Invista

Uses

Invista is used for the treatment of adults with:

• Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase.
• Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib.
• Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.

Invista is also used to associated treatment for these conditions: Acute Lymphoblastic Leukaemias (ALL), Chronic Myeloid Leukemia (CML)

How Invista works

Invista, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase. In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate sensitive and resistant disease. Invista inhibited the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, dasatinib was able to overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression.

Dosage

Invista dosage

The recommended starting dosage of Invista for:

• Chronic phase CML is 100 mg administered orally once daily.
• Accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL is 140 mg administered orally once daily.

Tablets should not be crushed or cut; they should be swallowed whole. Invista can be taken with or without a meal, either in the morning or in the evening.

In clinical studies, treatment with Invista was continued until disease progression or until no longer tolerated by the patient. The effect of stopping treatment on long-term disease outcome after the achievement of a cytogenetic response (including complete cytogenetic response [CCyR]) or major molecular response (MMR) is not known.

Side Effects

Reversible myelosuppression, neutropenia, anaemia, thrombocytopenia, fluid retention, pulmonary arterial HTN, QT prolongation, cardiac failure, arrhythmias, HTN, musculoskeletal pain, GI disturbances, headache, chills, fatigue, asthenia, myalgia, chest pain, arthralgia, pyrexia, mucositis, flushing, colitis, electrolyte disturbances, appetite and wt disturbances, rash, dermatitis, hyperhidrosis, pruritus, acne.

Toxicity

Acute overdose in animals was associated with cardiotoxicity.

Precaution

Patients with predisposing factors for QT prolongation (e.g. congenital long QT syndrome, hypokalaemia, hypomagnesaemia, on antiarrhythmic therapy, or receiving cumulative high doses of anthracyclines). Hepatic impairment. Lactation.

Interaction

Concomitant use with drugs that have narrow therapeutic index (e.g. alfentanil, cisapride, ciclosporin, fentanyl, pimozide, quinidine, simvastatin, sirolimus, tacrolimus, ergot alkaloids) as it may increase the serum levels of these drugs. Increased risk of bleeding and thrombocytopenia with antiplatelet drugs, anticoagulants, and NSAIDs.

Food Interaction

• Avoid grapefruit products. Grapefruit may reduce the CYP3A4 metabolism of dasatinib, increasing its serum levels.
• Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of dasatinib.
• Take with or without food. High fat meals may increase the AUC of dasatinib by to 14%.

[Major] GENERALLY AVOID: Grapefruit and grapefruit juice may significantly increase the plasma concentrations of dasatinib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit.

Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability).

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

Because dasatinib prolongs the QT interval, high plasma levels of dasatinib may increase the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

MANAGEMENT: Patients treated with dasatinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract.

Some authorities recommend close monitoring for toxicity (e.g., myelosuppression, bleeding complications, fluid retention, bradycardia or other conduction disturbances) and a reduction of dasatinib dosage to a range of 20 to 40 mg daily should be considered if there are no alternatives and concomitant use with a potent CYP450 3A4 inhibitor is necessary.

Invista Drug Interaction

Major: aspirin, aspirinModerate: loratadine, loratadine, diltiazem, diltiazemUnknown: glucose, glucose, levetiracetam, levetiracetam, furosemide, furosemide, metoprolol, metoprolol, metoprolol, metoprolol, cyanocobalamin, cyanocobalamin, cholecalciferol, cholecalciferol

Invista Disease Interaction

Moderate: cardiovascular disease, fluid retention, bone marrow suppression, hepatic impairment, pulmonary arterial hypertension, QT prolongation

Volume of Distribution

• 2505 L

Half Life

The overall mean terminal half-life of dasatinib is 3-5 hours.

Elimination Route

Invista is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. Elimination is primarily via the feces.

Pregnancy & Breastfeeding use

Pregnancy category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Concomitant use with CYP3A4 inhibitors (e.g. atazanavir, clarithromycin, erythromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole or grapefruit juice); CYP3A4 inducers (e.g. carbamazepine, dexamethasone, phenytoin, phenobarbital, rifampicin or St John's wort); antacid. Pregnancy.

Special Warning

Pediatric Use: The safety and efficacy of Invista in patients less than 18 years of age have not been established.

Geriatric Use: No differences in confirmed Complete Cytogenetic Response (cCCyR) and MMR were observed between older and younger patients. Of the 2712 patients in clinical studies of Invista, 617 (23%) were 65 years of age and older, and 123 (5%) were 75 years of age and older. While the safety profile of Invista in the geriatric population was similar to that in the younger population, patients aged 65 years and older are more likely to experience the commonly reported adverse reactions of fatigue, pleural effusion, diarrhea, dyspnea, cough, lower gastrointestinal hemorrhage, and appetite disturbance, and more likely to experience the less frequently reported adverse reactions of abdominal distention, dizziness, pericardial effusion, congestive heart failure, hypertension, pulmonary edema, and weight decrease, and should be monitored closely.

Hepatic Impairment: No dosage adjustment is necessary in patients with hepatic impairment. Caution is recommended when administering Invista to patients with hepatic impairment.

Renal Impairment: There are currently no clinical studies with Invista in patients with impaired renal function. Less than 4% of dasatinib and its metabolites are excreted via the kidney.

Acute Overdose

Symptoms: Significant platelet count reduction. Management: Closely monitor for myelosuppression. Supportive and symptomatic treatment.

Storage Condition

Invista tablets should be stored at 20°C to 25°C

Innovators Monograph

You find simplified version here Invista