Upadacitinib is an oral medication prescribed to treat moderate to severe rheumatoid arthritis (RA) in patients who are not responsive to first-line therapy, Methotrexate. It is a second-generation selective Janus Kinase (JAK) inhibitor that targets the JAK1 enzyme. Upadacitinib was approved by the United States FDA (Food and Drugs Administration) on 16th August 2019, based on the promising results obtained after phase III trials in subjects with moderate to severe rheumatoid arthritis (RA).
Upadacitinib is recommended in patients with inadequate response or intolerance when treated with the first-line therapy drug, Methotrexate. Studies have shown that Upadacitinib, combined with Methotrexate, has established a restricted disease progression and better clinical efficacy. It is not advised to use Upadacitinib with other JAK inhibitors or immunosuppressants like Azathioprine or Cyclosporine.
How Does Upadacitinib Work?
Upadacitinib works by inhibiting cytoplasmic enzymes Janus Kinases (JAK). JAK is a group of tyrosine kinases that cause immune-mediated inflammatory diseases. JAK1, JAK2, JAK3, and TYK2 are tyrosine kinases. Inhibiting JAK interferes with the growth factor and cytokine-mediated signals.
JAKs work by phosphorylating STATs (signal transducers and activators of transcription), regulating gene expression, and influencing immune cell function and hematopoiesis. Upadacitinib works predominantly on JAK1 compared to JAK2, JAK3, and TYK2 types. Upadacitinib restricts phosphorylation and intracellular activation of STATs, thereby reducing the inflammatory effects.
Indications and Usage:
Upadacitinib is recommended for treating moderate to severely active rheumatoid arthritis in patients who have shown an inadequate response to TNF blockers.
Upadacitinib with JAK inhibitors and immunosuppressants like Azathioprine and Cyclosporine is not recommended. In addition, though its use with DMARDs (nonbiologic disease-modifying anti-rheumatic drugs) like Methotrexate is approved, its use along with biologic DMARDs is not advised.
Dosage and Administration:
Dosage for Rheumatoid Arthritis:
The recommended dosage of Upadacitinib is an extended-release 15 mg tablet to be taken orally. Upadacitinib tablets must be swallowed as a whole and should not be split, crushed, or chewed. The drug can be used as monotherapy or combination therapy along with Methotrexate or nonbiologic DMARDs.
Important Administration Instructions:
The use of Upadacitinib is not recommended in the following patients:
An absolute lymphocyte count (ALC) of less than 500 cells/mm3 (cells per millimeter cube).
An absolute neutrophil count (ANC) of less than 1000 cells/mm3.
Hemoglobin level of less than 8 g/dL (grams per deciliter).
Severe hepatic impairment.
The dose of Upadacitinib must be interrupted in cases where the patient develops a severe infection and can be resumed once the infection subsides. In addition, treatment should be interrupted in cases where ALC is less than 500 cells/mm3, ANC is less than 1000 cells/mm3, Hb level is less than 8 g/dL, and in patients in whom a drug-induced liver injury is detected.
Dosage Forms and Strengths:
Upadacitinib extended-release tablets are available with a strength of 15 mg. They are purple, biconvex, and oblong. They are 14x8 mm in dimension and are debossed with "a15" on one side.
There are no contraindications to the use of Upadacitinib.
Warnings and Precautions:
Serious and fatal infections have been reported in patients who were receiving Upadacitinib. Pneumonia and cellulitis were the more frequent infections; apart from severe infections, opportunistic diseases like tuberculosis, oral and esophageal candidiasis, multidermatomal herpes zoster, and cryptococcosis were noted.
It is advisable to avoid using Upadacitinib in patients with an active and severe infection.
Also, the risks and benefits must be assessed before initiating the treatment in patients with:
A history of recurrent infections or chronic infection.
A severe or opportunistic infection.
Exposure to tuberculosis.
Who have resided in or traveled to places with endemic tuberculosis or mycosis.
Underlying conditions that can increase the risk of infection.
Close monitoring of the patients during and after the treatment course with Upadacitinib is recommended to check the development of signs and symptoms of infection. The therapy must be interrupted in patients who develop a serious or an opportunistic infection.
In patients who develop infections during treatment, drug use must be stopped, diagnostic testing appropriate for an immuno-compromised patient must be done, and antimicrobial therapy must be initiated. Upadacitinib use can be resumed once the infection gets controlled.
Before the start of therapy with Upadacitinib, patients must be screened for TB (tuberculosis). Patients with an active TB infection must not be started with Upadacitinib.
In addition, an anti-TB treatment must be considered in the following patients:
Previously untreated latent TB.
Negative for latent TB but who are at an increased risk for TB infection.
Patients with the above risks must be monitored for the development of signs and symptoms of TB before starting treatment with Upadacitinib. An opinion from a specialist doctor must be taken on deciding the start of therapy for each case.
Clinical studies have reported herpes zoster and hepatitis B virus reactivation using Upadacitinib. If a patient develops herpes zoster during treatment, the treatment must be stopped and resumed only after the episode subsides. Cases of hepatitis B reactivation were reported in subjects enrolled for phase 3 clinical studies. A liver specialist must be consulted if a hepatitis B viral DNA is detected during treatment.
A study involving patients older than 50 with at least a single cardiovascular disorder showed a higher risk of mortality due to sudden cardiovascular death in patients who were given JAK inhibitors compared to TNF blockers.
Malignancy and Lymphoproliferative Disorders:
A large, randomized, post-marketing study of another JAK inhibitor in rheumatoid arthritis patients showed a higher malignancy rate when treated with JAK inhibitors compared to TNF blockers. Lymphomas and lung cancers were reported. In addition, cases of non-melanoma skin cancer were reported in patients treated with Upadacitinib. Therefore, a periodic skin examination is advised in patients at an increased risk of skin cancer.
Adverse Cardiovascular Events:
Studies have shown that patients older than 50 with at least one cardiovascular risk factor had an increased risk of cardiovascular complications called significant adverse cardiovascular events (MACE) like cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. These risks increased in patients administered JAK inhibitors compared to TNF blockers. Also, past or current smokers are at an increased risk. Therefore, the drug use must be discontinued in patients with myocardial infarction or stroke. Also, patients must be informed about the symptoms of serious cardiovascular events.
Complications like deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis were reported in patients who received JAK inhibitors for inflammatory conditions. Some of the adverse effects were severe, leading to death. Therefore, the therapy must be discontinued in patients having an increased risk of thrombosis or symptoms of thrombosis.
GI (Gastrointestinal) Perforations:
The risk of gastrointestinal perforations was studied in populations taking NSAIDs (non-steroidal anti-inflammatory drugs) who reported GI perforations. Therefore, in patients with diverticulitis and those taking NSAIDs, Upadacitinib must be used with caution due to an increased risk of GI perforations.
Neutropenia, lymphopenia, and anemia were noted using Upadacitinib due to a decrease in neutrophils, lymphocytes, and hemoglobin levels, respectively. There was also an increase in the lipid parameters like total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL). The elevated levels of LDL responded well to statin therapy and decreased to the pre-treatment levels. However, the effects of these elevations on cardiovascular complications are yet to be studied. After the start of the treatment, patients must be monitored at 12 weeks and post that based on the clinical guidelines mentioned for hyperlipidemia management.
An elevation of liver enzymes was noted with Upadacitinib use. Therefore, cases of drug-induced liver enzyme elevation have to be diagnosed promptly. In addition, the drug use must be interrupted if there are elevated levels of ALT (alanine aminotransferase) or AST (aspartate transaminase) during routine management.
Animal studies have shown that Upadacitinib, when administered to pregnant women, causes fetal harm. In addition, there was an increase in fetal malformations studied in rats and rabbits during organogenesis. Therefore, women with reproductive potential are advised to use effective contraception when used concomitantly with Upadacitinib and also four weeks post completion of therapy.
Using live, attenuated vaccines during or immediately before drug use is not recommended. Before starting Upadacitinib, patients must be up to date with all the immunization schedules, including prophylactic zoster vaccination.
The adverse effects of Upadacitinib included the following:
Upper respiratory tract infections include:
Placebo-controlled studies in which the patients were administered an oral dose of 15 mg Upadacitinib presented with the above adverse effects. Severe side effects like herpes zoster viral infection were noted in patients administered 30 mg in double-blind, randomized, controlled phase 3 clinical trials. Clinical studies also reported thrombosis, malignancy, and GI perforations on concomitant use with NSAIDs.
What Is Rheumatoid Arthritis?
Rheumatoid arthritis is an auto-immune condition in which the body's immune cells mistakenly damage its cells. As a result, RA causes chronic inflammation in several joints. The inflammation occurs mainly in the joint lining, thereby leading to bone erosion and joint deformity. Apart from the bones, the condition can also affect the skin, eyes, lungs, heart, and blood vessels.
What Are the Symptoms of Rheumatoid Arthritis?
In RA patients, inflammation first affects the smaller joints, like those connecting the fingers to the hands and toes to the feet. However, with time the larger joints in various body parts like the wrists, ankles, knees, elbows, hips, and shoulders may be affected. There are periods when the disease activity is at its maximum, called a flare, followed by periods of remission.
The common signs and symptoms noted include:
Warm, tender, and swollen joints.
Joint stiffness is more prominent early in the mornings and after periods of inactivity.
Loss of appetite.
How Is Rheumatoid Arthritis Diagnosed?
Early diagnosis is difficult for RA as the symptoms mimic other conditions. A physical examination to check for the joints' redness, warmth, and swelling can help diagnose the condition. Also, blood tests that detect elevated levels of ESR (erythrocyte sedimentation rate) and CRP (C-reactive protein) indicate an elevated inflammatory process in the body. Rheumatoid factor and anti-CCP (anti-cyclic citrullinated peptide) antibodies can also be checked. Imaging tests like X-rays can help keep track of RA in the joints over time, and an MRI (magnetic resonance imaging) scan helps understand the severity of the condition.
How Is Rheumatoid Arthritis Treated?
There is no permanent cure for RA. However, the severity of the symptoms and flare-ups can be managed with medications, therapy, or surgery.
The type of medications depends on the time and severity of symptoms. Medicines called disease-modifying anti-rheumatic drugs (DMARDs) are recommended to work better when started early. There are different types of NSAIDs, steroids, conventional DMARDs, targeted DMARDs, and biologic agents. For example, Upadacitinib is a type of targeted synthetic DMARD.
Doctors may advise physical or occupational therapy in addition to medications. Physical therapy includes exercises that help in making the joints more flexible.
Surgery is advised in cases where the medications do not benefit in reducing pain and improving function. Various surgeries include synovectomy, tendon repair, joint fusion, and total joint replacement.
Strong CYP3A4 Inhibitors:
Upadacitinib must be used cautiously in patients receiving long-term treatment with potent CYP3A4 inhibitors. There is an increased exposure of Upadacitinib when co-administered with potent CYP3A4 inhibitors like Ketoconazole.
Strong CYP3A4 Inducers:
It is not recommended to co-administer Upadacitinib with strong CYP3A4 inducers as it decreases exposure to the drug. Studies have shown a reduced exposure of Upadacitinib when co-administered with CYP3A4 solid inducers like Rifampin.
Use in Specific Populations:
Limited human data is available to assess the drug-associated risk for miscarriage or significant congenital disabilities. However, published data suggest an increased disease activity that leads to an increased risk of adverse pregnancy outcomes like preterm delivery (before 37 weeks of gestation), low birth weight in infants (less than 2500 g), and early gestational age at birth. In patients in the United States, the risk of significant congenital disabilities and miscarriages was 2 % to 4 % and 15 % to 20 %, respectively.
Animal embryo-fetal developmental studies in which rats and rabbits were administered doses equal to or greater than the maximum recommended human dose (MRHD) showed an increased incidence of skeletal malformations (in rats), cardiovascular malformations, and increased post-implantation loss (in rabbits), and decreased fetal body weights in both rats and rabbits. However, there was no developmental toxicity in pregnant rats and rabbits during organogenesis when exposed to 0.3 to 2 times the MRHD.
There is no sufficient data on the presence of the drug in human milk, its effects on the breastfed infant, and milk production. However, animal studies have shown excretion of the drug in breast milk. Therefore, there are equal chances of Upadacitinib being excreted in human milk. Thus, drug use is not recommended in lactating mothers to avoid serious adverse effects on the breastfed infant. Also, breastfeeding has to be started only six days after stopping the drug.
Females of Reproductive Potential:
Contraception: As suggested by animal studies, Upadacitinib can cause fetal harm when administered to pregnant women. Therefore, it is advised women of potential reproductive use efficient contraception during the drug intake and continue using it up to four weeks after the final dose.
No data is available on the safe use of Upadacitinib in young patients between 0 to 18.
Not much difference was observed in patients above 65 years and 75 years compared to younger patients with drug use. However, there was a higher rate of adverse effects in geriatric patients.
No dose adjustment is required in patients with mild, moderate, or severe renal impairment. However, the effects of Upadacitinib on patients with end-stage renal disease have not been studied.
No dose adjustment is needed in patients with mild and moderate hepatic impairment. However, the drug is not recommended in patients with severe hepatic impairment.
In clinical trials, a daily dosage of Upadacitinib up to 60 mg extended-release was administered. There were no significant adverse effects other than those that occurred with regular dosages. Also, no specific toxicities were observed. About 90 % of Upadacitinib in the systemic circulation was eliminated within 24 hours of administration of the dose. In cases of overdosage, it is advised to monitor the patients for the signs and symptoms and give appropriate treatment if necessary.
Upadacitinib is a JAK inhibitor.
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The solubility of the drug in water is 38 to less than 0.2 mg/mL (milligrams per milliliter) across a pH range of 2 to 9 at 37 degrees Celsius.
389.38 g/mol (grams per mole).
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Mechanism of Action:
Upadacitinib is a Janus Kinase (JAK) inhibitor. JAKs are intracellular enzymes that transmit signals arising from cytokine or growth-factor receptor mediators on the cell membrane. This influences the cellular processes of hematopoiesis and immune cell function. Within the signaling pathways, JAKs phosphorylate and activate STATs (Signal Transducers and Activators of Transcription) which modulate intracellular activity like gene expression.
Cell-free isolated enzyme assay showed that the drug had a greater inhibitory potency at JAK1 and JAK2 compared to JAK3 and TYK2.
With Upadacitinib administration, there was a dose and concentration-dependent inhibition of IL-6 (JAK1/JAK2) - induced STAT3 and IL-7 (JAK1/JAK3) - induced STAT5 phosphorylation of the whole blood. The maximal inhibition was observed one hour after dosing and returned to near baseline by the end of the dosing interval.
Treatment with Upadacitinib showed a transient increase in ALC and a decrease in IgG and IgM levels. However, the mean values at baseline and all other visits were within the normal reference range. At a mean maximum exposure of six times with an oral dose of 15 mg, there was no significant clinical effect on the QT interval.
A steady-state plasma concentration of Upadacitinib was achieved within four days with minimal accumulation after being administered multiple once-daily doses.
An orally administered extended-release tablet of Upadacitinib was absorbed with a median Tmax of 2 to 4 hours. Co-administration of Upadacitinib with a high-fat or high-calorie meal did not impact the absorption of the drug.
Upadacitinib is 52 % bound to plasma proteins.
The drug's metabolism is mediated primarily by the CYP3A4 enzyme system, with a minor contribution by CYP2D6. The pharmacology is 79 % due to the parent molecule and the remaining 13 % due to the primary metabolite detected during the total plasma radioactivity.
The parent substance was excreted 24 % in urine, 38 % in feces, and 38 % of the primary metabolite was excreted after single-dose administration. The mean terminal half-life of Upadacitinib ranged from 8 hours to 14 hours.
Age, body weight, ethnicity, gender, and race did not clinically affect Upadacitinib exposure.
Renal impairment did not affect Upadacitinib exposure, and Upadacitinib Cmax was similar in subjects with normal renal functioning and patients with renal impairment.
Mild and moderate hepatic impairment did not affect the Cmax of Upadacitinib. The effects of drug use in patients with severe hepatic impairment have not been studied.
No evidence of tumorigenicity has been observed in rats and mice.
Upadacitinib showed negative results during in vitro bacterial mutagenicity assay (Ames assay), in vivo rat bone marrow micronucleus assay, and in vitro chromosome aberration assay in human peripheral blood lymphocytes.
There was no impairment of fertility in male and female rats who were administered oral doses of 50 mg/kg/day (milligrams per kilogram per day) and 75 mg/kg/day, respectively. However, the maintenance of pregnancy was adversely affected by increased post-implantation losses.
How Is Upadacitinib Stored and Handled?
Upadacitinib is available in a bottle that contains 30 tablets. It is supplied as a 15 mg extended-release tablet to be administered orally. It is purple in color, biconvex, oblong, with dimensions of 14mmx8mm, and debossed with "a15" on one side. Upadacitinib must be stored at 2 degrees Celsius to 25 degrees Celsius. In addition, it has to be stored in the original bottle to avoid moisture contamination.
Patient Counseling Information:
The patient must be advised to read the FDA-approved patient labeling thoroughly.
Patients must be informed about the severe infections they can develop when taking Upadacitinib. In addition, they must be instructed to consult a doctor if they develop any signs and symptoms of the disease.
As Upadacitinib usage can increase the risk of certain cancers, patients must be instructed about the same.
Patients must be informed about the risks of developing DVT (deep venous thrombosis) and PE (pulmonary embolism) and instructed to consult a doctor if any signs or symptoms appear.
Adverse Cardiovascular Events:
Patients must be informed about the risk of developing major cardiovascular problems like stroke, myocardial infarction, or cardiovascular death. They must be advised to be alert and report to the doctor in case of uneasiness or any symptoms.
Patients must be informed about the altered laboratory test reports during the use of Upadacitinib. Also, they must be informed about the need for blood tests before and during Upadacitinib use.
Women must be warned about the fetal harm of drug use. Also, they must be instructed to inform doctors in case of suspected pregnancy. In case of drug use, they must be advised to use effective contraception at least for four weeks after stopping the medication.
Patients must be advised to stop breastfeeding during Upadacitinib use.
Patients must be instructed not to split, crush, or chew the tablet.