Biktarvy

Biktarvy is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (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.

Testing When Initiating and During Treatment with Biktarvy

Prior to or when initiating Biktarvy, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1)].

Prior to or when initiating Biktarvy, and during treatment with Biktarvy, 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 [see Warnings and Precautions (5.4)].

Recommended Dosage

Biktarvy is a three-drug fixed dose combination product containing 50 mg of bictegravir (BIC), 200 mg of emtricitabine (FTC), and 25 mg of tenofovir alafenamide (TAF). The recommended dosage of Biktarvy is one tablet taken orally once daily with or without food [see Clinical Pharmacology (12.3)].

Not Recommended in Patients with Severe Renal Impairment

Biktarvy is not recommended in patients with estimated creatinine clearance below 30 mL per minute [see Use in Specific Populations (8.6)].

Not Recommended in Patients with Severe Hepatic Impairment

Biktarvy is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Biktarvy during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

There are insufficient human data on the use of Biktarvy during pregnancy to inform a drug-associated risk of birth defects and miscarriage. Bictegravir (BIC) and tenofovir alafenamide (TAF) use in women during pregnancy has not been evaluated; however, emtricitabine (FTC) use during pregnancy has been evaluated in a limited number of women reported to the APR. Available data from the APR show no difference in the overall risk of major birth defects for FTC compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15–20%. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation.

In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of Biktarvy at exposures that were either not maternally toxic (rabbits) or greater than (rats and mice) those in humans at the recommended human dose (RHD) (see Data). During organogenesis, systemic exposures (AUC) to BIC were approximately 36 (rats) and 0.6 times (rabbits), to FTC were approximately 60 (mice) and 108 times (rabbits), and to TAF were approximately 2 (rats) and 78 times (rabbits) the exposure at the RHD of Biktarvy. In rat pre/postnatal development studies, maternal systemic exposures (AUC) were 30 times (BIC), 60 times (FTC), and 19 times (TDF) the exposures of each component in humans at the RHD.

Data

Human Data

Emtricitabine: Based on prospective reports to the APR of 3,406 exposures to FTC-containing regimens during pregnancy resulting in live births (including 2,326 exposed in the first trimester and 1,080 exposed in the second/third trimester), there was no difference between FTC and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.7% to 3.0%) with first trimester exposure to FTC-containing regimens and 2.0% (95% CI: 1.3% to 3.1%) with the second/third trimester exposure to FTC-containing regimens.

Animal Data

Bictegravir: BIC was administered orally to pregnant rats (5, 30, or 300 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) on gestation days 7 through 17, and 7 through 19, respectively. No adverse embryo-fetal effects were observed in rats and rabbits at BIC exposures (AUC) of up to approximately 36 (rats) and 0.6 (rabbits) times the exposure in humans at the RHD of Biktarvy. Spontaneous abortion, increased clinical signs [fecal changes, thin body, and cold-to-touch], and decreased body weight were observed at a maternally toxic dose in rabbits (1000 mg/kg/day; approximately 1.4 times higher than human exposure at the RHD).

In a pre/postnatal development study, BIC was administered orally to pregnant rats (up to 300 mg/kg/day) from gestation days 6 to lactation/post-partum day 24. No significant adverse effects were observed in the offspring exposed daily from before birth (in utero) through lactation at maternal and pup exposures (AUC) of approximately 30 and 11 times higher, respectively, than human exposures at the RHD.

Emtricitabine: FTC was administered orally to pregnant mice (250, 500, or 1000 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures approximately 60 times higher and in rabbits at approximately 108 times higher than human exposures at the RHD.

In a pre/postnatal development study with FTC, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the RHD.

Tenofovir alafenamide: TAF was administered orally to pregnant rats (25, 100, or 250 mg/kg/day) and rabbits (10, 30, or 100 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures of approximately 2 (rats) and 78 (rabbits) times higher than the exposure in humans at the recommended daily dose of Biktarvy. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 55 (rats) and 86 (rabbits) times higher than human tenofovir exposures at the RHD. Since TAF is rapidly converted to tenofovir and lower tenofovir exposures in rats and mice were observed after TAF administration compared to TDF administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on gestation day 7 [and lactation day 20] at tenofovir exposures of approximately 12 [19] times higher than the exposures in humans at the RHD of Biktarvy.

Lactation

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

It is not known whether Biktarvy or all of the components of Biktarvy are present in human breast milk, affects human milk production, or has effects on the breastfed infant. Based on published data, FTC has been shown to be present in human breast milk. BIC was detected in the plasma of nursing rat pups likely due to the presence of BIC in milk, and tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF (see Data). It is unknown if TAF is present in animal milk.

Because of the potential for 1) HIV transmission (in HIV-negative infants); 2) developing viral resistance (in HIV-positive infants); and 3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving Biktarvy.

Data

Animal Data

Bictegravir: BIC was detected in the plasma of nursing rat pups in the pre/postnatal development study (post-natal day 10), likely due to the presence of BIC in milk.

Tenofovir alafenamide: Studies in rats and monkeys have demonstrated that tenofovir is secreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11. Tenofovir was excreted into the milk of lactating monkeys following a single subcutaneous (30 mg/kg) dose of tenofovir at concentrations up to approximately 4% of plasma concentration, resulting in exposure (AUC) of approximately 20% of plasma exposure.

Pediatric Use

Safety and effectiveness of Biktarvy in pediatric patients less than 18 years of age have not been established.

Geriatric Use

Clinical trials of Biktarvy did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Renal Impairment

Biktarvy is not recommended in patients with severe renal impairment (estimated creatinine clearance (CLcr) below 30 mL per minute, estimated by Cockcroft-Gault (C-G). No dosage adjustment of Biktarvy is recommended in patients with CLcr greater than or equal to 30 mL per minute [see Dosage and Administration (2.3)].

Hepatic Impairment

No dosage adjustment of Biktarvy is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Biktarvy has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, Biktarvy is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Biktarvy (bictegravir, emtricitabine, and tenofovir alafenamide) is a fixed dose combination tablet containing bictegravir (BIC), emtricitabine (FTC), and tenofovir alafenamide (TAF) for oral administration.

• BIC is an integrase strand transfer inhibitor (INSTI).
• FTC, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI).
• TAF, an HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate.

Each tablet contains 50 mg of BIC (equivalent to 52.5 mg of bictegravir sodium), 200 mg of FTC, and 25 mg of TAF (equivalent to 28 mg of tenofovir alafenamide fumarate) and the following inactive ingredients: croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material containing iron oxide black, iron oxide red, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

Bictegravir: The chemical name of bictegravir sodium is 2,5-Methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide, 2,3,4,5,7,9,13,13a-octahydro-8-hydroxy-7,9-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-, sodium salt (1:1), (2R,5S,13aR)-.

Bictegravir sodium has a molecular formula of C21H17F3N3NaO5 and a molecular weight of 471.4 and has the following structural formula:

Bictegravir sodium is an off-white to yellow solid with a solubility of 0.1 mg per mL in water at 20 °C.

Emtricitabine: The chemical name of FTC is 4-amino-5-fluoro-1-(2R-hydroxymethyl-1,3-oxathiolan-5S-yl)-(1H)-pyrimidin-2-one. FTC is the (-)enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5 position.

FTC has a molecular formula of C8H10FN3O3S and a molecular weight of 247.2 and has the following structural formula:

FTC is a white to off-white powder with a solubility of approximately 112 mg per mL in water at 25 °C.

Tenofovir alafenamide: The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1).

Tenofovir alafenamide fumarate has an empirical formula of C21H29O5N6P∙½(C4H4O4) and a formula weight of 534.5 and has the following structural formula:

Tenofovir alafenamide fumarate is a white to off-white or tan powder with a solubility of 4.7 mg per mL in water at 20 °C.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Bictegravir

BIC was not carcinogenic in a 6-month rasH2 transgenic mouse study at doses of up to 100 mg/kg/day in males and 300 mg/kg/day in females. A carcinogenicity study in rats is ongoing.

BIC was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.

BIC did not affect fertility, reproductive performance or embryonic viability in male and female rats at 29 times higher exposures (AUC) than in humans at the recommended dose of 50 mg BIC in Biktarvy.

Emtricitabine

In long-term carcinogenicity studies of FTC, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (25 times the human systemic exposure at the recommended dose of 200 mg per day in Biktarvy) or in rats at doses up to 600 mg per kg per day (30 times the human systemic exposure at the recommended dose in Biktarvy).

FTC was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.

FTC did not affect fertility in male rats at approximately 140 times or in male and female mice at approximately 60 times higher exposures (AUC) than in humans given the recommended 200 mg daily dose in Biktarvy. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended 200 mg daily dose in Biktarvy.

Tenofovir Alafenamide

Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to TDF administration, carcinogenicity studies were conducted only with TDF. Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the recommended dose of TDF (300 mg) for HIV-1 infection. The tenofovir exposure in these studies was approximately 151 times (mice) and 51 times (rat) those observed in humans after administration of the daily recommended dose of Biktarvy. At the high dose in female mice, liver adenomas were increased at tenofovir exposures approximately 10 times (300 mg TDF) and 151 times (Biktarvy) the exposure observed in humans. In rats, the study was negative for carcinogenic findings.

TAF was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.

There were no effects on fertility, mating performance or early embryonic development when TAF was administered to male rats at a dose equivalent to 155 times (25 mg TAF) the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 14 days prior to mating through Day 7 of gestation.

Animal Toxicology and/or Pharmacology

Minimal to slight infiltration of mononuclear cells in the posterior uvea was observed in dogs with similar severity after three and nine month administration of TAF; reversibility was seen after a three month recovery period. No eye toxicity was observed in the dog at systemic exposures of 7 (TAF) and 14 (tenofovir) times the exposure seen in humans with the recommended daily TAF dose in Biktarvy.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Post-treatment Acute Exacerbation of Hepatitis B in Patients with HBV Coinfection

Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing FTC and/or TDF, and may likewise occur with discontinuation of Biktarvy [see Warnings and Precautions (5.1)]. Advise the patient to not discontinue Biktarvy without first informing their healthcare provider.

Drug Interactions

Biktarvy may interact with certain drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products including St. John's wort [see Contraindications (4) and Drug Interactions (7)].

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any symptoms of infection, as 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 [see Warnings and Precautions (5.2)].

Renal Impairment

Advise patients to avoid taking Biktarvy with concurrent or recent use of nephrotoxic agents. Renal impairment including cases of acute renal failure has been reported in association with the use of tenofovir prodrugs [see Warnings and Precautions (5.4)].

Lactic Acidosis and Severe Hepatomegaly

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to Biktarvy. Advise patients that they should stop Biktarvy if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.3)].

Missed Dosage

Inform patients that it is important to take Biktarvy 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 (2.2)].

Pregnancy Registry

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

Lactation

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].

Biktarvy is a trademark of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners.

© 2018 Gilead Sciences, Inc. All rights reserved.

Biktarvy can cause serious side effects, including:

• Worsening of Hepatitis B virus infection. If you have hepatitis B virus (HBV) infection and take Biktarvy, your HBV may get worse (flare-up) if you stop treatment. A “flare-up” is when your HBV infection suddenly returns in a worse way than before.
  • Do not run out of Biktarvy. Refill your prescription or talk to your healthcare provider before your supply is all gone.
  • Do not stop treatment without first talking to your healthcare provider. If you do stop treatment, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your HBV infection. Tell your healthcare provider about any new or unusual symptoms you may have after you stop treatment.

For more information about side effects, see Biktarvy side effects.

Before taking Biktarvy, tell your healthcare provider about all your medical conditions, including if you:

• have liver problems, including hepatitis B virus infection
• have kidney problems
• are pregnant or plan to become pregnant. It is not known if Biktarvy can harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment.
  Pregnancy Registry: There is a pregnancy registry for women who take Biktarvy during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.
• are breastfeeding or plan to breastfeed. Do not breastfeed if you take Biktarvy.
  • You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.
  • At least one of the medicines in Biktarvy can pass to your baby in your breast milk. It is not known if the other medicines can also pass into your breast milk.
  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 over-the-counter medicines, antacids, laxatives, vitamins, and herbal supplements.

Some medicines may interact with Biktarvy. 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 Biktarvy.
• Do not start a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take Biktarvy with other medicines.

Breastfeeding is not recommended during use of this drug; if replacement feeding is not an option, a different drug may be preferred. Excreted into human milk: Yes (emtricitabine); Unknown (bictegravir, tenofovir alafenamide) Excreted into animal milk: Yes (bictegravir); Unknown (tenofovir alafenamide) Comments: -Tenofovir disoproxil fumarate (DF) is present in human breast milk. -The effects in the nursing infant are unknown; potential for HIV-infected infants developing viral resistance and breastfed infants developing side effects -The US CDC, American Academy of Pediatrics, and manufacturer advise HIV-infected women not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected. -Local guidelines should be consulted if replacement feeding is not an option.

EMTRICITABINE: Samples of breast milk obtained from 5 HIV-1-infected women show that emtricitabine is secreted in human milk. Average peak and trough drug levels in breast milk were 679 and 177 mcg/L, respectively. According to author estimation, an exclusively breastfed infant would receive about 2% of the proposed emtricitabine dose for infants and achieve serum levels that may lead to emergence of viral resistance to emtricitabine. Breastfeeding infants whose mothers are treated with emtricitabine may be at risk for developing viral resistance to emtricitabine; other emtricitabine-related risks in such infants are unknown. Preexposure prophylaxis, using emtricitabine (200 mg/day) and tenofovir disoproxil fumarate, was administered by directly observed therapy for 10 days to 50 women without HIV infection who were breastfeeding their infants. On days 7 and 10 of therapy, peak and trough milk samples were collected 1 to 2 hours after dosing and 23 to 24 hours after the previous dose, respectively; a single infant blood sample was collected after the mother's 7th dose. Median peak and trough milk emtricitabine levels were 212.5 and 183 mcg/L, respectively; these levels correspond to a daily dose of 27.5 to 31.5 mcg/kg (estimated), which is about 0.5% of the proposed therapeutic dose for infants. Of 49 infant blood samples collected, 47 had detectable emtricitabine levels (median plasma level: 13.2 mcg/L); plasma levels were 16.6 mcg/L in infants younger than 13 weeks and 10.5 mcg/L in infants at least 13 weeks of age. Diarrhea lasting 2 to 3 days was reported in 2 of the 50 breastfed infants; no other side effects were reported. During ongoing therapy, emtricitabine was measured after a 300-mg dose to 6 nursing mothers with HIV infection. Peak breast milk level was 872 mcg/L (range: 696 to 1063 mcg/L) at about 3 hours; 1 breastfed infant had detectable emtricitabine serum level of 17.5 mcg/L. Nigerian mothers (n=16) were using emtricitabine (200 mg once a day) as part of combination therapy for HIV; they exclusively breastfed their infants on demand. Expressed milk samples were collected before dosing and at various times (0.5, 1, 2, 4, 8, and 12 hours) after dosing; peak breast milk level from dried breast milk spots averaged 843 mcg/L (interquartile range [IQR]: 702 to 1132 mcg/L) at about 4 hours after dosing (IQR: 2 to 8 hours). Infant blood samples were collected 2 and 8 hours after maternal dosing; after analyzing the dried blood spots, only 3 samples had quantifiable (greater than 16.6 mcg/L) blood levels of 17.5, 18.8, and 19.4 mcg/L.

You should not use this medicine if you are allergic to antiviral medicines that contain emtricitabine or tenofovir (such as Atripla, Complera, Emtriva, Descovy, Genvoya, Odefsey, Stribild, or Truvada).

Some medicines can cause unwanted or dangerous effects when used with Biktarvy. Your doctor may need to change your treatment plan if you also use:

• dofetilide; or

• rifampin.

Tell your doctor if you have ever had:

• liver disease (especially cirrhosis or hepatitis B); or

• kidney disease.

Tell your doctor if you are pregnant. HIV can be passed to your baby if you are not properly treated during pregnancy. Take all of your HIV medicines to control your infection. Your name may be listed on a pregnancy registry to track the effects of Biktarvy on the baby.

Women with HIV or AIDS should not breast feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

Biktarvy is not approved for use by anyone younger than 18 years old.

Follow all directions on your prescription label and read all medication guides or instruction sheets. Use the medicine exactly as directed.

Biktarvy is a complete regimen and is not for use with other antiviral medications.

You may take Biktarvy with or without food. If you take a multivitamin or mineral supplement that contains iron or calcium, take it with food at the same time you take Biktarvy.

You will need frequent medical tests.

Store in the original container at room temperature, away from moisture and heat. Keep the bottle tightly closed when not in use.

If you've ever had hepatitis B, this virus may become active or get worse in the months after you stop using Biktarvy. You may need frequent liver function tests while using this medicine and for several months after your last dose.

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:

Less common

• Stomach pain

Rare

• Changes in behavior
• thoughts or attempts of killing oneself

Incidence not known

• Bloody urine
• dark urine
• decreased appetite
• decreased frequency or amount of urine
• diarrhea
• fast, shallow breathing
• general feeling of discomfort
• general tiredness and weakness
• increased blood pressure
• increased thirst
• light-colored stools
• loss of appetite
• lower back or side pain
• muscle pain or cramping
• nausea
• right upper abdominal pain and fullness
• sleepiness
• stomach discomfort
• swelling of the face, fingers, or lower legs
• troubled breathing
• unusual tiredness or weakness
• vomiting
• weight gain
• yellow eyes and skin

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:

Less common

• Abnormal dreams
• belching
• bloated feeling
• discouragement
• dizziness
• excess air or gas in the stomach or bowels
• feeling of fullness
• feeling sad or empty
• headache
• heartburn
• indigestion
• irritability
• loss of interest or pleasure
• passing gas
• rash
• stomach upset
• trouble concentrating
• trouble sleeping

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.