Hepsera

Your pharmacist can provide more information about adefovir.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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1.  Some people who stop taking Hepsera get a very serious form of hepatitis. This usually happens within 12 weeks after stopping. You will need to have regular blood tests to check for liver function and hepatitis B virus levels if you stop taking Hepsera.

• You feel very weak or tired.
• You have unusual (not normal) muscle pain.
• You have trouble breathing.
• You have stomach pain with nausea and vomiting.
• You feel cold, especially in your arms and legs.
• You feel dizzy or lightheaded.
• You have a fast or irregular heartbeat.

Some people who have taken medicines like Hepsera have developed serious liver problems called hepatotoxicity, with liver enlargement (hepatomegaly) and fat in the liver (steatosis). Call your doctor right away if you get any of the following signs of liver problems.

• Your skin or the white part of your eyes turns yellow (jaundice).
• Your urine turns dark.
• Your bowel movements (stools) turn light in color.
• You don't feel like eating food for several days or longer.
• You feel sick to your stomach (nausea).
• You have lower stomach pain.

You may be more likely to get lactic acidosis or serious liver problems if you are very overweight (obese) or have been taking nucleoside analog medicines [Atripla (efavirenz plus emtricitabine plus tenofovir disoproxil fumarate), Complera (emtricitabine plus rilpivirine plus tenofovir disoproxil fumarate), Combivir (zidovudine plus lamivudine), Emtriva (emtricitabine), Epivir, Epivir-HBV (lamivudine), Epzicom (abacavir plus lamivudine), Hivid (zalcitabine), Retrovir (zidovudine), Trizivir (zidovudine plus lamivudine plus abacavir), Truvada (emtricitabine plus tenofovir disoproxil fumarate), Videx (didanosine), Viread (tenofovir disoproxil fumarate), Zerit (stavudine), and Ziagen (abacavir)] for a long time.

• Do not take Hepsera if you are allergic to any of the ingredients in Hepsera. The active ingredient in Hepsera is adefovir dipivoxil.
• Do not take Hepsera if you are already taking Atripla, Complera, Stribild, Truvada, or Viread.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Hepsera, there are no specific foods that you must exclude from your diet when receiving this medication.

If you take too much Hepsera, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If Hepsera is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

This medicine may cause a serious condition called lactic acidosis. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired.

Adefovir can also cause serious kidney problems, especially if you have kidney disease or take certain medications.

Tell your doctor if you have been exposed to HIV, or if you have untreated HIV or AIDS. Taking medicines to treat chronic hepatitis B can cause HIV infection to become resistant to the standard HIV and AIDS medications. You may need to be tested for HIV before you start taking adefovir.

You may develop liver symptoms after you stop taking this medication. Your doctor may want to check your liver function for several months after you stop using adefovir.

You should not take adefovir if you are allergic to it.

Do not take adefovir if you also take Atripla, Complera, Stribild, Truvada, or Viread.

Some people taking adefovir develop a serious condition called lactic acidosis. This may be more likely in women, in people who are overweight or have liver disease, and in people who have taken HIV/AIDS medication for a long time. Talk with your doctor about your risk.

Tell your doctor if you have been exposed to HIV, or if you have untreated HIV or AIDS. Taking medicines to treat chronic hepatitis B can cause HIV infection to become resistant to the standard HIV and AIDS medications. You may need to be tested for HIV before you start taking adefovir.

To make sure adefovir is safe for you, tell your doctor if you have:

• kidney disease; or

• liver disease.

FDA pregnancy category C. It is not known whether adefovir will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

Your name may need to be listed on an antiviral pregnancy registry when you start using this medication.

It is not known whether adefovir passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Adefovir does not inhibit CYP isoenzymes, including CYP1A2, 2C9, 2C19, 2D6, and 3A4.1 Adefovir is not a substrate for CYP isoenzymes; potential of the drug to induce these enzymes is unknown.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions with drugs affecting or metabolized by CYP isoenzymes unlikely.1

Nephrotoxic Drugs or Drugs Eliminated by Renal Excretion

Concomitant use with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of adefovir and/or the other drug.1 Monitor closely for adverse effects if adefovir is used concomitantly with drugs excreted renally or with drugs known to affect renal function.1

Specific Drugs

Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. Also, do not stop using this medicine without checking first with your doctor.

This medicine comes with patient information leaflet. Read and follow these instructions carefully each time you get more medicine. Ask your doctor or pharmacist if you have any questions.

This medicine works best when there is a constant amount in the blood. To help keep the amount constant, do not miss any doses.

When your adefovir supply runs low, get more from your pharmacy or from your doctor. The amount of virus in your blood may increase if the medicine is stopped, even for a short time. The virus may develop resistance to adefovir and be harder to treat.

You may take this medicine with or without food.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For chronic hepatitis B infection:
    • Adults and children 12 years of age and older—10 milligrams (mg) once a day.
    • Children younger than 12 years of age—Use is not recommended.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Dark urine
• general tiredness and weakness
• light-colored stools
• nausea and vomiting
• upper right abdomen or stomach pain
• yellow eyes and skin

• Blood in the urine
• change in frequency of urination or amount of urine
• difficult breathing
• drowsiness
• increased thirst
• loss of appetite
• swelling of the feet or lower legs
• weakness

• Fast, shallow breathing
• general feeling of discomfort
• muscle pain or cramping
• shortness of breath
• sleepiness
• unusual tiredness or weakness

• Bloating
• bone fractures, especially of the thigh bone
• bone pain
• chills
• cloudy urine
• constipation
• convulsions
• darkened urine
• decreased frequency or amount of urine
• fast heartbeat
• fever
• increase in the amount of urine
• increased blood pressure
• indigestion
• lower back or side pain
• muscular pain, tenderness, wasting, or weakness
• pains in the stomach, side, or abdomen, possibly radiating to the back
• swelling of the face, fingers, or lower legs
• weight gain

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Abdominal or stomach pain
• headache
• lack or loss of strength

• Acid or sour stomach
• belching
• bloated or full feeling
• diarrhea
• excess air or gas in the stomach or intestines
• heartburn
• passing gas
• stomach discomfort, upset, or pain

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Signs of too much lactic acid in the blood (lactic acidosis) like fast breathing, fast heartbeat, a heartbeat that does not feel normal, very bad upset stomach or throwing up, feeling very sleepy, shortness of breath, feeling very tired or weak, very bad dizziness, feeling cold, or muscle pain or cramps.
• Signs of a pancreas problem (pancreatitis) like very bad stomach pain, very bad back pain, or very bad upset stomach or throwing up.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Muscle pain or weakness.
• Bone pain.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Hepsera, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Hepsera (adefovir). It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Hepsera.

Review Date: October 4, 2017

Studies 437 and 438 (Pivotal Studies)

HBeAg-Positive Chronic Hepatitis B

Study 437 was a randomized, double-blind, placebo-controlled, three-arm study in patients with HBeAg-positive chronic hepatitis B that allowed for a comparison between placebo and Hepsera. The median age of patients was 33 years. Seventy-four percent were male, 59% were Asian, 36% were Caucasian, and 24% had prior interferon-α treatment. At baseline, patients had a median total Knodell Histology Activity Index (HAI) score of 10, a median serum HBV DNA level as measured by the Roche Amplicor Monitor polymerase chain reaction (PCR) assay (LLOQ = 1000 copies/mL) of 8.36 log10 copies/mL and a median ALT level of 2.3 times the upper limit of normal.

HBeAg-Negative (Anti-HBe Positive/HBV DNA Positive) Chronic Hepatitis B

Study 438 was a randomized, double-blind, placebo-controlled study in patients who were HBeAg-negative at screening, and anti-HBe positive. The median age of patients was 46 years. Eighty-three percent were male, 66% were Caucasian, 30% were Asian and 41% had prior interferon-α treatment. At baseline, the median total Knodell HAI score was 10, the median serum HBV DNA level as measured by the Roche Amplicor Monitor PCR assay (LLOQ = 1000 copies/mL) was 7.08 log10 copies/mL, and the median ALT was 2.3 times the upper limit of normal.

The primary efficacy endpoint in both studies was histological improvement at Week 48; results of which are shown in Table 4.

Table 5 illustrates the changes in Ishak Fibrosis Score by treatment group.

At Week 48, improvement was seen with respect to mean change in serum HBV DNA (log10 copies/mL), normalization of ALT, and HBeAg seroconversion as compared to placebo in patients receiving Hepsera (Table 6).

Treatment Beyond 48 Weeks

In Study 437, continued treatment with Hepsera to 72 weeks resulted in continued maintenance of mean reductions in serum HBV DNA observed at Week 48. An increase in the proportion of patients with ALT normalization was also observed in Study 437. The effect of continued treatment with Hepsera on seroconversion is unknown.

In Study 438, patients who received Hepsera during the first 48 weeks were re-randomized in a blinded manner to continue on Hepsera or receive placebo for an additional 48 weeks. At Week 96, 50 of 70 (71%) of patients who continued treatment with Hepsera had undetectable HBV DNA levels (less than 1000 copies/mL), and 47 of 64 (73%) of patients had ALT normalization. HBV DNA and ALT levels returned towards baseline in most patients who stopped treatment with Hepsera.

From 141 eligible patients, there were 125 (89%) patients in Study 438 who chose to continue Hepsera for up to 192 weeks or 240 weeks (4 years or 5 years). As these patients had already received Hepsera for at least 48 weeks and appeared to be experiencing a benefit, they are not necessarily representative of patients initiating Hepsera. Of these patients, 89/125 (71%) and 47/70 (67%) had an undetectable HBV DNA level (less than 1000 copies/mL) at Week 192 and Week 240, respectively. Of the patients who had an elevated ALT at baseline, 77/104 (74%) and 42/64 (66%) had a normal ALT at Week 192 and Week 240, respectively. Six (5%) patients experienced HBsAg loss.

Study 435 (Pre- and Post- Liver Transplantation Patients)

Hepsera was also evaluated in an open-label, uncontrolled study of 467 chronic hepatitis B patients pre- (N=226) and post- (N=241) liver transplantation with clinical evidence of lamivudine- resistant hepatitis B virus (Study 435). At baseline, 60% of pre-liver transplantation patients were classified as Child-Pugh-Turcotte score of Class B or C. The median baseline HBV DNA as measured by the Roche Amplicor Monitor PCR assay (LLOQ = 1000 copies/mL) was 7.4 and 8.2 log10 copies/mL, and the median baseline ALT was 1.8 and 2.0 times the upper limit of normal in pre- and post-liver transplantation patients, respectively. Results of this study are displayed in Table 5. Treatment with Hepsera resulted in a similar reduction in serum HBV DNA regardless of the patterns of lamivudine-resistant HBV DNA polymerase mutations at baseline. The significance of the efficacy results listed in Table 7 as they relate to clinical outcomes is not known.

Study 461 (Clinical Evidence of Lamivudine Resistance)

In Study 461, a double-blind, active controlled study in 59 chronic hepatitis B patients with clinical evidence of lamivudine-resistant hepatitis B virus, patients were randomized to receive either Hepsera monotherapy or Hepsera in combination with lamivudine 100 mg or lamivudine 100 mg alone. At Week 48, the mean ± SD decrease in serum HBV DNA as measured by the Roche Amplicor Monitor PCR assay (LLOQ = 1000 copies/mL) was 4.00 ± 1.41 log10 copies/mL for patients treated with Hepsera and 3.46 ± 1.10 log10 copies/mL for patients treated with Hepsera in combination with lamivudine. There was a mean decrease in serum HBV DNA of 0.31 ± 0.93 log10 copies/mL in patients receiving lamivudine alone. ALT normalized in 47% of patients treated with Hepsera, in 53% of patients treated with Hepsera in combination with lamivudine, and 5% of patients treated with lamivudine alone. The significance of these findings as they relate to clinical outcomes is not known.

Study 518 (Pediatric Study)

Study 518 was a double-blind, placebo-controlled, study in which 173 pediatric patients (ages 2 to less than 18 years) with chronic hepatitis B (CHB) infection and elevated ALT were randomized 2:1 (115 receiving adefovir dipivoxil and 58 receiving placebo). Randomization was stratified by prior treatment and age 2 to less than 7 years old (cohort 1), 7 to less than 12 years old (cohort 2), and 12 to less than 18 years old (cohort 3). All patients in cohort 3 received 10 mg tablet formulation; all patients in cohorts 1 and 2 received an investigational suspension formulation (0.3 mg/kg/day cohort 1, 0.25 mg/kg/day cohort 2) once daily. The primary efficacy endpoint was HBV DNA less than 1000 copies/mL plus normalization of ALT at the end of Week 48.

In cohort 3 (N=83), significantly more patients treated with Hepsera achieved the primary efficacy endpoint at the end of 48 weeks of blinded treatment (23%) when compared to placebo-treated patients (0%). The proportion of patients from cohorts 1 and 2 who responded to treatment with adefovir dipivoxil was not statistically significant when compared to the placebo arm, although the adefovir plasma concentrations in these patients were comparable to those observed in older patients. Overall, 22 of 115 (19%) of pediatric patients who received adefovir dipivoxil versus 1 of 58 (2%) of placebo treated patients responded to treatment by Week 48 [See Adverse Reactions (6.3), Use In Specific Populations (8.4) and Clinical Pharmacology (12.3, 12.4)].

Hepsera is available as tablets. Each tablet contains 10 mg of adefovir dipivoxil. The tablets are white and debossed with "10" and "GILEAD" on one side and the stylized figure of a liver on the other side. They are packaged as follows: Bottles of 30 tablets (NDC 61958-0501-1) containing desiccant (silica gel) and closed with a child-resistant closure.

Store in original container at 25 °C (77 °F), excursions permitted to 15–30 °C (59–86 °F) (See USP Controlled Room Temperature).

Do not use if seal over bottle opening is broken or missing.