jueves, 8 de febrero de 2018

FDA Approves BIKTARVY (Fixed Dose Combination)

U.S. Food and Drug Administration Header

On February 7, 2018, FDA approved BIKTARVY (bictegravir, emtricitabine, and tenofovir alafenamide) which is a three drug fixed dose combination tablet indicated as a complete regimen for the treatment of HIV-1 infection in adults who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 3 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of BIKTARVY.

Highlights from the product labeling include the following:

DOSAGE AND ADMINISTRATION
  • Testing: Prior to or when initiating BIKTARVY test for hepatitis B virus infection. Prior to or when initiating BIKTARVY, and during treatment, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients as clinically appropriate. In patients with chronic kidney disease, also assess serum phosphorus.
  • Recommended dosage: One tablet taken once daily with or without food.
  • Renal impairment: BIKTARVY is not recommended in patients with estimated creatinine clearance below 30 mL per minute.
  • Hepatic impairment: BIKTARVY is not recommended in patients with severe hepatic impairment.
CONTRAINDICATIONS

BIKTARVY is contraindicated to be co-administered with:
  • dofetilide
  • rifampin
WARNINGS AND PRECAUTIONS
  • Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV
    • The BIKTARVY label also includes a Box Warning regarding Post Treatment Acute Exacerbation of Hepatitis B
  • Risk of adverse reactions or loss of virologic response due to drug interactions
  • Immune reconstitution syndrome: May necessitate further evaluation and treatment.
  • New onset or worsening renal impairment: Assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein when initiating BIKTARVY and during therapy as clinically appropriate in all patients. Also assess serum phosphorus in patients with chronic kidney disease.
  • Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.
ADVERSE REACTIONS

Most common adverse reactions (incidence greater than or equal to 5%, all grades) are diarrhea, nausea, and headache.

Clinical Trials in Adults with No Antiretroviral Treatment History

The primary safety assessment of BIKTARVY was based on Week 48 data from two randomized, double-blind, active-controlled trials, Trial 1489 and Trial 1490, that enrolled 1274 HIV-1 infected adult subjects with no antiretroviral treatment history. A total of 634 subjects received one tablet of BIKTARVY once daily [see Clinical Studies (14.2)].
The most common adverse reactions (all Grades) reported in at least 5% of subjects in the BIKTARVY group in either Trial 1489 or Trial 1490 were diarrhea, nausea, and headache. The proportion of subjects who discontinued treatment with BIKTARVY, abacavir [ABC]/dolutegravir [DTG]/ lamivudine [3TC]), or DTG + FTC/TAF, due to adverse events, regardless of severity, was 1%, 1%, and < 1%, respectively. Table 1 displays the frequency of adverse reactions (all Grades) greater than or equal to 2% in the BIKTARVY group.

Table 1           Adverse Reactionsa (All Grades) Reported in ≥ 2% of HIV-1 Infected Adults with No Antiretroviral Treatment History Receiving BIKTARVY in Trials 1489 or 1490 (Week 48 analysis)


 
 Trial 1489Trial 1490
Adverse ReactionsBIKTARVY
N=314
ABC/DTG/3TC
N=315
BIKTARVY
N=320
DTG + FTC/TAF
N=325
Diarrhea6%4%3%3%
Nausea5%17%3%5%
Headache5%5%4%3%
Fatigue3%3%2%2%
Abnormal dreams3%3%< 1%1%
Dizziness2%3%2%1%
Insomnia2%3%2%< 1%

a Frequencies of adverse reactions are based on all adverse events attributed to trial drugs by the investigator. No adverse reactions of Grade 2 or higher occurred in ≥ 1% of subjects treated with BIKTARVY.

Additional adverse reactions (all Grades) occurring in less than 2% of subjects administered BIKTARVY in Trials 1489 and 1490 included vomiting, flatulence, dyspepsia, abdominal pain, rash, and depression.

Suicidal ideation, suicide attempt, and depression suicidal occurred in < 1% of subjects administered BIKTARVY; all events were serious and primarily occurred in subjects with a preexisting history of depression, prior suicide attempt or psychiatric illness.

The majority (87%) of adverse events associated with BIKTARVY were Grade 1.

Clinical Trials in Virologically Suppressed Adults

The safety of BIKTARVY in virologically-suppressed adults was based on Week 48 data from 282 subjects in a randomized, double-blind, active-controlled trial (Trial 1844) in which virologically-suppressed subjects were switched from either DTG + ABC/3TC or ABC/DTG/3TC to BIKTARVY; and Week 48 data from 290 subjects in an open-label, active-controlled trial in which virologically-suppressed subjects were switched from a regimen containing atazanavir (ATV) (given with cobicistat or ritonavir) or darunavir (DRV) (given with cobicistat or ritonavir) plus either FTC/TDF or ABC/3TC, to BIKTARVY (Trial 1878). Overall, the safety profile in virologically suppressed adult subjects in Trials 1844 and 1878 was similar to that in subjects with no antiretroviral treatment history [see Clinical Studies (14.3)].

Laboratory Abnormalities

The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving BIKTARVY in Trials 1489 and 1490 are presented in Table 2.

Table 2   Laboratory Abnormalities (Grades 3–4) Reported in ≥ 2% of Subjects Receiving BIKTARVY in Trials 1489 or 1490 (Week 48 analysis)
 Trial 1489Trial 1490
Laboratory Parameter AbnormalityaBIKTARVY
N=314
ABC/DTG/3TC
N=315
BIKTARVY
N=320
DTG + FTC/TAFN=325
Amylase (> 2.0 x ULN)2%2%2%2%
ALT (> 5.0 × ULN)1%1%2%1%
AST  (> 5.0 × ULN)2%1%1%3%
Creatine Kinase (≥10.0 × ULN)4%3%4%2%
Neutrophils (< 750 mm3)2%3%2%1%
LDL-cholesterol (fasted) (> 190 mg/dL)2%3%3%3%
ULN = Upper limit of normal
a Frequencies are based on treatment-emergent laboratory abnormalities.

Changes in Serum Creatinine: BIC has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology (12.2)]. Increases in serum creatinine occurred by Week 4 of treatment and remained stable through Week 48. In Trials 1489 and 1490, median (Q1, Q3) serum creatinine increased by 0.10 (0.03, 0.17) mg per dL from baseline to Week 48 in the BIKTARVY group and was similar to the comparator groups who received ABC/DTG/3TC, or DTG + FTC/TAF.  There were no discontinuations due to renal adverse events through Week 48 in BIKTARVY clinical trials.

Changes in Bilirubin: In Trials 1489 and 1490, total bilirubin increases were observed in 12% of subjects administered BIKTARVY through Week 48.  Increases were primarily Grade 1 (1.0 to 1.5 x ULN) (9%) and Grade 2 (1.5 to 2.5 x ULN) (3%).  Graded bilirubin increases in the ABC/DTG/3TC, and DTG + FTC/TAF groups, were 4% and 6%, respectively. Increases were primarily Grade 1 (3% ABC/DTG/3TC and 5% DTG + FTC/TAF) or Grade 2 (1% ABC/DTG/3TC and 1% DTG + FTC/TAF). There were no discontinuations due to hepatic adverse events through Week 48 in BIKTARVY clinical studies.

DRUG INTERACTIONS

Other Antiretroviral Medications

Because BIKTARVY is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended [see Indications and Usage (1)]. Comprehensive information regarding potential drug-drug interactions with other antiretroviral medications is not provided because the safety and efficacy of concomitant HIV-1 antiretroviral therapy is unknown.

Potential for BIKTARVY to Affect Other Drugs

BIC inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1)in vitro. Coadministration of BIKTARVY with drugs that are substrates of OCT2 and MATE1 (e.g., dofetilide) may increase their plasma concentrations (see Table 3).

Potential Effect of Other Drugs on One or More Components of BIKTARVY

BIC is a substrate of CYP3A and UGT1A1. A drug that is a strong inducer of CYP3A and also an inducer of UGT1A1 can substantially decrease the plasma concentrations of BIC which may lead to loss of therapeutic effect of BIKTARVY and development of resistance [see Clinical Pharmacology (12.3)].
The use of BIKTARVY with a drug that is a strong inhibitor of CYP3A and also an inhibitor of UGT1A1 may significantly increase the plasma concentrations of BIC (see Table 3).
TAF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Co-administration of drugs that inhibit  P-gp and BCRP may increase the absorption and plasma concentrations of TAF [see Clinical Pharmacology (12.3)]. Co-administration of drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF, which may lead to loss of therapeutic effect of BIKTARVY and development of resistance (see Table 3).

Drugs Affecting Renal Function 

Because FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of BIKTARVY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of FTC, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.4)].

Established and Potentially Significant Drug Interactions 

Table 3 provides a listing of established or potentially  clinically significant drug interactions with recommended prevention or management strategies. The drug interactions described are based on studies conducted with either BIKTARVY, the components of BIKTARVY (BIC, FTC, and TAF) as individual agents, or are drug interactions that may occur with BIKTARVY [see Contraindications (4), Warnings and Precautions (5.2), and Clinical Pharmacology (12.3)].

 
The updated label will soon be available at drugs@fda or DailyMed
 
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
 
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
 
Visit the FDA Patient Network for more Information about the HIV Liaison Program 

4 comentarios:

  1. I was diagnosed of hepatitis b in 2012,I have tried all possible means to get cure but all my effort proved abortive, until a friend of mine introduced me to a herbal doctor from Africa,Dr Eveoko who prepare herbal medicine to cure all kind of diseases including hepatitis b virus (HBV), CANCER. ALS Hepatitis A,B/C, fertility spell, Herpes HIV and all types of STDs Infections, when i contacted this herbal doctor via his email: eveokoherbalhome@gmail.com he sent me hepatitis b herbal medicine via courier service, when I received the herbal medicine through DHL Postal courier service, he gave me the step by step instructions on how to use it. when i make used of it as instructed by him,i was totally cured from the virus within 10 days of usage. i recomment this great Dr to anyone who is seeking for cure to his\her Ailment Indeed he is a very good man, Contact this great herbal doctor . whats-app him with: +2348022010422. you can also reach me at austincalnor@gmail.com

    ResponderEliminar
  2. AS FAR AS HERBAL MEDICINE IS CONCERNED ALL DISEASE AND VIRUS CAN BE CURED WITHOUT ANY SIDE EFFECT,I READ A BLOG ON HOW DR.Kennedy Allalhye HAS BEEN CURING ALL KINDS OF STD AND DEADLY DISEASE LIKE HIV/AIDS,HERPES SIMPLEX VIRUS,DIABETES,Epstein barr,CANCER,AND LOTS MORE WITH HIS HERBAL REMEDY (HERBAL MEDICATION),I CONFIRMED THE HIS POWERFUL MEDICATION WHEN I HAD HSV 2 OUR YEARS AGO,WHEN I CAME ACROSS HIS TESTIMONIALS ON PEOPLE MAKING APPRECIATION TO HIM I CONTACTED HIM VIA HIS MAIL (dr.allalhyehomeofsolution@yahoo.com) HE POSTED HIS HERBS TO MY ADDRESS AND I WAS FULLY CURED AFTER FOLLOWING HIS PRESCRIPTIONS ON HOW TO USE THE MEDICINE AND NOW TO GOD BE THE GLORY AM HERPES SIMPLEX NEGATIVE KINDLY CONTACT HIM NOW FOR YOUR CURE ON HIS EMAIL.HE IS A VERY GOOD AND HONEST MAN TO WORK WITH CONTACT HIM AND THANK ME LATER (dr.allalhyehomeofsolution@yahoo.com) GOOD LUCK .

    ResponderEliminar
  3. I am bold enough among many others to state that there is now a potent cure to this sickness but many are unaware of it. I discovered that I was infected with the virus 3 months ago, after a medical check-up. My doctor told me and I was shocked, confused and felt like my world has crumbled. I was dying slowly due to the announcement of my medical practitioner but he assured me that I could leave a normal life if I took my medications (as there was no medically known cure to Herpes). I went from churches to churches but soon found that my case needed urgent attention as I was growing lean due to fear of dying anytime soon. In a bid to look for a lasting solution to my predicament, I sought for solutions from the herbal world. I went online and searched for every powerful trado-medical practitioner that I could severe, cos I heard that the African Herbs had a cure to the Herpes syndrome. It was after a little time searching the web that I came across one Dr Itua(A powerful African Herbal Doctor), who offered to help me at a monetary fee. I had to comply as this was my final bus-stop to receiving a perfect healing. My last resolve was to take my life by myself, should this plan fail. At last it worked out well. He gave me some steps to follow and I meticulously carried out all his instructions. Last month, to be precise, I went back to the hospital to conduct another test and to my amazement, the results showed that negative,Dr Itua Can As Well Cure The Following Desease…Cancer,Hiv,Herpes, Hepatitis B,Liver Inflammatory,Diabetis,Fribroid,Get Your Ex Back, You can free yourself of this Herpes virus by consulting this great African Herbal Doctor via this e-mail: drituaherbalcenter@gmail.com or call and whatsapp him on +2348149277967 He will help you and his herb medication is sure. he has the cure on all disease .You can talk to me on INSTAGRAM..tashamoore219....

    ResponderEliminar
  4. My life is beautiful thanks to you, Mein Helfer. Lord Jesus in my life as a candle light in the darkness. You showed me the meaning of faith with your words. I know that even when I cried all day thinking about how to recover, you were not sleeping, you were dear to me. I contacted the herbal center Dr Itua, who lived in West Africa. A friend of mine here in Hamburg is also from Africa. She told me about African herbs but I was nervous. I am very afraid when it comes to Africa because I heard many terrible things about them because of my Christianity. god for direction, take a bold step and get in touch with him in the email and then move to WhatsApp, he asked me if I can come for treatment or I want a delivery, I told him I wanted to know him I buy ticket in 2 ways to Africa To meet Dr. Itua, I went there and I was speechless from the people I saw there. Patent, sick people. Itua is a god sent to the world, I told my pastor about what I am doing, Pastor Bill Scheer. We have a real battle beautifully with Spirit and Flesh. Adoration that same night. He prayed for me and asked me to lead. I spent 2 weeks and 2 days in Africa at Dr Itua Herbal Home. After the treatment, he asked me to meet his nurse for the HIV test when I did it. It was negative, I asked my friend to take me to another nearby hospital when I arrived, it was negative. I was overwhite with the result, but happy inside of me. We went with Dr. Itua, I thank him but I explain that I do not have enough to show him my appreciation, that he understands my situation, but I promise that he will testify about his good work. Thank God for my dear friend, Emma, I know I could be reading this now, I want to thank you. And many thanks to Dr. Itua Herbal Center. He gave me his calendar that I put on my wall in my house. Dr. Itua can also cure the following diseases ... Cancer, HIV, Herpes, Hepatitis B, Inflammatory Liver, Diabetis, Fribroid,Parkinson's disease,Inflammatory bowel disease ,Fibromyalgia, recover your ex. You can contact him by email or whatsapp, @ .. drituaherbalcenter@gmail.com, phone number .. + 2348149277967 .. He is a good doctor, talk to him kindly. I'm sure he will also listen to you.

    ResponderEliminar