Ruxolitinib

Ruxolitinib is an antineoplastic agent belonging to the pharmacological class of kinase inhibitors, specifically Janus kinase (JAK) inhibitors.

The FDA approved Ruxolitinib for treating polycythemia vera, myelofibrosis, and acute/chronic graft-versus-host disease in certain patients.

Ruxolitinib is well absorbed from the gastrointestinal tract and exhibits strong plasma protein binding, predominantly to albumin (97%). It is metabolized by the liver primarily by CYP3A4 enzymes, with minor assistance from CYP2C9 enzymes. Urine (74%, <1% unchanged) and faeces (22%, <1% unchanged) are the primary routes of elimination.

The most common side effects of Ruxolitinib include headache, dizziness, and low platelet count.

Ruxolitinib is available as an oral tablet.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Ruxolitinib is an antineoplastic agent belonging to the pharmacological class of kinase inhibitors, specifically Janus kinase (JAK) inhibitors.

A selective inhibitor of Janus Associated Kinases (JAKs), specifically JAK1 and JAK2, rufolitinib facilitates the signalling of growth factors and cytokines which is crucial for the immune system and hematopoiesis. Dysregulation of JAK 1/2 has been linked to polycythaemia vera and myelofibrosis. Gene expression is regulated through JAK-mediated signalling, which entails the recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors. The proliferation, development, and activation of immune cell types crucial to GVHD pathophysiology are regulated by JAK-STAT signalling.

Peak plasma concentration is usually achieved within 1-2 hours after administration.

Ruxolitinib is available as an oral tablet.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

The physician recommends taking this medication orally twice daily, with or without food.

Ruxolitinib is indicated for the following conditions:

Orally: Administer ruxolitinib orally twice a day, approximately simultaneously. Chew, break, or open the tablets, and swallow them whole with a glass of water. If a dose is missed, take it as soon as you remember the same day and return to the routine the next day. Never take additional pills or capsules to make up for a dose that was missed. If the treatment has to be discontinued for a reason other than thrombocytopenia, consider reducing the dosage gradually (e.g., by 5 mg q12hr per week).

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Ruxolitinib is available as an oral tablet.

Starting dose (based on platelet count): 20 mg bid for >200,000/mm3, 15 mg bid for 100,000-200,000/mm3, and 5 mg bid for 50,000-<100,000/mm3. Doses of titrate are determined by tolerability and efficacy. Stop if the absolute neutrophil count (ANC) is less than 500/mm3 or the platelet count is less than 50,000/mm3. The dosage might be decreased if the platelet count is less than 100,000/mm3. Doses may be raised by up to 5 mg bid if the response is inadequate and blood counts are sufficient. Maximum: 25 milligrams bid. After the first four weeks of treatment, the starting dose may be increased, but no more frequently than every two weeks after that. After six months, stop if there is no improvement in symptoms or a decrease in the size of the spleen.

In individuals who are hydroxyurea-resistant or intolerant, 10 mg was the initial bid. Doses of titrate are determined by tolerability and efficacy. If Hb falls below 12 g/dL, the dosage may be lowered. If Hb is less than 8 g/dL, stop dosing. Doses may be raised by up to 5 mg bid if the response is inadequate and blood counts are sufficient. Maximum: 25 milligrams bid. After the first four weeks of treatment, the starting dose may be increased, but no more frequently than every two weeks after that.

If platelet and neutrophil counts are not reduced by at least 50% from baseline, the initial 5 mg twice a daymay be increased to 10 mg after at least three days. After six months, gradually decrease the dosage in responsive patients who have finished corticosteroid treatment by one dose level, roughly every eight weeks. If symptoms or signs return during or after dose reduction, retreatment might be necessary. Depending on the results of blood parameters, the dosage may be changed.

Before starting therapy, get a complete blood count (CBC) and platelet count. Once the doses are stable, repeat these tests every two to four weeks or as a clinician directs.

While undergoing Ruxolitinib treatment, it is crucial to refrain from smoking and alcohol consumption. Follow a good balanced diet that contain a range of fruits, whole grains, and vegetables. Conversely, limit fast food intake, processed meats, salty snacks, and highly processed foods and beverages. Adhering to these recommendations promotes the patient's health and enhances the overall efficacy of ruxolitinib therapy.

The dietary restriction should be individualized as per patient requirements.

Maintain a healthy diet, quit smoking, and limit alcohol.

The adverse reactions related to Ruxolitinib can be categorized as:

Infections and infestations: Reactivation and spread of the Herpes simplex virus

The clinically relevant drug interactions of Ruxolitinib are briefly summarized here.

The common side effects of Ruxolitinib include:

Dizziness

Headache

Weight gain

Anaemia, or low red blood cell count

Fever

Low blood platelets

Cough

Urinary tract infections(UTIs)

Constipation

Hypertriglyceridemia, or elevated cholesterol

Pregnancy Category C (FDA): If the benefits outweigh the risks, use caution. Animal research has established risk, and human studies are either unavailable or have not been conducted.

There is no data regarding ruxolitinib use in pregnant women.

Ruxolitinib has been demonstrated to be both embryotoxic and foetotoxic in animal studies. Rats and rabbits did not exhibit teratogenicity. However, the results had little human relevance due to the low exposure margins compared to the highest clinical dose. Unknown is the possible risk to humans. Use of Ruxolitinib during pregnancy is not advised as a measure of caution.

Women who could become pregnant or use contraception

When taking ruxolitinib, potentially fertile women should use effective contraception.

If a woman becomes pregnant while taking ruxolitinib, a risk/benefit analysis and thorough counselling about possible hazards to the fetus must be done for every individual.

There is no information on ruxolitinib's presence in human milk, its effects on the breastfed infants, or how it affects milk production.

Ruxolitinib and/or its metabolites were shown to be present in the milk of lactating rats.

Avoid breastfeeding during treatment for atleast two weeks following the last dose due to the presence of numerous drugs in human milk and the possibility of thrombocytopenia and anaemia observed with ruxolitinib in human studies.

The use of Ruxolitinib in pediatric populations was limited, and safety and efficacy in this age group may have yet to be extensively studied or established.

<12 years: Safety and effectiveness of acute graft versus host disease are undetermined.

≥12 years

Starting dosage: 5 mg PO BID; if ANC and platelet counts have not dropped by at least 50% from baseline after at least three days, the dosage may be increased to 10 mg BID.

Patients who show response and have stopped receiving therapeutic doses of corticosteroids may benefit from tapering after six months of treatment.

reducing the dosage

One dose level should be tapered off every eight weeks (10 mg BID to 5 mg BID to 5 mg qDay).

People who can't take 5 mg qDay: Stop the treatment until the parameters in the laboratory or clinical settings improve.

If symptoms or signs of acute GVHD return during or after taper, retreatment may be needed.

<12 years: Safety and efficacy of chronic graft versus host disease are undetermined

>12 years

First dosage: 10 mg PO BID

Patients who respond and have stopped receiving therapeutic doses of corticosteroids should think about tapering after six months.

reducing the dosage

Reducing the dosage by 1 dose level approximately every 8 weeks (for example, going from 10 mg BID to 5 mg BID and then back to 5 mg BID daily).

If symptoms or signs of acute GVHD return during or after taper, retreatment may be necessary.

Moderate-to-severe (CrCl 15-59 mL/min) with any platelet count: The starting dose is 5 mg twice a day orally

ESRD (CrCl <15 mL/min) on dialysis: 10 mg once orally after dialysis session

ESRD (CrCl <15 mL/min) not on dialysis: Not recommended

Ruxolitinib exposure increased in patients with mild, moderate, and severe hepatic impairment (Child-Pugh A, B, and C).

Patients with MF or PV who have hepatic impairment ought to reduce their ruxolitinib dosage as advised. For patients with Stage 4 liver aGVHD, lower the dosage of ruxolitinib as instructed.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Ruxolitinib.

Overconsumption of Ruxolitinib could result in Myelosuppression (e.g. anaemia, leucopenia, thrombocytopenia).

There isn't a specific antidote for a Ruxolitinib overdose. Since the medication is primarily metabolized in the liver, discontinue it promptly and initiate supportive care while closely monitoring the liver's function. If the overdose occurred recently, the use of gastric lavage or activated charcoal may be considered to remove any drug that was not absorbed from the gastrointestinal tract. Ruxolitinib's high protein binding renders hemodialysis unlikely to be beneficial.

Ruxolitinib inhibits JAK-induced phosphorylation of signal transducer and activator of transcription (STAT), which inhibits cell proliferation, induces apoptosis of malignant cells, and lowers pro-inflammatory cytokine plasma levels. Ruxolitinib inhibits STAT3 phosphorylation, which is a marker of JAK activity. This effect is seen two hours after dosing, and in patients with myelofibrosis and polycythemia vera, it returns to near baseline by ten hours. Ruxolitinib lessened splenomegaly and enhanced myelofibrosis symptoms in clinical trials. Ruxolitinib treatment was linked to a longer survival time in a mouse model of myeloproliferative neoplasms. Both mutant and wild-type JAK2 are inhibited by ruxolitinib; however, the JAK2V617F mutation, which is frequently observed in about 50% of myelofibrosis patients, has been demonstrated to decrease ruxolitinib sensitivity. This mutation may also be linked to potential resistance to JAK inhibitor treatment.