Tenofovir Disoproxil Fumarate

WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B

BOXED WARNING SECTION

Severe acute exacerbations of hepatitis B virus (HBV) have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including tenofovir disoproxil fumarate. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in HBV-infected patients who discontinue anti-hepatitis B therapy, including tenofovir disoproxil fumarate. If appropriate, resumption of anti-hepatitis B therapy may be warranted [See Warnings and Precautions (5.1) ] .

1 INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

2 DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

3 DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION

Tenofovir disoproxil fumarate is available as tablets in three dose strengths. • 200 mg Tablets: 200 mg of TDF (equivalent to 163 mg of tenofovir disoproxil): round-shaped, white, film coated, debossed with “27” on one side. • 250 mg Tablets: 250 mg of TDF (equivalent to 204 mg of tenofovir disoproxil): capsule-shaped, white, film coated, debossed with “31” on one side. • 300 mg Tablets: 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil): almond-shaped, blue, film coated, debossed with “32” on one side.

4 CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

None.

5 WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS SECTION

6 ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection [see Warnings and Precautions (5.1) ]. New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.2) ] . Immune Reconstitution Syndrome [see Warnings and Precautions (5.4) ] . Bone Loss and Mineralization Defects [see Warnings and Precautions (5.5) ] . Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.6) ] .

7 DRUG INTERACTIONS

DRUG INTERACTIONS SECTION

8 USE IN SPECIFIC POPULATIONS

USE IN SPECIFIC POPULATIONS SECTION

10 OVERDOSAGE

OVERDOSAGE SECTION

If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir disoproxil fumarate, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

11 DESCRIPTION

DESCRIPTION SECTION

Tenofovir disoproxil fumarate (TDF) (a prodrug of tenofovir) is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. TDF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5’-monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase. The chemical name of TDF is 9-[( R )-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C 19 H 30 N 5 O 10 P • C 4 H 4 O 4 and a molecular weight of 635.52. It has the following structural formula: Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in distilled water at 25 °C. It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25 °C. Tenofovir disoproxil fumarate is available as tablets. Tenofovir disoproxil fumarate tablets are for oral administration and are available in the following strengths: 200 mg, 250 mg, and 300 mg of TDF (equivalent to 163 mg, 204 mg, and 245 mg of tenofovir disoproxil, respectively). All strengths of tenofovir disoproxil fumarate tablets contain the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The 300 mg strength tablets are coated with Opadry II 32K605004, which contains FD&C blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin. The 200, and 250 mg strength tablets are coated with Opadry II 32K18425, which contains hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin. In this insert, all dosages are expressed in terms of TDF except where otherwise noted.

12 CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

NONCLINICAL TOXICOLOGY SECTION

14 CLINICAL STUDIES

CLINICAL STUDIES SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

HOW SUPPLIED SECTION

17 PATIENT COUNSELING INFORMATION

INFORMATION FOR PATIENTS SECTION

Advise the patient to read the FDA-approved patient labeling (Patient Information). 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 by: Qilu Pharmaceutical Co., Ltd. Jinan, 250101, China Revised: June 2019 All brand names listed are the registered trademarks of their respective owners and are not trademarks of Qilu Pharmaceutical Co., Ltd..

SPL PATIENT PACKAGE INSERT SECTION

SPL PATIENT PACKAGE INSERT SECTION

Patient Information Tenofovir Disoproxil Fumarate (ten-OF-oh-vir dye-soe-PROX-il FUE-ma-rate) Tablets This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: June 2019 Read this Patient Information before you start taking tenofovir disoproxil fumarate 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 treatment. What is the most important information I should know about tenofovir disoproxil fumarate? Tenofovir disoproxil fumarate 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 of tenofovir disoproxil fumarate. Refill your prescription or talk to your healthcare provider before your tenofovir disoproxil fumarate are all gone. Do not stop taking tenofovir disoproxil fumarate 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. For more information about side effects, see “ What are the possible side effects of tenofovir disoproxil fumarate? ” What is tenofovir disoproxil fumarate? Tenofovir disoproxil fumarate is a prescription medicine that is 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 48.5 pounds (22 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 48.5 pounds (22 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? Before you take tenofovir disoproxil fumarate, tell your healthcare provider about all of your medical conditions, including if you: have liver problems, including 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 tenofovir disoproxil fumarate 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? Take tenofovir disoproxil fumarate 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 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 48.5 pounds (22 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. 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, 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? Tenofovir disoproxil fumarate may cause serious side effects, including: See " What is the most important information I should know about tenofovir disoproxil fumarate? " 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, or 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 taking tenofovir disoproxil fumarate are: nausea rash diarrhea headache pain depression weakness In some people with advanced HBV-infection, other common side effects may include: fever itching vomiting stomach-area pain dizziness 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 FDA at 1-800-FDA-1088. How should I store tenofovir disoproxil fum...

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PRINICPAL DISPLAY PANEL - 300 mg Bottle Label NDC 67184- 0521 -1 Tenofovir disoproxil fumarate tablets 300 mg 30 tablets R x only Qilu Pharmaceutical Co., Ltd.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PRINICPAL DISPLAY PANEL - 200 mg Bottle Label NDC 67184- 0519 -1 Tenofovir disoproxil fumarate tablets 200 mg 30 tablets Rx only Qilu Pharmaceutical Co., Ltd.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PRINICPAL DISPLAY PANEL - 250 mg Bottle Label NDC 67184- 0520 -1 Tenofovir disoproxil fumarate tablets 250 mg 30 tablets R x only Qilu Pharmaceutical Co., Ltd.