Efavirenz/lamivudine/tenofovir

What is Efavirenz/lamivudine/tenofovir?

• Efavirenz/lamivudine/tenofovir (Symfi; Symfi Lo), is a three-drug combination of efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, and lamivudine (3TC) and tenofovir disoproxil fumarate (TDF), both nucleo(t)side reverse transcriptase inhibitors.

Efavirenz

Lamivudine

Tenofovir disoproxil fumarate

What are the uses of this medicine?

• Efavirenz/lamivudine/tenofovir (Symfi; Symfi Lo), tablets are a prescription medicine that is used without other antiretroviral medicines to treat Human Immunodeficiency Virus-1 (HIV-1) in adults and children weighing at least 88 pounds (40 kg).
• HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).
• Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets contains the prescription medicines efavirenz, lamivudine and tenofovir disoproxil fumarate.

How does this medicine work?

• Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are a fixed-dose combination of antiviral drugs EFV, 3TC, and TDF with antiviral activity against HIV-1.

Efavirenz:

• EFV is an NNRTI of HIV-1.
• EFV activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase (RT).
• HIV-2 RT and human cellular DNA polymerases α, β, γ, and δ are not inhibited by EFV.

Lamivudine:

• 3TC is a synthetic nucleoside analogue with activity against HIV-1 and HBV.
• Intracellularly, 3TC is phosphorylated to its active 5’-triphosphate metabolite, lamivudine triphosphate (3TC-TP).
• The principal mode of action of 3TC-TP is inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue.

Tenofovir Disoproxil Fumarate:

• TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate.
• TDF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate (TDF-DP), an obligate chain terminator.
• Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) and HBV RT by competing with the natural substrate deoxyadenosine 5’-triphosphate and, after incorporation into DNA, by DNA chain termination.
• Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.

Who Should Not Use this medicine ?

This medicine cannot be used in patients who:

• are allergic to efavirenz, lamivudine, tenofovir disoproxil fumarate, or any of the ingredients in efavirenz, lamivudine and tenofovir disoproxil fumarate tablets.
• are currently taking elbasvir and grazoprevir.

What drug interactions can this medicine cause?

• Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Be sure to mention any of the following:

• efavirenz, lamivudine and tenofovir are also available individually with the brand names of Sustiva, Epivir, Epivir-HBV (used to treat hepatitis B), Vemlidy (used to treat hepatitis B), and Viread, as well as in combination with other medications with brand names of Atripla, Biktarvy, Combivir, Complera, Descovy, Epzicom, Genvoya, Odefsey, Stribild, Symfi, Triumeq, Trizivir, and Truvada. Tell your doctor if you are taking any of these medications to be sure you do not receive the same medication twice.
• elbasvir/grazoprevir (Zepatier). Your doctor will probably tell you not to take efavirenz, lamivudine, and tenofovir if you are taking this medication.
• acyclovir (Sitavig, Zovirax); adefovir (Hepsera); aminoglycosides such as gentamicin; artemether/lumefantine (Coartem); aspirin and other nonsteroidal anti-inflammatory medications (NSAIDs) such as ibuprofen (Advil, Motrin) and naproxen (Aleve, Naprosyn); atorvastatin (Lipitor, in Caduet); atovaquone/proguanil (Malarone); bupropion (Forfivo, Wellbutrin, Zyban, others); calcium channel blockers such as diltiazem (Cardizem, Cartia, Diltzac, others), felodipine, nicardipine (Cardene), nifedipine (Adalat, Afeditab, Procardia), and verapamil (Calan, Verelan, in Tarka); carbamazepine (Carbatrol, Equetro, Tegretol, others); cidofovir; cyclosporine (Gengraf, Neoral, Sandimmune); ganciclovir (Cytovene); glecaprevir/pibrentasvir (Mavynet); itraconazole (Sporanox, Onmel); ketoconazole; ledipasvir/sofosbuvir (Harvoni); macrolide antibiotics such as clarithromycin (Biaxin, in Prevpac); methadone (Dolophine, Methadose); phenobarbital; phenytoin (Dilantin, in Phenytek); posaconazole (Noxafil); pravastatin (Pravachol);
• rifabutin (Mycobutin); rifampin (Rimactane, in Rifamate, Rifater); sertraline (Zoloft); simeprevir (Olyslo); simvastatin (Flolopid, Zocor, in Vytorin); sirolimus (Rapamune); sofosbuvir/velpatasvir (Epculsa); sofosbuvir/velpatasvir/voxilaprevir (Vosevi); sorbitol or medications that are sweetened with sorbitol; tacrolimus (Astagraf, Envarsus, Prograf); trimethoprim (Primsol, in Bactrim, Septra); valacyclovir (Valtrex); valganciclovir (Valcyte); and warfarin (Coumadin, Jantoven).
• St. John's wort.

Is this medicine FDA approved?

• The combination received tentative approval in the United States in 2014, and was granted approval in February 2018.
• Its availability and importance is supported by Medecins Sans Frontieres.
• It is available as a generic medication.

How should this medicine be used?

• Prior to initiation and during treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, patients should be tested for hepatitis B virus infection, and estimated creatinine clearance, urine glucose, and urine protein should be obtained.

Recommended dosage:

• One tablet taken orally once daily on an empty stomach, preferably at bedtime.
• Renal Impairment: Not recommended in patients with CrCL less than 50 mL/min or patients with end-stage renal disease requiring hemodialysis.
• Hepatic Impairment: Not recommended for patients with moderate or severe hepatic impairment. Use caution in patients with mild hepatic impairment.

Administration:

• Take efavirenz, lamivudine and tenofovir disoproxil fumarate tablets exactly as your healthcare provider tells you to take it.
• Take efavirenz, lamivudine and tenofovir disoproxil fumarate tablets 1 time each day, preferably at bedtime. Taking efavirenz, lamivudine and tenofovir disoproxil fumarate tablets at bedtime might help to make some of the side effects less bothersome.
• Take efavirenz, lamivudine and tenofovir disoproxil fumarate tablets on an empty stomach.
• Do not miss a dose of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets. If you miss a dose, take the missed dose as soon as you remember. If it is almost time for your next dose of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, do not take the missed dose. Take the next dose at your regular time.
• Stay under the care of your healthcare provider during treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate tablets.
• Do not run out of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.

What are the dosage forms and brand names of this medicine?

This medicine is available in fallowing doasage form:

• As Tablets: 600 mg efavirenz, 300 mg lamivudine and 300 mg tenofovir disoproxil fumarate (equivalent to 245 mg of tenofovir disoproxil).

This medicine is available in fallowing brand namesː

• Symfi; Symfi Lo

What side effects can this medication cause?

The most common side effects of this medicine include:

• trouble concentrating
• abnormal dreams
• headache
• nausea
• not feeling well
• tiredness
• nasal signs and symptoms
• diarrhea
• dizziness
• pain
• depression
• weakness
• cough

Less common,but serious side effects may include:

• Worsening of Hepatitis B virus infection
• lactic acidosis
• Severe liver problems
• New or worse kidney problems, including kidney failure
• Serious mental health problems
• Nervous system symptoms
• Skin reactions and allergic reactions
• pancreatitis

What special precautions should I follow?

• Severe acute exacerbations of hepatitis have been reported in patients who are infected with HBV or coinfected with HBV and HIV-1 and have discontinued 3TC and TDF, components of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets. Test patients with HIV-1 for hepatitis B virus (HBV) before initiating antiretroviral therapy. In patients with chronic hepatitis B, it is important to obtain HIV antibody testing prior to initiating 3TC and TDF, components of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets.
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness)
• Cases of acute renal failure and Fanconi syndrome, has been reported. Advise patients with impaired renal function (i.e., creatinine clearance less than 50 mL/min) or patients with end-stage renal disease (ESRD) requiring hemodialysis to avoid efavirenz, lamivudine and tenofovir disoproxil fumarate with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs) for patients
• Serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, psychosis-like symptoms and catatonia have been reported in patients receiving EFV. Advise patients to seek immediate medical evaluation if they experience severe psychiatric adverse experiences. Advise patients to inform their physician of any history of mental illness or substance abuse.
• Central nervous system symptoms (NSS) including dizziness, insomnia, impaired concentration, drowsiness, and abnormal dreams are commonly reported during the first weeks of therapy with EFV, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets. Dosing at bedtime may improve the tolerability of these symptoms, which are likely to improve with continued therapy. Alert patients to the potential for additive effects when used concomitantly with alcohol or psychoactive drugs. Instruct patients that if they experience NSS they should avoid potentially hazardous tasks such as driving or operating machinery.
• Inform patients that there is a risk of developing late-onset neurotoxicity, including ataxia and encephalopathy, which may occur months to years after beginning efavirenz therapy.
• Advise female patients that EFV, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets may cause fetal harm when administered during the first trimester to a pregnant woman. Advise females of reproductive potential to use effective contraception as well as a barrier method during treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate and for 12 weeks after discontinuation of use. Advise patients to contact their healthcare provider if they plan to become pregnant, become pregnant, or if pregnancy is suspected during treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate.
• Rash is a common side effect of EFV. Rashes usually go away without any change in treatment. However, since rash may be serious, patients should be advised to contact their physician promptly if rash occurs.
• Inform patients to watch for early warning signs of liver inflammation or failure, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice, confusion, abdominal swelling, and discolored feces and to consult their healthcare provider promptly if such symptoms occur.
• In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis. Advise patients or guardians to monitor pediatric patients for signs and symptoms of pancreatitis.
• Convulsions have been observed in patients receiving EFV, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, generally in patients with known medical history of seizures
• A component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets has resulted in increases in the concentration of total cholesterol and triglycerides.
• Inform patients that decreases in bone mineral density have been observed with the use of 3TC and TDF, components of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, in patients with HIV.
• Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started.
• Redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including efavirenz, lamivudine and tenofovir disoproxil fumarate, and that the cause and long-term health effects of these conditions are not known at this time
• Inform patients that it is important to take efavirenz, lamivudine and tenofovir disoproxil fumarate tablets once daily on a regular dosing schedule on an empty stomach, preferably at bedtime, and to avoid missing doses as it can result in development of resistance. Advise patients if a dose is missed, take it as soon as possible unless it is almost time for the next dose. Also advise patients that dosing at bedtime may improve the tolerability of nervous system symptoms.
• Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.

What to do in case of emergency/overdose?

Symptoms of overdose may include: Efavirenz overdose:

• nervous system symptoms
• involuntary muscle contractions

Management of overdosage:

• In case of overdose, call the poison control helpline of your country. In the United States, call 1-800-222-1222.

• Overdose related information is also available online at poisonhelp.org/help.
• In the event that the victim has collapsed, had a seizure, has trouble breathing, or can't be awakened, immediately call emergency services. In the United States, call 911.
• Treatment of overdose with EFV should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status.
• Administration of activated charcoal may be used to aid removal of unabsorbed drug.
• There is no specific antidote for overdose with efavirenz.
• Since efavirenz is highly protein bound, dialysis is unlikely to significantly remove the drug from blood.
• There is no known specific treatment for overdose with 3TC.

If overdose occurs, the patient should be monitored and standard supportive treatment applied as required because a negligible amount of 3TC was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a 3TC overdose event.

• Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir disoproxil fumarate, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

Can this medicine be used in pregnancy?

• Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets may harm your unborn baby.
• You should not become pregnant during treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate tablets. Tell your healthcare provider right away if you think you may be pregnant or become pregnant during treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate tablets.
• Females who are able to become pregnant should use effective birth control during treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate tablets and for 12 weeks after stopping treatment. A barrier form of birth control should always be used along with another type of birth control.
• If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start efavirenz, lamivudine and tenofovir disoproxil fumarate tablets.
• There is a pregnancy registry for women who take efavirenz, lamivudine and tenofovir disoproxil fumarate tablets during pregnancy.

Can this medicine be used in children?

• The safety and effectiveness of efavirenz, lamivudine and tenofovir disoproxil fumarate as a fixed-dose tablet in pediatric patients infected with HIV-1 and weighing at least 40 kg have been established.

What are the active and inactive ingredients in this medicine?

• Active ingredients: efavirenz USP, lamivudine USP, and tenofovir disoproxil fumarate
• Inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, pregelatinized starch, polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, talc and titanium dioxide.

Who manufactures and distributes this medicine?

Manufactured for:

• Laurus Generics Inc.
• 400 Connell Drive
• Suite 5200
• Berkeley Heights, NJ

Manufactured by:

• Laurus Labs Limited
• Visakhapatnam
• India

What should I know about storage and disposal of this medication?

• Store efavirenz, lamivudine and tenofovir disoproxil fumarate tablets at 20° to 25°C (68° to 77°F).
• Keep efavirenz, lamivudine and tenofovir disoproxil fumarate tablets in the original container.]

• Dailymed label info on Efavirenz/lamivudine/tenofovir
• FDA Efavirenz/lamivudine/tenofovir

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