Ribociclib and letrozole

Ribociclib and letrozole Uses, Dosage, Side Effects, Food Interaction and all others data.

Letrozole is a nonsteroidal aromatase inhibitor. It inhibits the conversion of androgen to estrogen. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis. Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect the adrenal corticosteroid synthesis, ldosterone synthesis, or synthesis of thyroid hormones.

Letrozole is an aromatase inhibitor used in the treatment of breast cancer. Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing recurrence of the breast tumor tissue.

Letrozole is a third generation type II aromatase inhibitor used to treat estrogen dependant breast cancers. It has a long duration of action as it has a half life of over 42 hours in breast cancer patients. Patients should be counselled regarding the risk of interstitial lung disease, pneumonitis, QT prolongation, elevated transaminase levels, neutropenia, and embryo-fetal toxicity.

Ribociclib is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably. Ribociclib was approved by the U.S. FDA in March, 2017 as Kisqali.

Ribociclib and letrozole
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Ribociclib and letrozole
Generic	Letrozole + ribociclib
Type	Oral
Therapeutic Class
Manufacturer
Available Country	United States
Last Updated:	September 19, 2023 at 7:00 am

Uses

Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer.
Extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy.
First-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer.
Treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

Ribociclib is a kinase inhibitor used to treat HR+, HER2- advanced or metastatic breast cancer.

Kisqali (ribociclib) is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably.

Ribociclib and letrozole is also used to associated treatment for these conditions: Advanced Breast Cancer, Anovulatory cycle, Early Breast Cancer, Ovarian Epithelial Cancer, Advanced HR + HER2 - breast cancer, Metastatic HR + HER2 - breast cancerAdvanced Breast Cancer, Metastatic Breast Cancer

How Ribociclib and letrozole works

Letrozole is a non-steroidal type II aromatase inhibitor. It blocks the active site, and therefore the electron transfer chain of CYP19A1. This competitive inhibition prevents the conversion of androgens to estrogen. This action leads to a reduction in uterine weight and elevated leuteinizing hormone. In postmenopausal women, the action of aromatase is responsible for the majority of estrogen production. With reduced availability of estrogen, estrogen-dependant tumors regress. Third generation aromatase inhibitors do not significantly affect cortisol, aldosterone, and thyroxine levels.

Inhibition of cyclin-dependent kinase 4 and 6 (CDK4/6) may provide protection against oncogenic processes in specific tissue types. For example, CDK4 is not required for normal mammary tissue development based on knockout mouse studies, but it is needed for growth of Ras-induced mammary tumors, suggesting a potential therapeutic window for treatment with lower toxicity. Ribociclib was reported to be a most selective CDK4/6 inhibitor and to have dose dependent antitumor activity in a number of preclinical models. It inhibited growth of tumor cells by arresting the cells at the G1 checkpoint, which prevents the tumor cells from proliferating.

Dosage

Ribociclib and letrozole dosage

The recommended dose is one 2.5 mg tablet administered once a day, regardless to meals. In patients with advanced disease, treatment with Letrozole Tablet should be continued until tumor progression is evident. Treatment should be discontinued at tumor relapse. No dose adjustment is required for elderly patients. Patients treated with Letrozole Tablet do not require glucocorticoid or mineralocorticoid replacement therapy.

Side Effects

Letrozole is generally well tolerated. The observed adverse reactions are mild or moderate in nature including hot flashes, night sweats, weight increase, nausea, vaginal bleeding & irritation, endometrial proliferation disorders etc.

Toxicity

Overdose data in humans is not readily available, however 1 reported case was not associated with serious adverse reactions. Animal studies do not report serious adverse effects with high dose treatment. Patients experiencing and overdose should be treated with symptomatic and supportive measures.

Oral doses over 2000mg/kg were associated with reduced motor activity, ataxia, dyspnea, and death in mice and rats.

Precaution

Since fatigue and dizziness have been observed with the use of Letrozole and somnolence was uncommonly reported, caution is advised when driving or using machinery.

Interaction

A pharmacokinetic interaction study with cimetidine & warfarin showed no clinically significant effect on Letrozole pharmacokinetics. In in-vitro experiments, Letrozole & diazepam showed no significant inhibition in the metabolism of each other. Coadministration of Letrozole and tamoxifen 20 mg daily resulted in a reduction of Letrozole plasma levels of 38% on average. Clinical experience in the second-line breast cancer pivotal trials indicates that the therapeutic effect of Letrozole therapy is not impaired if Letrozole is administered immediately after tamoxifen.

Volume of Distribution

The volume of distribution of letrozole is 1.87L/kg.

Elimination Route

Letrozole is 99.9% orally bioavailable. A 2.5mg oral dose reaches a C_max of 104nmol/L with a T_max of 8.10h, and an AUC of 7387nmol*h/L.

Ribociclib is orally bioavailable, highly selective inhibitor of CDK4/6 kinases with inhibitory IC50 concentrations in the low nanomolar range. Following oral dosing, ribociclib was rapidly absorbed with median Tmax ranging from 1 to 5 hours. Plasma concentrations increased approximately 2- to 3-fold from Cycle 1 Day 1 to Cycle 1 Day 18/21 due to accumulation, with steady state reached by approximately Day 8 on the basis of trough concentrations after repeated daily dosing. Dose-proportionality analyses demonstrated that exposure to ribociclib increased with dose, with both Cmax and area under the curve (AUC) increasing slightly more than proportional to dose, over the dose range 50–1,200 mg/day

Half Life

The terminal elimination half life of letrozole is approximately 42h in healthy volunteers, but longer in breast cancer patients.

32.6 hours

Clearance

The average clearance after a single dose of letrozole was 1.52L/h and at steady state was 1.20L/h.

Elimination Route

Letrozole is 90% eliminated in the urine. 75% of the dose is recovered as a glucuronide metabolite, 9% is in the form of the ketone and carbinol metabolites, and 6% is recovered in urine as unchanged letrozole.

Pregnancy & Breastfeeding use

Pregnancy Category D. It is not known if Letrozole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Letrozole is administered to a nursing woman.

Contraindication

Letrozole may cause fetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. Letrozole is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Special Warning

Renal Impairment: No dosage adjustment is required for patients with renal impairment if creatinine clearance is 10 ml/min.

Hepatic Impairment: No dosage adjustment is recommended for patients with mild to moderate hepatic impairment. The dose of Letrozole in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50%. The recommended dose for such patients is 2.5 mg administered every other day.

Pediatric Use: The safety and effectiveness in pediatric patients have not been established.

Acute Overdose

Isolated cases of overdosage with Letrozole have been reported. No specific treatment for overdosage is known; treatment should be symptomatic and supportive.