Ruxolitinib Phosphate

Registered South African indications:

• Myelofibrosis

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding

Cautions

• Severe renal impairment
• Hepatic impairment
• Low platelet count <200,000/mm³
• Absolute neutrophil <500/mm³ 
• Haemoglobin <10g/dL
• Active and inactive ("latent") tuberculosis
  - Previous medical history
  - Possible previous contact with tuberculosis
• Severely ill or immunocompromised patients
• Chronic hepatitis B infections
• History of extended treatment with hydroxyurea and prior non-melanoma skin cancers or pre-malignant skin lesions
• Risk factors for skin cancer
• Abrupt withdrawal
• Acute intercurrent illness
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption 
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: tab

Used for the treatment of

• Myelofibrosis - disease-related splenomegaly or symptoms in
  - Primary myelofibrosis (also known as chronic idiopathic myelofibrosis)
  - Post polycythaemia vera myelofibrosis
  - Post essential thrombocythaemia myelofibrosis
• Polycythaemia vera
  - Resistant or intolerant of hydroxyurea

Consult specialist for dosages and regimens

Not established for use in children

Pregnancy

• Contraindicated
• There is no data from the use of ruxolitinib phosphate in pregnant women
• Animal studies have shown that ruxolitinib is embryotoxic and foetotoxic. Teratogenicity was not observed in rats or rabbits. However, the exposure margins compared to the highest clinical dose were low and the results are therefore of limited relevance for humans. The potential risk for humans is unknown
• As a precautionary measure, the use of ruxolitinib during pregnancy is contraindicated. Women of childbearing potential should use effective contraception during treatment with ruxolitinib. In case pregnancy should occur during treatment, a risk/benefit evaluation must be carried out on an individual basis with careful counselling regarding potential risks to the foetus

Breastfeeding

• Contraindicated 
• It is unknown whether ruxolitinib and/or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of ruxolitinib and its metabolites in milk. A risk to the breastfed child cannot be excluded
• Ruxolitinib must not be used during breastfeeding and breastfeeding should therefore be discontinued when treatment is started

Fertility

• There is no human data on the effect of ruxolitinib on fertility. In animal studies, no effect on fertility was observed

Renal Impairment

• Mild to moderate: No dose adjustment recommended
• Severe and end-stage renal disease (ESRD) on haemodialysis: Caution; dose adjustment recommended

Hepatic Impairment

• Caution; dose adjustment recommended
  Reduce the recommended starting dose based on platelet count with any hepatic impairment. Patients diagnosed with hepatic impairment while receiving ruxolitinib should have complete blood counts, including a white blood cell count differential, monitored at least every one to two weeks for the first 6 weeks after initiation of therapy with ruxolitinib and as clinically indicated thereafter once their liver function and blood counts have been stabilised

Elderly

• No dose adjustment recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Dizziness
• Headache

Cardiovascular Disorders

• Hypertension

Gastrointestinal Disorders

• Flatulence
• Constipation
• Increased lipase

Hepatobiliary Disorders

• Raised alanine aminotransferase
• Raised aspartate aminotransferase

Endocrine and Metabolic Disorders

• Increased weight
• Hypercholesterolaemia
• Hypertriglyceridaemia

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Thrombocytopenia
• Neutropenia
• Bleeding
  - Intracranial bleeding
  - Gastrointestinal bleeding
  - Bruising
  - Epistaxis
  - Post-procedural haemorrhage
  - Haematuria
• Bruising
• Urinary tract infections
• Herpes zoster
• Pneumonia
• Sepsis
• Tuberculosis

• Cytoreductive therapies
• Strong CYP3A4 inhibitors
• Boceprevir
• Clarithromycin
• Indinavir
• Itraconazole
• Ketoconazole
• Lopinavir/ritonavir
• Ritonavir
• Mibefradil
• Nefazodone
• Nelfinavir
• Posaconazole
• Saquinavir
• Telaprevir
• Telithromycin
• Voriconazole
• Mild or moderate CYP3A4 inhibitors (increased cytopenia risk)
• Ciprofloxacin
• Erythromycin
• Amprenavir
• Atazanavir
• Diltiazem
• Cimetidine  
• CYP2C9 inhibitors
• Fluconazole
• CYP3A4 inducers
• Avasimibe
• Carbamazepine
• Phenobarbital
• Phenytoin
• Rifabutin
• Rifampicin
• P-glycoprotein substrates
• Breast cancer resistance protein substrates
• Dabigatran etexilate
• Ciclosporin
• Rosuvastatin
• Digoxin
• St John's wort (Hypericum perforatum)

• Full blood count
• Lipid profile
• Renal function
• Hepatic function
• Tuberculin skin test
• Skin examination

Specific cases may require

• Hepatitis B viral load

Ruxolitinib is a selective inhibitor of the Janus Associated Kinases (JAKs) JAK1 and JAK2. These mediate the signalling of a number of cytokines and growth factors that are important for haematopoiesis and immune function. Myelofibrosis and Polycythaemia vera myelofibrosis are myeloproliferative neoplasms known to be associated with dysregulated JAK1 and JAK2 signalling. The basis for the dysregulation is believed to include high levels of circulating cytokines that activate the JAK-STAT pathway, gain-of-function mutations such as JAK2V617F, and silencing of negative regulatory mechanisms. MF patients exhibit dysregulated JAK signalling regardless of JAK2V617F mutation status. Ruxolitinib inhibits JAK-STAT signalling and cell proliferation of cytokine-dependent cellular models of haematological malignancies, as well as of Ba/F3 cells rendered cytokine-independent by expressing the JAK2V617F mutated protein.

Tablet 5mg

• Jakavi (Novartis) originator

Tablet 15mg

• Jakavi (Novartis) originator

Tablet 20mg

• Jakavi (Novartis) originator