Ruxolitinib- Indications, Dosage, Mechanism, and Side Effects

Overview:

Ruxolitinib is an approved FDA (Food and Drug Association) drug for the treatment of non-segmental vitiligo. Ruxolitinib received its approval in September 2021 and has been distributed in the market under the name Opzelura cream from the manufacturer Incyte. Ruxolitinib is a Janus kinase or JAK inhibitor that has been additionally indicated for the treatment of topical short-term as well as non-continuous chronic treatment of atopic dermatitis that is mild to moderate in nature in patients who are non-immunocompromised and are adult and 12 years of age and above whose underlying medical conditions have not been adequately corrected with other kinds of topical prescription therapies.

There are a few limitations of Ruxolitinib that include the concomitant use of Ruxolitinib with therapeutic biologics, except for Janus kinase inhibitors and potent immunosuppressants- azathioprine and cyclosporine. Ruxolitinib must not be used in more than a 60-gram tube every seven days or a 100-gram tube every two weeks. Ruxolitinib is indicated strictly for topical use and not for intraocular, oral, and intravaginal routes of administration. For atopic dermatitis, Ruxolitinib must be applied as a thin layer twice a day to affect the areas. For non-segmental vitiligo, Ruxolitinib must be applied as a thin layer twice a day on affected areas. Certain studies have shown the presence of note-worthy changes that require precautions-

Serious Infections such as the following are mentioned below.

• Severe bacterial.

• Mycobacterial.

• Viral infections.

• Fungal infections.

• Non-melanoma skin cancers.

• Basal cell carcinoma.

• Squamous cell carcinoma.

• Thrombosis.

• Thromboembolic events have occurred.

• Thrombocytopenia.

• Anemia.

• Neutropenia.

• Thrombocytopenia.

Some of the most common adverse reactions after the application of Ruxolitinib include the following mentioned below.

• Nasopharyngitis.

• Diarrhea.

• Bronchitis.

• Ear infection.

• Eosinophil count increased.

• Urticaria.

• Folliculitis.

• Tonsillitis.

• Rhinorrhea.

• Application site acne.

• Application site pruritus.

• Nasopharyngitis.

• Headache.

• Urinary tract infection.

• Application site erythema.

• Pyrexia.

Warning:

Patients who have been treated with Janus kinase inhibitors such as Ruxolitinib hold a strong potential to develop the following events mentioned below.

Severe infections- The infections that develop after the administration of Janus kinase inhibitors may lead to hospital administration or even turn fatal. Avoid the use of Ruxolitinib in patients who are suffering from an active and severe form of infection that includes localized diseases. In case an intense kind of infection may develop, interrupt Ruxolitinib until the infectious conditions have been controlled. The risks and the benefits of the management and treatment with Ruxolitinib must be strictly taken into consideration before the initial therapy of patients suffering from chronic and recurrent types of infections. Patients must be closely monitored for the signs and symptoms of severe conditions during the treatment as well as after treatment with Ruxolitinib.

They include the following mentioned below.

• Tuberculosis.

• Pulmonary disease.

• Extrapulmonary disease.

• Invasive fungal infections.

• Cryptococcosis.

• Pneumocystosis.

• Bacterial infection.

• Lower respiratory tract infection.

• Endemic mycoses.

• Viral infection.

• Herpes zoster.

• Opportunistic pathogens.

• Hepatitis B.

• Hepatitis C.

Mortality- A considerable number of randomized, post-marketing safety studies in patients who have rheumatoid arthritis or RA in patients who are 50 years and older and are with at least any one of the cardiovascular risk factors against an oral Janus kinase inhibitor and a tumor necrosis factor or TNF blocker management has shown an elevated rate of mortality that include sudden cardiovascular death.

Malignancy- There were reports of malignancies in patients who have been treated with Janus kinase inhibitors such as Ruxolitinib for the treatment of inflammatory diseases, lymphoma, and several other malignancies except for non-melanoma skin cancer or NMSC with current or past smokers being at additional increased risk. Ruxolitinib must be immediately discontinued in patients who show any of the above manifestations.

MACE or Major Adverse Cardiovascular Events- There were reports of at least one severe cardiovascular event in patients who have been treated with Janus kinase inhibitors such as Ruxolitinib. A few of the major adverse cardiovascular events include cardiovascular death, myocardial infarction, and stroke. Current and past smokers are at a higher risk of developing such adverse events. Ruxolitinib must be immediately discontinued in patients who show any kind of cardiovascular events such as those mentioned above.

Thrombosis- Trials and studies with Ruxolitinib have reported the presence of thromboembolic events such as thrombosis, pulmonary embolism or PE, deep vein thrombosis or DVT, and arterial thrombosis in patients who are undergoing treatment with Janus kinase inhibitors for anti-inflammatory effect. Several of such changes have resulted in severe and life-threatening consequences and, unfortunately, even death. Therefore, Ruxolitinib must be immediately discontinued in patients who show any kind of thrombotic changes such as those mentioned above.

Indications:

Ruxolitinib is a prescription drug that is used for topical application on the skin for the conditions mentioned below in patients who are 12 years and above.

• Non-segmental vitiligo.

• Atopic dermatitis.

Limitations of Use:

Ruxolitinib is not recommended to be used in the following situations mentioned below.

• Along with therapeutic biologics.

• Janus kinase inhibitors.

• Strong immunosuppressants.

• Azathioprine.

• Cyclosporine.

• Patients less than 12 years of age.

Contraindications:

None.

Dosage and Administration:

Ruxolitinib must not be used in more than a 60-gram tube every seven days or a 100-gram tube every two weeks. Ruxolitinib is indicated strictly for topical use and not for intraocular, oral, and intravaginal routes of administration. For atopic dermatitis, Ruxolitinib must be applied as a thin layer twice a day to affect the areas. For non-segmental vitiligo, Ruxolitinib must be applied as a thin layer twice a day on affected areas. In case there is the development of itch, rash, or redness, the application of Ruxolitinib must be immediately stopped.

Dosage Form and Strength:

1.5 % cream Ruxolitinib that is white or off-white in color.

Clinical Trials for Non-Segmental Vitiligo:

In two double-blind, vehicle-controlled clinical trials, 449 subjects, 12 years and older with nonsegmental vitiligo were treated with Ruxolitinib twice per day for 24 weeks, including 55 % females, 81 % white, 5 % black, and 4 % Asian candidates.

The adverse reactions reported after the same are mentioned below.

• Application site acne.

• Application site pruritus.

• Nasopharyngitis.

• Headache.

• Urinary tract infection.

• Application site erythema.

• Pyrexia.

Drug Interactions:

There have not been extensive studies on the drug interaction of Ruxolitinib. However, after a mere amount of clinical trials and studies, it has been reported that the concomitant use of Ruxolitinib with therapeutic biologics, except for Janus kinase inhibitors and potent immunosuppressants- azathioprine and cyclosporine, is not suggested.

Use in Specific Populations:

Pregnancy: The available data from pregnancies reported in clinical studies with Ruxolitinib are not near sufficient to evaluate the drug-associated risk for pregnancy defects such as miscarriage or other adverse maternal and fetal outcomes. Thus, the background risks of significant pregnancy defects for the indicated populations remain unknown.

Lactation: There is no data on the presence of Ruxolitinib in human milk and the effects on a breastfed child or on the production of milk.

Pediatric Use: The safety and effectiveness of Ruxolitinib for the topical treatment of nonsegmental vitiligo have been positively established in pediatric patients between 12 to 17 years of age. Unfortunately, the safety and effectiveness of Ruxolitinib in pediatric patients younger than 12 years suffering from nonsegmental vitiligo have not yet been established.

Geriatric Use: Clinical trials of Ruxolitinib in patients with nonsegmental vitiligo did not have a sufficient number of individuals above 65 years of age in order to determine if they respond in a different manner from younger and adult individuals.

For Doctors

Description:

Ruxolitinib phosphate is a kind of Janus kinase inhibitor or JK inhibitor with a chemical name of (R)-3-(4-(7Hpyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1-yl)-3-cyclopentylpropanenitrile phosphate and the molecular weight of 404.36 g/mol. It is a cream that is white to off-white oil-in-water and is a solubilized emulsion strictly for topical use. Each gram of the drug contains 15 mg of Ruxolitinib, which is equivalent to 19.8 mg in a cream that includes the following mentioned below.

• Cetyl alcohol.

• Dimethicone 350.

• Edetate disodium.

• Glyceryl stearate SE.

• Light mineral oil.

• Medium chain triglycerides.

• Methylparaben.

• Phenoxyethanol.

• Polyethylene glycol 200.

• Polysorbate 20.

• Propylene glycol.

• Propylparaben.

• Stearyl alcohol.

• Purified water.

• White petrolatum.

• Xanthan gum.

Indications:

Ruxolitinib is a prescription drug that is used for topical application on the skin for the conditions mentioned below in patients who are 12 years and above.

• Nonsegmental vitiligo.

• Atopic dermatitis.

Contraindications:

None.

Mechanism of Action:

Ruxolitinib, which is a Janus kinase or JAK inhibitor, inhibits the JAK1 and JAK2 that are known to mediate the signaling of several kinds of cytokines as well as growth factors that are critical for hematopoiesis and a smooth immune function. JAK signaling includes the recruitment of STATs- signal transducers and activators of transcription into cytokine receptors activation and the subsequent localization to the nucleus that leads to the modulation of gene expression.

Pharmacodynamics:

Ruxolitinib is not expected to prolong the QT interval.

Pharmacokinetics:

Absorption: After several studies were done on individuals with Ruxolitinib, the rate of absorption from 0 to 12 hours on the first day was 449 ± 883 nM and 3215 ± 6184 nM.

Distribution: The plasma protein binding of Ruxolitinib is approximately 97 %.

Elimination: The mean half-life of Ruxolitinib after the topical application is approximately 116 hours.

Metabolism: Ruxolitinib is metabolized by the CYP3A4 pathways and, to a lesser extent, by the CYP2C9 pathway in vitro.

Excretion: Ruxolitinib is 74 % excreted by urine and 22 % by feces, with less than 1 % as unchanged drug excretion.

Carcinogenesis, Mutagenesis, Impairment of Fertility: The topical application of Ruxolitinib has not been studied for carcinogenesis, mutagenesis, and impairment of fertility.

Storage and Supply:

Ruxolitinib is a white to off-white cream that contains 1.5 % of Ruxolitinib. It is supplied in 60 g and 100 g tubes. Store Ruxolitinib at 20 degrees celsius to 25 degrees celsius or 68 degrees Fahrenheit to 77 degrees Fahrenheit with excursions permitted between 15 degrees celsius to 30 degrees celsius or 59 degrees Fahrenheit to 86 degrees Fahrenheit.

For Patient:

Important: Ruxolitinibis for use only on the skin. Do not use Ruxolitinib in your eyes, mouth, or vagina.

Warning:

Patients who have been treated with Janus kinase inhibitors such as Ruxolitinib hold a strong potential to develop the following events mentioned below.

• Serious infections.

• Thrombosis.

• Mortality.

• Malignancy.

• MACE or major adverse cardiovascular event.

What Is Non-Segmental Vitiligo?

Non-segmental vitiligo refers to depigmentation of the skin with depigmented lesions of the skin, hair, and mucosa.

What Is Ruxolitinib?

Ruxolitinib is a topical treatment for non-segmental vitiligo in patients above 12 years of age.

When Is Ruxolitinib Used?

Ruxolitinib is a prescription drug that is used for topical application on the skin for the conditions mentioned below in patients who are 12 years and above.

• Nonsegmental vitiligo

• Atopic dermatitis.

When Should Ruxolitinib Not Be Used?

Ruxolitinib is not recommended to be used in the following situations mentioned below.

• Along with therapeutic biologics.

• Janus kinase inhibitors.

• Strong immunosuppressants.

• Azathioprine.

• Cyclosporine.

• Patients less than 12 years of age.

How to Use Ruxolitinib?

Ruxolitinib must not be used in more than a 60-gram tube every seven days or a 100-gram tube every two weeks. Ruxolitinib is indicated strictly for topical use and not for intraocular, oral, and intravaginal routes of administration. For atopic dermatitis, Ruxolitinib must be applied as a thin layer twice a day to affect the areas. For non-segmental vitiligo, Ruxolitinib must be applied as a thin layer twice a day on affected areas. In case there is the development of itch, rash, or redness, the application of Ruxolitinib must be immediately stopped.

What Are the Ingredients of Ruxolitinib?

• Ruxolitinib 1.5 %.

• Cetyl alcohol.

• Dimethicone 350.

• Edetate disodium.

• Glyceryl stearate SE.

• Light mineral oil.

• Medium chain triglycerides.

• Methylparaben.

• Phenoxyethanol.

• Polyethylene glycol 200.

• Polysorbate 20.

• Propylene glycol.

• Propylparaben.

• Stearyl alcohol.

• Purified water.

• White petrolatum.

• Xanthan gum.

What Are the Side Effects of Ruxolitinib?

• Nasopharyngitis.

• Diarrhea.

• Bronchitis.

• Ear infection.

• Eosinophil count increased.

• Urticaria.

• Folliculitis.

• Tonsillitis.

• Rhinorrhea.

• Application site acne.

• Application site pruritus.

• Nasopharyngitis.

• Headache.

• Urinary tract infection.

• Application site erythema.

• Pyrexia.

Conclusion:

Ruxolitinib is an approved FDA (Food and Drug Association) drug for the treatment of non-segmental vitiligo. It is manufactured by Incyte with a commercial name of Opzelura. Other than non-segmental vitiligo, Ruxolitinib is used for the treatment of atopic dermatitis. There are several precautionary measures that need to be taken into consideration. The significant side effects of the topical application of Ruxolitinib are itching redness and skin irritation. There are other side effects as well that change from person to person. There have been several studies done on the safety and effectiveness of the topical administration of Ruxolitinib. The drug has been given a go signal for patients who are 12 years and older.