Farydak Side Effects, Cost, Dosage, FDA Approval and Prescribing Information for Multiple Myeloma | Wing (Bernadette) Cheung, PharmD | RxEconsult
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Farydak (panobinostat) Side Effects, Cost, Dosing, Approval and Prescribing Information for Multiple Myeloma Category: Cancer by - April 14, 2015 | Views: 21580 | Likes: 0 | Comment: 0  

Farydak for multiple myeloma

Brand Name: Farydak
Generic Name: panobinostat

Drug Class: Histone deacetylase inhibitor
Manufacturer: Novartis Pharmaceuticals
FDA Approval Date: February 2015

What is Farydak and its mechanism of action?

Farydak is a histone deacetylase (HDAC) inhibitor. Normally, DNA wraps around histone proteins. When acetylated, DNA is less structurally condensed, leaving room for transcription complexes to attach and start making more copies of the DNA. HDACs are responsible for removing these acetyl groups from DNA, leading to more densely packed DNA that a is less accessible for transcription complexes and fewer copies of DNA are made. Although the exact mechanism of HDAC’s anti-tumor activity is unknown, it is thought that by blocking the HDAC, HDAC inhibitors are able to increase the transcription of a protein called p21. The p21 protein is responsible for promoting cell cycle arrest. As more p21 proteins are made, the overgrowth of cancerous cells is slowed and cell death ultimately occurs. Cancerous cells are more sensitive to HDAC inhibitors than normal cells.

What is Farydak used for treating?

Farydak is combined with bortezomib and dexamethasone for the treatment of multiple myeloma. Patients must have received at least 2 prior treatments with bortezomib and an immunomodulatory agent.

Multiple myeloma is a type of cancer that occurs in white blood cells. When plasma cells grow uncontrollably and become cancerous, tumors called plasmacytomas are formed. Most cases evolve into multiple myeloma. According to the National Cancer Institute, there are  24,050 estimated new cases and 11,090 estimated deaths caused by multiple myeloma in 2014. The lifetime risk of acquiring  multiple myeloma is 1 in 143 (0.7%). 

How effective is Farydak for treating multiple myeloma?

In a clinical study in patients with relapsed multiple myeloma and 1 to 3 prior lines of therapy, 768 patients were randomly assigned to receive either the combination of Farydak 20 mg orally, bortezomib 1.3mg/m2 IV, and dexamethasone 20 mg orally or the combination of placebo with bortezomib 1.3mg/m2 IV, and dexamethasone 20 mg orally. Treatment was administered 3 times per week in Weeks 1 and 2 of each 21-day cycle, for a maximum of 16 cycles (48 weeks). 

  • The median progression-free survival (PFS) was 12 months for the Farydak group versus 8.1 months for the placebo group.
  • The PFS was measured using modified European Bone Marrow Transplant Group (EBMT) criteria. This is a widely used response criteria that assesses the efficacy of therapy for multiple myeloma.
  • In a subgroup of patients with prior treatment to both bortezomib and an immunomodulatory agent, the overall response rate was 58.5% for the Farydak group and 41.4% for the placebo group.

Interesting facts about Farydak?

  • Farydak is the first HDAC inhibitor approved to treat multiple myeloma.
  • Patients are required to enroll in a Risk Evaluation and Mitigation Strategy (REMS) to manage the risks associated with Farydak.
  • Farydak was approved under FDA’s accelerated approval program, which allows earlier patient access while confirmatory clinical trials are being done.
  • It is important to avoid eating star fruit, pomegranate or pomegranate juice, and grapefruit or grapefruit juice because they may affect the concentration of Farydak.

What are side effects of Farydak?

Common adverse reactions with at least 20% of incidence include diarrhea, fatigue, nausea, swelling, decreased appetite, fever, and vomiting. Farydak also causes abnormal heart rhythm, bleeding, bone marrow suppression  and increases the risk of infections. Bone marrow suppression causes reduced number of platelets (thrombocytopenia), red blood cells (anemia), and while blood cells (neutropenia).  

What is the dosage of Farydak?

  • Farydak is available as 10 mg light green capsules, 15 mg orange capsules, and  20 mg red capsules in blister packs.
  • The recommended dose is 20 mg orally once every other day (3 doses per week) specifically on days 1, 3, 5, 8, 10, and 12 of Weeks 1 and 2 of each 21-day cycle, in combination with bortezomab injection and dexamethasone, for a  total of 8 cycles. Additional 8 cycles may be considered for patients  who may benefit from it.
  • Dose reductions may be warranted in patients with mild to moderate hepatic impairment, drug interactions, or are experiencing serious side effects.
  • Store Farydak at room temperature between 68°F to 77°F (20°C to 25°C) in its original carton.

Farydak drug interactions

Farydak is metabolized by CYP3A4 enzymes. CYP3A4 is a group of liver enzymes that breakdown medications, including Farydak. Therefore, any drug that inhibits or increases the activity of CYP3A4 enzymes will affect the concentration of Farydak in the body. Strong CYP3A4 inhibitors  will increase the concentration of Farydak in the body. Examples of such drugs are clarithromycin, indinavir, itraconazole, and ketoconazole. Star fruit, pomegranate or pomegranate juice, and grapefruit or grapefruit juice may also inhibit CYP3A4 and affect the concentration of Farydak. It is important to reduce the starting dose of Farydak to 10 mg when used with such medications.

Strong CYP3A4 inducers  will reduce the concentration and effectiveness of Farydak. Examples of such drugs include carbamazepine, phenytoin, and rifampin. Avoid concomitant use of Farydak with these medications.

Farydak also inhibits CYP2D6 causing an increase in concentration of drugs broken down by CYP2D6 enzymes. Patients should consult their doctor or pharmacist before using Farydak or starting any new medications while taking Farydak.

Anti-arrhythmic drugs, such as amiodarone, procainamide, quinidine, or medications that can affect heart rhythm , such as clarithromycin, methadone, moxifloxacin, should not be combined with Farydak.

What are warnings and precautions for Farydak?

Farydak can cause serious side effects. It is important for patients to contact their healthcare providers immediately  if any of the following side effects occur:

  • Diarrhea: stomach cramps, loose stool, or dehydration.
  • Cardiac toxicity: chest pain, faster or slower heartbeat, feeling lightheaded, blue colored lips, shortness of breath, or swelling in the legs.
  • Hemorrhage: blood in stools or black stools, pink or brown urine, unexpected or uncontrollable bleeding, blood in vomit  or coffee-ground-like vomit, increased bruising, feeling dizzy or weak, confusion, change in speech, or persistent headache. 
  • Myelosuppression : low platelet count, low white cell count, or low red blood cell count.
  • Infections: cough, flu-like symptoms, blood in phlegm, shortness of breath, warm or painful areas on body.
  • Liver toxicity: tiredness or weakness, loss of appetite, dark amber colored urine, upper stomach pain, yellowing of skin or whites of the eyes are sings and symptoms of liver toxicity. 
  • Embryo-Fetal Toxicity: fetal malformations and anomalies such as cleft palate, short tail and extra ribs may occur if used during pregnancy.

Can pregnant women take Farydak?

Farydak can cause birth defects. Women should avoid becoming pregnant while taking Farydak. They should use effective contraception while taking Farydak and for at least 1 month after the last dose of Farydak. Also, it is important to advise sexually active men to use condoms while on treatment and for 3 months after their last dose of Farydak.

It is not known whether Farydak will pass into breast milk. Women should be discontinue breast-feeding or discontinue Farydak.

What is the cost of Farydak?

The average wholesale price for each pill is $1,372.00. Novartis, the manufacturer of Farydak, offers patient co-pay assistance and a patient access program to help eligible patients with the cost of treatment. Visit Novartis Patient Assistance Now for more information. 

References

Abbas, Tarek, and Anindya Dutta. P21 In Cancer: Intricate Networks and Multiple Activities. Nature Reviews Cancer 9.6 (2009): 400-14.

 

Farydak Prescribing Information (Package Insert). East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.

 

Kim, Hyun-Jung, and Suk-Chul Bae. Histone Deacetylase Inhibitors: Molecular Mechanisms of Action and Clinical Trials As Anti-Cancer Drugs. American Journal of Translational Research 3.2 (2010): 166-79.

 

Multiple Myeloma. MedlinePlus. U.S. National Library of Medicine

 

Rachid, Baz. Multiple Myeloma. Cleveland Clinic. 1 Jan. 2009.

 

Stephanie, Liou. Histones and HDAC Inhibitors. Histones and HDAC Inhibitors. Huntington's Outreach Project For Education, At Stanford, 30 June 2010.

 

Surveillance, Epidemiology, and End Results Program: Turning Cancer Data Into Discovery. National Cancer Institute.

 

U.S. Food and Drug Administration. FDA Approves Farydak for Treatment of Multiple Myeloma.

 

What Is Multiple Myeloma? American Cancer Society.

 

Editor: Karine Wong, PharmD



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