TENOFOVIR DISOPROXIL FUMARATE (Page 9 of 10)

14.5 Clinical Trial Results in Pediatric Subjects with Chronic Hepatitis B

Pediatric Subjects 12 Years to less than 18 Years of Age with Chronic HBV

In Trial 115, 106 HBeAg negative (9%) and positive (91%) subjects aged 12 to less than 18 years with chronic HBV infection were randomized to receive blinded treatment with tenofovir disoproxil fumarate 300 mg (N=52) or placebo (N=54) for 72 weeks. At trial entry, the mean HBV DNA was 8.1 log10 copies/mL and mean ALT was 101 U/L. Of 52 subjects treated with tenofovir disoproxil fumarate, 20 subjects were nucleos(t)ide naïve and 32 subjects were nucleos(t)ide-experienced. Thirty-one of the 32 nucleos(t)ide-experienced subjects had prior lamivudine experience. At Week 72, 88% (46/52) of subjects in the tenofovir disoproxil fumarate group and 0% (0/54) of subjects in the placebo group had HBV DNA <400 copies/mL (69 IU/mL). Among subjects with abnormal ALT at baseline, 74% (26/35) of subjects receiving tenofovir disoproxil fumarate had normalized ALT at Week 72 compared to 31% (13/42) in the placebo group. One tenofovir disoproxil fumarate treated subject experienced sustained HBsAg-loss and seroconversion to anti-HBs during the first 72 weeks of trial participation.

In Trial 115, sequencing data from paired baseline and on treatment HBV isolates from subjects who received VIREAD were available for 14 of 15 subjects who had plasma HBV DNA ≥400 copies/mL. No amino acid substitutions associated with resistance to VIREAD were identified in these isolates by Week 72 (Trial 115).

Pediatric use information is approved for Gilead Sciences, Inc.’s VIREAD® (tenofovir disoproxil fumarate) tablets. However, due to Gilead Sciences, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

16 HOW SUPPLIED/STORAGE AND HANDLING

Tablets

Tenofovir Disoproxil Fumarate Tablets 300 mg are white circular film-coated convex tablets containing 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil, engraved TDF on one side and plain on other side and are available in a 40 cc/ 50 cc HDPE container containing a desiccant (silica gel sachet) and closed with child-resistant screw cap.

NDC 50268-758-12 (10 tablets per card, 2 cards per carton).

Store tenofovir disoproxil fumarate tablets at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Keep the bottle tightly closed. Dispense only in original container. Do not use if seal over bottle opening is broken or missing.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Severe Acute Exacerbation of Hepatitis B in Patients Infected with HBV

Inform patients that severe acute exacerbations of hepatitis B have been reported in patients infected with hepatitis B virus (HBV) and have discontinued tenofovir disoproxil fumarate. Advise patients not to discontinue tenofovir disoproxil fumarate without first informing their healthcare provider. All patients should be tested for HBV infection before or when starting tenofovir disoproxil fumarate and those who are infected with HBV need close medical follow-up for several months after stopping tenofovir disoproxil fumarate to monitor for exacerbations of hepatitis [see Warnings and Precautions (5.1)].

New Onset or Worsening Renal Impairment

Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of tenofovir disoproxil fumarate. Advise patients to avoid tenofovir disoproxil fumarate with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs) [see Warnings and Precautions (5.2)]. The dosing interval of tenofovir disoproxil fumarate may need adjustment in HIV-1 infected patients with renal impairment.

Immune Reconstitution Syndrome

Inform patients that in some patients with advanced HIV infection (AIDS) signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body’s immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection [see Warnings and Precautions (5.4)].

Bone Loss and Mineralization Defects

Inform patients that decreases in bone mineral density have been observed with the use of tenofovir disoproxil fumarate. Consider bone monitoring in patients who have a history of pathologic bone fracture or at risk for osteopenia [see Warnings and Precautions (5.5)].

Lactic Acidosis and Severe Hepatomegaly

Inform patients that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with tenofovir disoproxil fumarate should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.6)].

Drug Interactions

Advise patients that tenofovir disoproxil fumarate may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other medication, including other HIV drugs and drugs for treatment of hepatitis C virus [see Warnings and Precautions (5.7) and Drug Interactions (7)].

Dosing Recommendations

Inform patients that it is important to take tenofovir disoproxil fumarate on a regular dosing schedule with or without food and to avoid missing doses as it can result in development of resistance [see Dosage and Administration (2)].

Pregnancy Registry

Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to tenofovir disoproxil fumarate [see Use in Specific Populations (8.1)].

Lactation

Instruct mothers not to breastfeed if they are taking tenofovir disoproxil fumarate for the treatment of HIV-1 infection because of the risk of passing the HIV-1 virus to the baby [see Use in Specific Populations (8.2)].

Treatment Duration

Advise patients that in the treatment of chronic hepatitis B, the optimal duration of treatment is unknown. The relationship between response and long-term prevention of outcomes such as hepatocellular carcinoma is not known.

Manufactured for:

AvKARE

Pulaski, TN 38478

Mfg. Rev. 12/19

AV 03/20 (P)

VIREAD, ATRIPLA, COMPLERA, EPCLUSA, HARVONI, HEPSERA, SOVALDI, STRIBILD, TRUVADA and all other trademarks referenced herein are the property of their respective owners.

PATIENT MEDICATION INFORMATION SECTION

Tenofovir Disoproxil Fumarate Tablets

( ten of’ oh vir )

Read this Patient Information before you start taking tenofovir disoproxil fumarate tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about tenofovir disoproxil fumarate tablets?

Tenofovir disoproxil fumarate tablets can cause serious side effects, including:

• Worsening of Hepatitis B virus infection (HBV). Your healthcare provider will test you for HBV and HIV before starting treatment with Tenofovir Disoproxil Fumarate. If you have HBV infection and take tenofovir disoproxil fumarate your HBV may get worse (flare- up) if you stop taking tenofovir disoproxil fumarate . A “flare-up” is when your HBV infection suddenly returns in a worse way than before.
  • Do not run out tenofovir disoproxil fumarate tablet Refill your prescription or talk to your healthcare provider before your tenofovir disoproxil fumarate tablets are all gone.
  • Do not stop taking tenofovir disoproxil fumarate tablet without first talking to your healthcare provider.
  • If you stop taking tenofovir disoproxil fumarate, your healthcare provider will need to check your health often and do blood tests regularly to check your HBV infection. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking tenofovir disoproxil fumarate tablet.

For more information about side effects, see “What are the possible side effects of tenofovir disoproxil fumarate?”

What is tenofovir disoproxil fumarate tablet?

Tenofovir disoproxil fumarate tablet is a prescription medicine used to:

• treat HIV-1 infection when used with other anti-HIV-1 medicines in adults and children 2 years of age and older who weigh at least 22 pounds (10 kg). HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).
• treat HBV infection in adults and children 12 years of age and older who weigh at least 22 pounds (10 kg). It is not known if Tenofovir Disoproxil Fumarate is safe and effective in children under 2 years of age.

What should I tell my healthcare provider before taking tenofovir disoproxil fumarate tablet?

Before you take tenofovir disoproxil fumarate tablet, tell your healthcare provider about all of your medical conditions, including if you:

• have liver problems, including hepatitis B (HBV) infection
• have kidney problems or receive kidney dialysis treatment
• have bone problems
• have HIV infection
• are pregnant or plan to become pregnant. Tell your healthcare provider if you become pregnant during treatment with tenofovir disoproxil fumarate

Pregnancy Registry. There is a pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.

• are breastfeeding or plan to breastfeed. tenofovir disoproxil fumarate can pass to your baby in your breast milk.
  • Do not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.
  • If you take tenofovir disoproxil fumarate for treatment of HBV infection, talk with your healthcare provider about the best way to feed your baby.

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

Some medicines may interact with Tenofovir Disoproxil Fumarate. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

• You can ask your healthcare provider or pharmacist for a list of medicines that interact with tenofovir disoproxil fumarate.
• Do not start a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take tenofovir disoproxil fumarate with other medicines.

How should I take tenofovir disoproxil fumarate tablet?

• Take tenofovir disoproxil fumarate tablet exactly as your healthcare provider tells you to take it.
• Do not change your dose or stop taking tenofovir disoproxil fumarate without first talking with your healthcare provider. Stay under a healthcare provider’s care when taking tenofovir disoproxil fumarate.
• Take tenofovir disoproxil fumarate tablet at the same time every day.
• For adults and children 2 years of age and older who weigh at least 77 pounds (35 kg), the usual dose of tenofovir disoproxil fumarate. is one 300 mg tablet each day.
• For children 2 years of age and older who weigh between 37 pounds (17 kg) and 77 pounds (35 kg), your healthcare provider will prescribe the right dose of tenofovir disoproxil fumarate tablets based on your child’s body weight.
• Tell your healthcare provider if you or your child has problems with swallowing tablets.
• If your healthcare provider prescribes tenofovir disoproxil fumarate. powder for you or your child, see the “Instructions for Use” that comes with your Tenofovir Disoproxil Fumarate powder for information about the right way to measure and take tenofovir disoproxil fumarate. powder.
• Take tenofovir disoproxil fumarate. tablets by mouth, with or without food.
• Do not miss a dose of tenofovir disoproxil fumarate. Missing a dose lowers the amount of medicine in your blood. Refill your tenofovir disoproxil fumarate. prescription before you run out of medicine.
• If you take too much tenofovir disoproxil fumarate tablet, call your local poison control center or go right away to the nearest hospital emergency room.

What are the possible side effects of tenofovir disoproxil fumarate tablet?

Tenofovir disoproxil fumarate tablet may cause serious side effects, including:

• See “What is the most important information I should know about tenofovir disoproxil fumarate tablet?
• New or worse kidney problems, including kidney failure. Your healthcare provider should do blood and urine tests to check your kidneys before you start and during treatment with tenofovir disoproxil fumarate. Your healthcare provider may tell you to take tenofovir disoproxil fumarate less often, or to stop taking tenofovir disoproxil fumarate if you get new or worse kidney problems.
• Changes in your immune system (Immune Reconstitution Syndrome) can happen when an HIV-1 infected person starts taking HIV medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after starting your tenofovir disoproxil fumarate for the treatment of HIV-1 infection.
• Bone problems can happen in some children or adults who take tenofovir disoproxil fumarate . Bone problems include bone pain, softening or thinning of bones,which may lead to fractures. Your healthcare provider may need to do tests to check your bones or your child’s bones
• Too much lactic acid in your blood (lactic acidosis). Too much lactic acid is a serious but rare medical emergency that can lead to death. Tell your healthcare provider right away if you get these symptoms: weakness or being more tired than usual, unusual muscle pain, being short of breath or fast breathing, stomach pain with nausea and vomiting, cold or blue hands and feet, feel dizzy or lightheaded, or a fast or abnormal heartbeat.
• Severe liver problems. In rare cases, severe liver problems can happen that can lead to death. Tell your healthcare provider right away if you get these symptoms: skin or the white part of your eyes turns yellow, dark “tea-colored” urine, light-colored stools, loss of appetite for several days or longer, nausea, or stomach-area pain.

The most common side effects in all people who take tenofovir disoproxil fumarate are:

• nausea • pain
• rash • depression
• diarrhea • weakness
• headache

In some people with advanced HBV-infection, other common side effects may include:

• fever • stomach-area pain
• itching • dizziness
• vomiting • sleeping problems

These are not all the possible side effects of tenofovir disoproxil fumarate.

Call your doctor for medical advice about side effects. You may report side effects to AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088.

How should I store tenofovir disoproxil fumarate tablet?

• Store tenofovir disoproxil fumarate tablets at room temperature between 68 °F to 77 °F (20 °C to 25 °C).
• Keep tenofovir disoproxil fumarate tablets in the original container.
• Keep the bottle tightly closed.
• Do not use tenofovir disoproxil fumarate tablets if the seal over the bottle opening is broken or missing.

Keep tenofovir disoproxil fumarate tablet and all medicines out of the reach of children.

General information about the safe and effective use tenofovir disoproxil fumarate tablet.

Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use tenofovir disoproxil fumarate tablet for a condition for which it was not prescribed. Do not give tenofovir disoproxil fumarate tablet to other people, even if they have the same condition you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Tenofovir Disoproxil Fumarate that is written for health professionals.

A vaccine is available to protect people at risk for becoming infected with HBV. You can ask your healthcare provider for information about this vaccine.

You may report side effects to AvKARE at 1-855-361-3993 or go to www.avkare.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

What are the ingredients in tenofovir disoproxil fumarate tablet?

Active Ingredient: tenofovir disoproxil fumarate

Inactive Ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The tablets are coated with Opadry White Y-1-7000 , which contains Hypromellose, Titanium dioxide USP & Polyethylene glycol 400 (Macrogol) USP.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Pediatric use information is approved for Gilead Sciences, Inc.’s VIREAD® (tenofovir disoproxil fumarate) tablets. However, due to Gilead Sciences, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Manfactured for:

AvKARE

Pulaski, TN 38478

Mfg. Rev. 12/19

AV 03/20 (P)

COMPLERA, DESCOVY, GENVOYA, HARVONI, HEPSERA, ODEFSEY, STRIBILD, TRUVADA, VEMLIDY and TENOFOVIR DISOPROXIL FUMARATE are registered trademarks of Gilead Sciences Inc., or its related companies. ATRIPLA is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC. All other trademarks herein are the property of their respective owners and are not trademarks of AvKARE. The makers of these brands are not affiliated with and do not endorse AvKARE or its products.