other nonsteroidal anti-inflammatory medications, such as Ibuprofen and Naproxen, Carbamazepine; Clarithromycin; certain medications for HIV including Indinavir, Nelfinavir, and Ritonavir; Nefazodone; Phenobarbital; Phenytoin; Rifabutin; and Rifampin.

  • Inform the doctor if one is taking any herbal products, especially St. John's wort.

  • Inform the doctor if one has undiagnosed stomach pain and if one has or ever had ulcers, swelling of the lining of the large intestine, liver diseases like hepatitis B or hepatitis C, cancer, anemia, is on dialysis, or any kidney disease. If one is taking extended-release tablets, inform the doctor in case of narrowing or blockage of the digestive system.

  • Inform the doctor if one is pregnant or planning to become pregnant.

  • Inform the doctor if one is breastfeeding.

  • Tofacitinib may decrease fertility in women.

  • Inform the doctor if one has recently received or is about to receive any vaccinations. Do not take any vaccinations during the treatment without the doctor's consent.

Is Tofacitinib Safe?

Tofacitinib is safe to use with the prescribed dosage.

Is Tofacitinib Effective?

Tofacitinib is effective in the treatment of rheumatoid arthritis.

What Side Effects Can One Expect With Tofacitinib?

Some serious side effects include the following:

  • Swelling of face, eyes, lips, or throat.

  • Difficulty in breathing or swallowing.

  • Stomach pain.

  • Yellowish skin or eyes.

  • Appetite loss.

  • Dark urine.

  • Rashes.

  • Clay-colored stools.

  • Vomiting.

  • Shortness of breath.

Can One Stop Taking Tofacitinib Without the Doctor's Approval?

The medication should only be stopped with the doctor's approval. It should never be stopped abruptly.

Are There Any Dietary Restrictions to Consider When Taking Tofacitinib?

Continue taking a normal diet unless prescribed by the doctor.

How Should One Store Tofacitinib?

The medication should be kept in a tightly closed container and out of the reach of children. In addition, the medication should be stored at room temperature and away from heat and moisture.

How Should One Dispose of Tofacitinib?

Discard any unused medicine within 60 days after opening the bottle. Unused medications should be disposed of in certain ways to ensure that pets, kids, and others cannot take them. For example, the medication should not be flushed down the toilet. The best way to dispose of the medicine is through a medicine take-back program.

What To Do in Case of Overdose?

In case of an overdose, the poison control team should be immediately contacted.

For Doctors

Indications:

Tofacitinib is indicated to treat the following conditions:

  • Rheumatoid arthritis.

  • Psoriatic arthritis.

  • Ulcerative colitis.

What Is the Pharmacology of Tofacitinib?

Description

Tofacitinib is a white to off-white powder with the chemical name: (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3-d]pyrimidin-4-ylamino)-B-oxo-1­ piperidine propane nitrile, 2-hydroxy-1,2,3-propane-tri carboxylate (1:1). The solubility of Tofacitinib in water is 2.9 mg/mL. 23. Tofacitinib has a molecular weight of 504.5 Daltons (or 312.4 Daltons as the Tofacitinib free base) and a molecular formula of C16H20N6O.C6H8O7.

Components

1. Active Ingredients

  • Tofacitinib.

2. Inactive Ingredients

  • Croscarmellose sodium.

  • HPMC 2910 or Hypromellose 6cP.

  • Lactose monohydrate.

  • Macrogol/PEG3350.

  • Magnesium stearate.

  • Microcrystalline cellulose.

  • Titanium dioxide.

  • Triacetin.

Clinical Pharmacology:

Mechanism of Action

Tofacitinib is a Janus kinase inhibitor. Janus kinase is an enzyme that transmits the signals from cytokines or growth factor-receptor interactions to influence the cellular processes of immune cell function or hematopoiesis. The Janus kinase phosphorylates, thereby activating the signal transducers and activators of transcription, which regulate certain intracellular activities such as gene expression. Tofacitinib regulates the signaling pathway at the point of Janus kinase, preventing the activation of signal transducers and activators of transcription. Janus kinase transmits cytokine signaling through pairing such as JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, and JAK2/JAK2). Tofacitinib is found to inhibit the in vitro activities of the combinations JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 with IC50 of 406, 56, and 1377 nm.

Pharmacodynamics:

Tofacitinib has been found to be associated with reductions of circulating natural killer cells, with maximum reductions occurring at eight to ten weeks after beginning therapy. These changes were resolved within two to six weeks after discontinuation of the treatment. Treatment with Tofacitinib has been associated with dose-dependent increases in the B cell. There were small changes in the circulating T-lymphocytes and T-lymphocyte subsets. Total serum levels of IgG, IgM, and IgA after six-month dosing in patients with rheumatoid arthritis were lower than that of the placebo. But the changes were small and not dependent on dose. Patients with rheumatoid arthritis, after treatment with Tofacitinib, have shown a rapid decrease in serum C-reactive protein (CRP). The changes in C-reactive protein observed with Tofacitinib treatment do not reverse fully within two weeks after discontinuation, thus indicating a longer duration of pharmacodynamic activity compared to the pharmacokinetic half-life. Similar changes have been observed in T cells, B cells, and serum CRP in patients with active psoriatic arthritis.

Pharmacokinetics:

After oral administration of Tofacitinib, the peak plasma concentrations are reached within 0.5 to one hour; the elimination half-life is about three hours and an increase in systemic exposure in the therapeutic dose range. The steady-state concentrations are achieved in 24 to 48 hours with very less accumulation after twice daily administration.

  • Pharmacokinetic Changes:

A. Distribution:

  • Bound to Plasma Protein Bound - 40 percent.

  • The Volume of Distribution - 87 L.

  • Distributed equally between the red blood cells and plasma.

B. Metabolism and Excretion:

Tofacitinib is metabolized approximately 70 percent in hepatic metabolism and 30 percent in renal excretion. The metabolism of Tofacitinib is mediated by CYP3A4 with a minor contribution from CYP2C19. It has been found that more than 65 percent of the total circulating radioactivity was by unchanged Tofacitinib, with the remaining 35 percent attributed to eight metabolites, each accounting for less than eight percent of the total radioactivity.

C. Elimination:

  • Seventy percent metabolized in the liver.

  • Thirty percent is eliminated in the urine.

Special Considerations:

  • Pregnancy: The data available for the use of Tofacitinib in pregnant women is insufficient to establish the risk of major birth defects, miscarriage, or any maternal or fetal side effects. Rheumatoid arthritis is associated with pregnancy risks to the mother and fetus. In certain studies, foeticide and teratogenic effects were seen in pregnant rats and rabbits receiving Tofacitinib.

  • Breastfeeding: No data is available on the presence of Tofacitinib in human milk, its effects on the infant, or milk production. Tofacitinib is present in the milk of lactating rats. Keeping in mind the severe adverse reactions seen in adults treated with Tofacitinib, such as the increased risk of serious infections, the patients are advised not to breastfeed during treatment and at least 18 hours after the last dose of Tofacitinib.

  • Females of Reproductive Potential: Tofacitinib has been associated with adverse embryo-fetal findings and reduced fertility in females of reproductive age. However, there is not much data to prove how these animal findings relate to females of reproductive age treated with Tofacitinib. Therefore, pregnancy planning and prevention are recommended for females of reproductive potential.

  • Pediatric Usage: The safety and efficacy of Tofacitinib have not been assessed in pediatric populations.

  • Geriatric Usage: The infection rate is high in the elderly population, so they should be treated cautiously.

  • Use in Diabetics: People with diabetes have an increased incidence of catching infections; hence they should be treated with caution.

  • Moderate To Severe Renal Impairment: Individuals with moderate to severe renal impairment have been found to have a higher concentration of Tofacitinib in their blood. Therefore, dosage adjustment is recommended in such individuals.

  • Hepatic Impairment: Tofacitinib is not recommended for severe hepatic impairment. Dose adjustment is required in moderate hepatic impairment.

Drug Interactions:

  • Abametapir - The serum concentration of Tofacitinib can be increased in combination with Abametapir.

  • Acebutolol - The bradycardic activities of Tofacitinib can be increased with Acebutolol.

  • Beclomethasone Dipropionate - The immunosuppressive activities of Tofacitinib can be increased with Beclomethasone Dipropionate.

What Have Clinical Trials Shown With Regard to Tofacitinib?

  • Dose-Ranging Study 1: This study was a six-month monotherapy trial conducted on 384 patients with rheumatoid arthritis. Patients were randomized to one of seven monotherapy treatments, such as Tofacitinib 1, 3, 5, 10, or 15 mg twice daily, Adalimumab 40 mg subcutaneously every other week for ten weeks, followed by Tofacitinib 5 mg twice daily for three months, or placebo.

  • Dose-Ranging Study 2: This was a six-month trial in which 507 patients with active rheumatoid arthritis who had an inadequate response to Methotrexate sodium alone received one of six dose regimens of Tofacitinib (20 mg once daily; 1, 3, 5, 10, or 15 mg twice daily), or placebo added to Methotrexate sodium.

  • Results: A dose-response relationship was observed in study one. In the second study, a smaller proportion of patients achieved an ACR20 response in the placebo and Tofacitinib 1 mg groups compared to patients treated with the other Tofacitinib doses. No difference was seen among patients treated with Tofacitinib 3, 5, 10, 15 mg twice daily or 20 mg once daily doses.

Patient Counseling Information:

  • Infections: The patients should be informed that Tofacitinib might impair their immune system to fight infections. They should not take Tofacitinib in case of an active infection. Instruct the patients to contact their doctor immediately if symptoms of infection appear to ensure detection and treatment. The risk of herpes zoster infection is increased in patients treated with Tofacitinib.

  • Malignancies and Lymphoproliferative Disorders: Inform the patients that Tofacitinib may increase the risk of certain cancers. In addition, the patients should inform their doctor if they have ever had any cancer.

  • Pregnancy: Pregnant women and females of reproductive age should be advised of the risk to the fetus. In addition, they should inform their doctor about the pregnancy.

  • Lactation: Women should breastfeed during treatment with Tofacitinib and for at least 18 hours after the last dose.

  • Infertility: Tofacitinib may impair fertility. It is yet to be determined whether this effect is reversible.

Complications or Side Effects

  • Nasopharyngitis.

  • Diarrhea.

  • Upper respiratory tract infection.

  • Headache.

  • Hypertension.

  • Increased cholesterol levels.

  • Nausea.

  • Herpes zoster infection.

  • Gastroenteritis.

  • Rashes.

Dr. Muhammad Zohaib Siddiq
Dr. Muhammad Zohaib Siddiq

Cardiology

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