Maraviroc

Black Box Warnings

Hepatotoxicity reported; may be preceded by systemic allergic reaction (eg, pruritic rash, eosinophilia, elevated IgE)

Immediately evaluate if signs or symptoms of hepatitis or allergic reaction occur

Contraindications

Hypersensitivity

Severe renal impairment or end-stage renal disease (CrCl <30 mL/min) in patients taking potent CYP3A4 inhibitors or inducers

Cautions

Risks of hepatotoxicity

Risk of immune reconstitution syndrome if used in combination with other antiretroviral drugs

Autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) reported in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment

Do not use in treatment-naïve patients; more likely to experienced virologic failure and developed lamivudine resistance compared to efavirenz

Tropism testing with a highly sensitive tropism assay is required for the appropriate use

Evaluate if signs/symptoms of hepatitis, increase LFTs, or rash develop

Preexisting liver dysfunction or viral hepatitis B or C coinfection

Patient history of increased risk for cardiovascular events

History of postural hypotension or concomitant use of blood pressure lowering medication

Caution in renal and hepatic impairment; postural hypotension reported in patients with renal impairment

Monitor for developing infections

When administering to patients with pre-existing liver dysfunction or who are co-infected with hepatitis B and/or C virus, additional monitoring may be warranted

Cardiovascular adverse events triggered by postural hypotension’ additional monitoring may be warranted

Antiretroviral Pregnancy Registry has been established.to monitor maternal-fetal outcomes of pregnant women; register patients by calling 1-800-258-4263

Unless your doctor tells you otherwise, continue your normal diet.

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include the following:

• dizziness, lightheadedness, or fainting when getting up too quickly from a lying position

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Maraviroc may also cause an allergic reaction with severe liver symptoms. Stop taking maraviroc and call your doctor at once if you have:

• fever, itching or rash;
• vomiting, upper stomach pain; or
• dark urine, jaundice (yellowing of the skin or eyes).

Call your doctor at once if you have a side effect such as:

• a light-headed feeling, like you might pass out;
• chest pressure, tight feeling in your neck or jaw, sweating, pain spreading to your arm or shoulder; or
• severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Maraviroc may increase your risk of certain infections or autoimmune disorders by changing the way your immune system works. Symptoms may occur weeks or months after you start treatment with maraviroc. Tell your doctor if you have:

• signs of a new infection--fever, night sweats, swollen glands, diarrhea, stomach pain, weight loss;
• chest pain (especially when you breathe), dry cough, wheezing, feeling short of breath;
• cold sores, sores on your genital or anal area;
• rapid heart rate, feeling anxious or irritable, weakness or prickly feeling, problems with balance or eye movement;
• trouble speaking or swallowing, severe lower back pain, loss of bladder or bowel control; or
• swelling in your neck or throat (enlarged thyroid), menstrual changes, impotence, loss of interest in sex.

Common side effects may include:

• cold symptoms such as stuffy nose, sneezing, cough, sore throat;
• dizziness; or
• mild skin rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

The following adverse reactions are discussed in other sections of the labeling:

Hepatotoxicity [see BOXED WARNING, WARNINGS AND PRECAUTIONS]

Severe Skin and Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]

Cardiovascular events [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety profile of SELZENTRY is primarily based on 840 HIV-1-infected subjects who received at least 1 dose of SELZENTRY during two Phase 3 trials. A total of 426 of these subjects received the indicated twice-daily dosing regimen.

Assessment of treatment-emergent adverse events is based on the pooled data from 2 trials in subjects with CCR5-tropic HIV-1 (A4001027 and A4001028). The median duration of therapy with SELZENTRY for subjects in these trials was 48 weeks, with the total exposure on SELZENTRY twice daily at 309 patient-years versus 111 patient-years on placebo + optimized background therapy (OBT). The population was 89% male and 84% white, with mean age of 46 years (range: 17 to 75 years). Subjects received dose equivalents of 300 mg maraviroc once or twice daily.

The most common adverse events reported with twice-daily therapy with SELZENTRY with frequency rates higher than placebo, regardless of causality, were upper respiratory tract infections, cough, pyrexia, rash, and dizziness. In these 2 trials, the rate of discontinuation due to adverse events was 5% for subjects who received SELZENTRY twice daily + OBT as well as those who received placebo + OBT. Most of the adverse events reported were judged to be mild to moderate in severity. The data described below occurred with twice-daily dosing of SELZENTRY.

The total number of subjects reporting infections were 233 (55%) and 84 (40%) in the group receiving SELZENTRY twice daily and the placebo group, respectively. Correcting for the longer duration of exposure on SELZENTRY compared with placebo, the exposure-adjusted frequency (rate per 100 subject-years) of these events was 133 for both SELZENTRY twice daily and placebo.

Dizziness or postural dizziness occurred in 8% of subjects on either SELZENTRY or placebo, with 2 subjects (0.5%) on SELZENTRY permanently discontinuing therapy (1 due to syncope, 1 due to orthostatic hypotension) versus 1 subject on placebo (0.5%) permanently discontinuing therapy due to dizziness.

Treatment-emergent adverse events, regardless of causality, from Trials A4001027 and A4001028 are summarized in Table 3. Selected events occurring at greater than or equal to 2% of subjects and at a numerically higher rate in subjects treated with SELZENTRY are included; events that occurred at the same or higher rate on placebo are not displayed.

Table 3: Percentage of Subjects with Selected Treatment-emergent Adverse Events (All Causality) Greater than or Equal to 2% on SELZENTRY (and at a higher rate compared with placebo) Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks)

Table 4 shows the treatment-emergent Grade 3-4 laboratory abnormalities that occurred in greater than 2% of subjects receiving SELZENTRY.

Table 4: Maximum Shift in Laboratory Test Values (without Regard to Baseline) Incidence Greater than or Equal to 2% of Grade 3-4 Abnormalities (ACTG Criteria) Trials A4001027 and A4001028 (Pooled Analysis, 48 Weeks)

Treatment-emergent Adverse Events: Treatment-emergent adverse events, regardless of causality, from Trial A4001026, a double-blind, comparative, controlled trial in which 721 treatment-naive subjects received SELZENTRY 300 mg twice daily (n = 360) or efavirenz 600 mg once daily (n = 361) in combination with lamivudine/zidovudine (COMBIVIR®) for 96 weeks, are summarized in Table 5. Selected events occurring in greater than or equal to 2% of subjects and at a numerically higher rate in subjects treated with SELZENTRY are included; events that occurred at the same or higher rate on efavirenz are not displayed.

Table 5: Percentage of Subjects with Selected Treatment-emergent Adverse Events (All Causality) Greater than or Equal to 2% on SELZENTRY (and at a higher rate compared with efavirenz) Trial A4001026 (96 Weeks)

Table 6: Maximum Shift in Laboratory Test Values (without Regard to Baseline) Incidence Greater than or Equal to 2% of Grade 3-4 Abnormalities (ACTG Criteria) Trial A4001026 (96 Weeks)

Percentages based on total subjects evaluated for each laboratory parameter. If the same subject in a given treatment group had greater than 1 occurrence of the same abnormality, only the most severe is counted.

The following adverse events occurred in less than 2% of subjects treated with SELZENTRY or at a rate similar to the comparator. These events have been included because of their seriousness and either increased frequency on SELZENTRY or are potential risks due to the mechanism of action. Events attributed to the subjects' underlying HIV-1 infection are not listed.

Blood and Lymphatic System: Marrow depression and hypoplastic anemia.

Cardiac Disorders: Unstable angina, acute cardiac failure, coronary artery disease, coronary artery occlusion, myocardial infarction, myocardial ischemia.

Hepatobiliary Disorders: Hepatic cirrhosis, hepatic failure, cholestatic jaundice, portal vein thrombosis, jaundice.

Infections and Infestations: Endocarditis, infective myositis, viral meningitis, pneumonia, treponema infections, septic shock, Clostridium difficile colitis, meningitis.

Musculoskeletal and Connective Tissue Disorders: Myositis, osteonecrosis, rhabdomyolysis, blood CK increased.

Neoplasms Benign, Malignant, and Unspecified (Including Cysts and Polyps): Abdominal neoplasm, anal cancer, basal cell carcinoma, Bowen's disease, cholangiocarcinoma, diffuse large B-cell lymphoma, lymphoma, metastases to liver, esophageal carcinoma, nasopharyngeal carcinoma, squamous cell carcinoma, squamous cell carcinoma of skin, tongue neoplasm (malignant stage unspecified), anaplastic large cell lymphomas T-and null-cell types, bile duct neoplasms malignant, endocrine neoplasms malignant and unspecified.

Nervous System Disorders: Cerebrovascular accident, convulsions and epilepsy, tremor (excluding congenital), facial palsy, hemianopia, loss of consciousness, visual field defect.

Postmarketing Experience

The following events have been identified during post-approval use of SELZENTRY and are not listed above. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to estimate their frequency or establish a causal relationship to exposure to SELZENTRY.

Stevens-Johnson syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN).

Included as part of the PRECAUTIONS section.

SELZENTRY®
(sell-ZEN-tree)
(maraviroc) Tablets

Read the Medication Guide that comes with SELZENTRY before you start taking it 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 SELZENTRY?

Serious side effects have occurred with SELZENTRY, including liver problems (liver toxicity). An allergic reaction may happen before liver problems occur. Stop taking SELZENTRY and call your healthcare provider right away if you get any of the following symptoms:

• an itchy rash on your body (allergic reaction)
• yellowing of your skin or whites of your eyes (jaundice)
• dark (tea-colored) urine
• vomiting
• upper right stomach area (abdominal) pain

What is SELZENTRY?

SELZENTRY is an anti-HIV medicine called a CCR5 antagonist. HIV-1 (Human Immunodeficiency Virus) is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).

SELZENTRY is used with other anti-HIV medicines in adults with CCR5-tropic HIV-1 infection.

Use of SELZENTRY is not recommended in people with dual/mixed or CXCR4-tropic HIV-1.

• SELZENTRY will not cure HIV-1 infection.
• People taking SELZENTRY may still develop infections, including opportunistic infections or other conditions that happen with HIV-1 infection.
• It is very important that you stay under the care of your healthcare provider during treatment with SELZENTRY.
• The long-term effects of SELZENTRY are not known at this time. SELZENTRY has not been studied in children less than 18 years of age.

General information about SELZENTRY

SELZENTRY does not cure HIV-1 infection and you may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. You should remain under the care of a doctor when using SELZENTRY.

Avoid doing things that can spread HIV-1 infection to others.

• Do not share or re-use needles or other injection equipment.
• Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

Ask your healthcare provider if you have any questions about how to prevent passing HIV to other people.

How does SELZENTRY work?

HIV-1 enters cells in your blood by attaching itself to structures on the surface of the cell called receptors. SELZENTRY blocks a specific receptor called CCR5 that CCR5-tropic HIV-1 uses to enter CD4 or T-cells in your blood. Your healthcare provider will do a blood test to see if you have been infected with CCR5-tropic HIV-1 before prescribing SELZENTRY for you.

• When used with other anti-HIV medicines, SELZENTRY may:
  • reduce the amount of HIV-1 in your blood. This is called “viral load”.
  • increase the number of white blood cells called T (CD4) cells.

SELZENTRY does not work in all people with CCR5-tropic HIV-1 infection.

Who should not take SELZENTRY?

People with severe kidney problems or who are on hemodialysis and are taking certain other medications should not take SELZENTRY. Talk to your healthcare provider before taking this medicine if you have kidney problems.

What should I tell my healthcare provider before taking SELZENTRY?

Before you take SELZENTRY, tell your healthcare provider if you:

• have liver problems including a history of hepatitis B or C.
• have heart problems.
• have kidney problems.
• have low blood pressure or take medicines to lower blood pressure.
• have any other medical condition.
• are pregnant or plan to become pregnant. It is not known if SELZENTRY may harm your unborn baby.
  Antiretroviral Pregnancy Registry. There is a pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of the 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. Do not breastfeed. We do not know if SELZENTRY can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the 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 non-prescription medicines, vitamins, and herbal supplements. Certain other medicines may affect the levels of SELZENTRY in your blood. Your healthcare provider may need to change your dose of SELZENTRY when you take it with certain medicines

• darunavir (PREZISTA®)
• elvitegravir (VITEKTA®)
• lopinavir/ritonavir (KALETRA®, NORVIR®)
• delavirdine (RESCRIPTOR®)
• atazanavir (REYATAZ®)
• ketoconazole (NIZORAL®)
• saquinavir (INVIRASE®)
• itraconazole (SPORANOX®)
• nelfinavir (VIRACEPT®)
• clarithromycin (BIAXIN®)
• indinavir (CRIXIVAN®)
• nefazodone
• fosamprenavir (LEXIVA®)
• telithromycin (KETEK®)
• etravirine (INTELENCE®)
• efavirenz (SUSTIVA®, ATRIPLA®)
• carbamazepine (TEGRETOL®)
• rifampin (RIFADIN®, RIFATER®)
• phenytoin (DILANTIN®)
• phenobarbital
• ritonavir (NORVIR®)
• boceprevir (VICTRELIS®)

Do not take products that contain St. John's wort (Hypericum perforatum). St. John's wort may lower the levels of SELZENTRY in your blood so that it will not work to treat your CCR5-tropic HIV-1 infection.

Know the medicines you take. Keep a list of your medicines. Show the list to your healthcare provider and pharmacist when you get a new medicine.

How should I take SELZENTRY?

Take SELZENTRY exactly as prescribed by your healthcare provider.

SELZENTRY comes in 150-mg and 300-mg tablets. Your healthcare provider will prescribe the dose that is right for you.

• Take SELZENTRY 2 times a day.
• Swallow SELZENTRY tablets whole. Do not chew the tablets.
• Take SELZENTRY tablets with or without food.
• Always take SELZENTRY with other anti-HIV drugs as prescribed by your healthcare provider.

Do not change your dose or stop taking SELZENTRY or your other anti-HIV medicines without first talking with your healthcare provider.

• If you take too much SELZENTRY, call your healthcare provider or the poison control center right away.
• If you forget to take SELZENTRY, take the next dose of SELZENTRY as soon as possible and then take your next scheduled dose at its regular time. If it is less than 6 hours before your next dose, do not take the missed dose. Wait and take the next dose at the regular time. Do not take a double dose to make up for a missed dose.
• It is very important to take all your anti-HIV medicines as prescribed. This can help your medicines work better. It also lowers the chance that your medicines will stop working to fight HIV-1 (drug resistance).
• When your SELZENTRY supply starts to run low, ask your healthcare provider or pharmacist for a refill. This is very important because the amount of virus in your blood may increase and SELZENTRY could stop working if it is stopped for even a short period of time.

What are the possible side effects of SELZENTRY?

There have been serious side effects when SELZENTRY has been given with other anti-HIV drugs including:

• Liver problems. See “What is the most important information I should know about SELZENTRY?”
• Serious skin rash and allergic reactions. Severe and potentially life-threatening skin reactions and allergic reactions have been reported in some patients taking SELZENTRY. If you develop a rash with any of the following symptoms, stop using SELZENTRY and contact your doctor right away:
  • fever
  • generally ill feeling
  • muscle aches
  • blisters or sores in your mouth
  • blisters or peeling of the skin
  • redness or swelling of the eyes
  • swelling of the mouth or face or lips
  • problems breathing
  • yellowing of the skin or whites of your eyes
  • dark or tea colored urine
  • pain, aching, or tenderness on the right side below the ribs
  • loss of appetite
  • nausea/vomiting
• Heart problems including heart attack.
• Low blood pressure when standing up (postural hypotension). Low blood pressure when standing up can cause dizziness or fainting. Do not drive a car or operate heavy machinery if you have dizziness while taking SELZENTRY.
• Changes in your immune system. A condition called Immune Reconstitution Syndrome can happen when you start taking HIV medicines. Your immune system may get stronger and could begin to fight infections that have been hidden in your body such as pneumonia, herpes virus, or tuberculosis. Tell your healthcare provider if you develop new symptoms after starting your HIV medicines.
• Possible chance of infection or cancer. SELZENTRY affects other immune system cells and therefore may possibly increase your chance for getting other infections or cancer.

The most common side effects of SELZENTRY include colds, cough, fever, rash, and dizziness.

Tell your healthcare provider about any side effect that bothers you or does not go away.

These are not all of the side effects with SELZENTRY. For more information, ask your healthcare provider or pharmacist.

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 SELZENTRY?

• Store SELZENTRY tablets at room temperature from 59°F to 86°F (15°C to 30°C).
• Safely throw away medicine that is out of date or that you no longer need.

Keep SELZENTRY and all medicines out of the reach of children.

General information about SELZENTRY

Medicines are sometimes prescribed for conditions that are not mentioned in Medication Guides. Do not use SELZENTRY for a condition for which it was not prescribed. Do not give SELZENTRY to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about SELZENTRY. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for more information about SELZENTRY that is written for health professionals.

For more information, go to www.selzentry.com.

What are the ingredients in SELZENTRY?

Active ingredient: maraviroc

Inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate (anhydrous), sodium starch glycolate, magnesium stearate

Film-coat: FD&C blue #2 aluminum lake, soya lecithin, polyethylene glycol (macrogol 3350), polyvinyl alcohol, talc, and titanium dioxide

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Before you take maraviroc, tell your health care provider if you:

• have liver problems including a history of hepatitis B or C
• have heart problems
• have kidney problems
• have low blood pressure or take medicines to lower blood pressure
• have any other medical condition
• are pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed

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

Take maraviroc exactly as prescribed by your health care provider.

Maraviroc comes in tablet and oral solution forms. Your health care provider will prescribe the dose that is right for you.

Before starting treatment, your health care provider will test you for CCR5 tropism. 

If you take the tablets, be sure to swallow maraviroc tablets whole. Do not chew the tablets.

• Take maraviroc 2 times a day.
• Take maraviroc with or without food.
• Always take maraviroc with other anti-HIV drugs as prescribed by your health care provider.

Do not change your dose or stop taking maraviroc or your other anti-HIV medicines without first talking with your health care provider.

• If you take too much maraviroc, call your health care provider or the poison control center right away.
• If you forget to take maraviroc, take the next dose of maraviroc as soon as possible and then take your next scheduled dose at its regular time. If it is less than 6 hours before your next dose, do not take the missed dose. Wait and take the next dose at the regular time. Do not take a double dose to make up for a missed dose.
• It is very important to take all your anti-HIV medicines as prescribed. This can help your medicines work better. It also lowers the chance that your medicines will stop working to fight HIV (drug resistance).
• When your maraviroc supply starts to run low, ask your health care provider or pharmacist for a refill. This is very important because the amount of virus in your blood may increase and maraviroc could stop working if it is stopped for even a short period of time.

Maraviroc is an antiviral medication that prevents certain viral cells from multiplying in your body.

Maraviroc is used together with other medications. to treat CCR5-tropic human immunodeficiency virus (HIV) type 1.

Maraviroc is not a cure for HIV or AIDS.

Maraviroc may also be used for purposes not listed in this medication guide.

You should not use this medication if you are allergic to it.

To make sure you can safely take maraviroc, tell your doctor if you have any of these other conditions:

• kidney disease;
• liver disease, especially hepatitis B or C;
• heart disease;
• low blood pressure;
• any type of allergy;
• circulation problems; or
• if you have ever had a stroke.

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby, but HIV can be passed to your baby if you are not properly treated during pregnancy. Take all of your HIV medicines as directed to control your infection.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of maraviroc 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.

• HIV and AIDS: Antiretroviral Drugs, Treatments and Medications
• Human Immunodeficiency Virus (HIV)

Many drugs can interact with maraviroc. Not all possible interactions are listed here. Tell your doctor about all your medications and any you start or stop using during treatment with maraviroc, especially:

• all of your HIV/AIDS medications;

• bosentan;

• imatinib;

• nefazodone;

• an antibiotic--clarithromycin, telithromycin;

• antifungal medicine--itraconazole, ketoconazole, posaconazole, voriconazole;

• heart medication--nicardipine, quinidine;

• hepatitis C medicine--boceprevir or telaprevir;

• seizure medicine--carbamazepine, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone; or

• tuberculosis medicine--isoniazid, rifabutin, rifampin, rifapentine.

This list is not complete and many other drugs can interact with maraviroc. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

It is very important that your doctor check your progress at regular visits to make sure maraviroc is working properly. Blood tests may be needed to check for unwanted effects.

Your immune system may get stronger when you start taking HIV medicines. Tell your doctor right away if you notice any changes in your health. Sometimes the immune system will start to fight infections that were hidden in your body, such as pneumonia, herpes, or tuberculosis. Autoimmune disorders such as Graves' disease, polymyositis, and Guillain-Barré syndrome may also occur.

maraviroc may cause some people to become dizzy. If this happens, do not drive, use machines, or do anything else that could be dangerous if you are dizzy. You may also feel lightheaded when getting up suddenly from a lying or sitting position, so stand up slowly.

Liver problems with allergic reactions may occur while you are using maraviroc. Check with your doctor right away if you have a skin rash with fever, dark-colored urine, pain in the upper right stomach area, vomiting, or yellow eyes or skin.

Serious allergic and skin reactions may occur while using maraviroc. These could be life-threatening and require immediate medical attention. Check with your doctor right away if you have blistering, peeling, or loosening of the skin, red skin lesions, severe acne or skin rash, joint or muscle aches, sores or ulcers on the skin, or fever or chills while you are using maraviroc.

Using maraviroc may increase your risk of getting infections or cancer. Talk to your doctor if you have concerns about this risk.

maraviroc will not keep you from giving HIV to your partner during sex. Make sure you understand and practice safe sex, even if your partner also has HIV, by using a latex condom or other barrier method. maraviroc will also not keep you from giving HIV to other people if they are exposed to your blood. Do not re-use or share needles with anyone.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (eg, St. John's wort) or vitamin supplements.

• Antiretroviral, CCR5 Antagonist (Anti-HIV)

Maraviroc, a CCR5 antagonist, selectively and reversibly binds to the chemokine (C-C motif receptor 5 [CCR5]) coreceptors located on human CD4 cells. CCR5 antagonism prevents interaction between the human CCR5 coreceptor and the gp120 subunit of the viral envelope glycoprotein, thereby inhibiting gp120 conformational change required for CCR5-tropic HIV-1 fusion with the CD4 cell and subsequent cell entry.

Distribution

Vd: ~194 L

Metabolism

Hepatic, via CYP3A to inactive metabolites

Excretion

Urine (~20%, 8% as unchanged drug); feces (76%, 25% as unchanged drug)

Time to Peak

Plasma: 0.5 to 4 hours

Half-Life Elimination

14 to 18 hours

Protein Binding

~76%

HIV-1 infection, treatment: Oral: 300 mg twice daily; dose recommended when maraviroc administered concomitantly with other medications that are not potent CYP3A inhibitors or inducers, including tipranavir/ritonavir, nevirapine, raltegravir, all NRTIs and enfuvirtide.

Dosage adjustment for concomitant CYP3A inhibitors/inducers:

CYP3A inhibitors (with or without a potent CYP3A inducer): 150 mg twice daily; dose recommended when maraviroc administered concomitantly with potent CYP3A inhibitors including (but not limited to) protease inhibitors (excluding tipranavir/ritonavir), delavirdine, elvitegravir/ritonavir, ketoconazole, itraconazole, clarithromycin, nefazodone, telithromycin, and boceprevir.

CYP3A inducers (without a potent CYP3A inhibitor): 600 mg twice daily; dose recommended when maraviroc administered concomitantly with potent CYP3A inducers including (but not limited to) efavirenz, etravirine, rifampin, carbamazepine, phenobarbital, and phenytoin

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Maraviroc. Management: Increase maraviroc adult dose to 600 mg twice daily when used with strong CYP3A4 inducers. This does not apply to patients also receiving strong CYP3A4 inhibitors. Do not use maraviroc with strong CYP3A4 inducers in patients with CrCl less than 30 mL/min. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Maraviroc. Management: Reduce the adult dose of maraviroc to 150 mg twice daily when used with a strong CYP3A4 inhibitor. Do not use maraviroc with strong CYP3A4 inhibitors in patients with Clcr less than 30 mL/min. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Efavirenz: May decrease the serum concentration of Maraviroc. Of note, this effect only applies in the absence of a strong CYP3A4 inhibitor Management: Increase maraviroc adult dose to 600 mg twice daily if used with efavirenz. This does not apply to patients also receiving strong CYP3A4 inhibitors. This combination is contraindicated in patients with CrCl less than 30 mL/min. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Etravirine: May decrease the serum concentration of Maraviroc. Of note, this effect only applies in the absence of a strong CYP3A4 inhibitor Management: Increase maraviroc adult dose to 600 mg twice daily if used with etravirine. This does not apply to patients also receiving strong CYP3A4 inhibitors. This combination is contraindicated in patients with CrCl less than 30 mL/min. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of Maraviroc. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Maraviroc has moderate transfer across the human placenta. Data collected by the antiretroviral pregnancy registry are insufficient to evaluate human teratogenic risk. Maternal antiretroviral therapy may increase the risk of preterm delivery, although available information is conflicting possibly due to variability of maternal factors (disease severity; initiation of therapy); however, maternal antiretroviral medication should not be withheld due to concerns of preterm birth. Information related to stillbirth, low birth weight, and small for gestational age infants is limited. Long-term follow-up is recommended for all infants exposed to antiretroviral medications; children who develop significant organ system abnormalities of unknown etiology (particularly of the CNS or heart) should be evaluated for potential mitochondrial dysfunction.

Combination antiretroviral therapy (cART) therapy is recommended for all HIV-infected pregnant women to keep the viral load below the limit of detection and reduce the risk of perinatal transmission. When HIV is diagnosed during pregnancy in a woman who has never received antiretroviral therapy, cART should begin as soon as possible after diagnosis. The Health and Human Services (HHS) Perinatal HIV Guidelines note there are insufficient data to recommend use of maraviroc as initial therapy in antiretroviral-naive pregnant women. Dose adjustments are not needed in pregnancy. In general, women who become pregnant on a stable cART regimen may continue that regimen if viral suppression is effective, appropriate drug exposure can be achieved, contraindications for use in pregnancy are not present, and the regimen is well tolerated. Monitoring during pregnancy is more frequent than in non-pregnant adults; cART should be continued postpartum.

For HIV-infected couples planning a pregnancy, maximum viral suppression with cART is recommended prior to conception for the HIV-infected partner(s) and expert consultation is recommended; modification of therapy (if needed) and optimization of the woman’s health should be done prior to conception. HIV-infected women not planning a pregnancy may use any available type of contraception, considering possible drug interactions and contraindications of the specific method. In addition, consistent use of condoms is also recommended (even during pregnancy) to prevent transmission of HIV or other sexually transmitted diseases.

Health care providers are encouraged to enroll pregnant women exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-258-4263 or www.APRegistry.com). Health care providers caring for HIV-infected women and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation (HHS [perinatal] 2016).

Applies to maraviroc: oral liquid, oral tablet

General

The most common side effects reported with twice-daily treatment were cough, pyrexia, upper respiratory tract infections, rash, and dizziness. The most common side effects reported with once-daily dosing were diarrhea, edema, influenza, esophageal candidiasis, sleep disorders, rhinitis, parasomnias, and urinary abnormalities. Nausea, diarrhea, fatigue, and headache were common in Phase 2b/3 trials.[Ref]

Respiratory

Very common (10% or more): Upper respiratory tract infection (up to 32%), coughing and associated symptoms (14%), bronchitis (up to 13%)
Common (1% to 10%): Upper respiratory tract signs/symptoms, sinusitis, upper respiratory tract signs/symptoms, nasal congestion and inflammations, breathing abnormalities, paranasal sinus disorders, lower respiratory tract and lung infections, pneumonia, influenza
Frequency not reported: Rhinitis, bronchospasm and obstruction, respiratory tract disorders, epistaxis[Ref]

Other

Very common (10% or more): Pyrexia (13%)
Common (1% to 10%): Asthenia, herpes infection, bacterial infections, herpes zoster/varicella, pain and discomfort, Neisseria infections, viral infections, body temperature perception, ear disorders, otitis media
Frequency not reported: Edema, fatigue, hot flushes, condyloma acuminatum, treponema infections, septic shock[Ref]

Dermatologic

Very common (10% or more): Rash (up to 11%)
Common (1% to 10%): Nail and nail bed conditions (excluding infections and infestations), apocrine and eccrine gland disorders, pruritus, folliculitis, tinea infections, lipodystrophies, acnes, erythemas, alopecias
Frequency not reported: Dermatitis, eczema
Postmarketing reports: Severe skin reactions (including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms [DRESS], toxic epidermal necrolysis)[Ref]

Severe, potentially life-threatening skin and hypersensitivity reactions were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. In most cases, other drugs associated with such reactions were coadministered.[Ref]

Hypersensitivity

Severe, potentially life-threatening skin and hypersensitivity reactions were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. In most cases, other drugs associated with such reactions were coadministered.[Ref]

Postmarketing reports: Severe hypersensitivity reactions[Ref]

Gastrointestinal

Elevated amylase (greater than 2 to 5 times upper limit of normal [ULN]: up to 5.7%; greater than 5 times ULN: up to 0.3%) and elevated lipase (greater than 2 to 5 times ULN: 5%; greater than 5 times ULN: 1.3%) have been reported.[Ref]

Very common (10% or more): Flatulence, bloating, and distention (10%)
Common (1% to 10%): Gastrointestinal atonic and hypomotility disorders, constipation, elevated amylase, elevated lipase, gastrointestinal signs/symptoms, abdominal pain, flatulence, nausea
Uncommon (0.1% to 1%): Esophageal candidiasis
Frequency not reported: Diarrhea, gastrointestinal pain, dyspeptic signs/symptoms, ulceration stomatitis, gingivitis, dry mouth, vomiting, Clostridium difficile colitis[Ref]

Nervous system

Common (1% to 10%): Dizziness/postural dizziness, paresthesias and dysesthesias, sensory abnormalities, disturbances in consciousness, peripheral neuropathies, memory loss (excluding dementia)
Uncommon (0.1% to 1%): Seizures and seizure disorders/convulsions and epilepsy
Frequency not reported: Headache, sleep disorders, syncope, cerebrovascular accident, tremor (excluding congenital), facial palsy, hemianopia, loss of consciousness, viral meningitis, meningitis, visual field defect[Ref]

Hematologic

Common (1% to 10%): Anemias, decreased absolute neutrophil count, neutropenias, decreased hemoglobin
Rare (0.01% to 0.1%): Pancytopenia, granulocytopenia
Frequency not reported: Marrow depression, hypoplastic anemia[Ref]

Decreased absolute neutrophil count (500 to 749/mm3: up to 4.3%; less than 500/mm3: up to 1.4%) and decreased hemoglobin (6.5 to 6.9 g/dL: 0.6%; less than 6.5 g/dL: 2.3%) have been reported.[Ref]

Metabolic

Common (1% to 10%): Appetite disorders, anorexia
Rare (0.01% to 0.1%): Increased alkaline phosphatase
Frequency not reported: Unintentional weight loss (wasting), hyperlipidemia[Ref]

Psychiatric

Common (1% to 10%): Disturbances in initiating and maintaining sleep/insomnia, depressive disorders/depression, anxiety symptoms
Frequency not reported: Parasomnias, somnolence[Ref]

Musculoskeletal

Common (1% to 10%): Joint-related signs/symptoms, elevated creatine kinase, muscle pains
Uncommon (0.1% to 1%): Myositis, increased blood creatine phosphokinase
Rare (0.01% to 0.1%): Muscle atrophy
Frequency not reported: Infective myositis, osteonecrosis, rhabdomyolysis[Ref]

Elevated creatine kinase (greater than 10 to 20 times ULN: 2.8%; greater than 20 times ULN: 1.1%) has been reported.[Ref]

Hepatic

Elevated total bilirubin (greater than 2 to 5 times ULN: 5%; greater than 5 times ULN: 5.5%), elevated AST (greater than 5 times ULN: up to 4.8%; greater than 10 times ULN: up to 1.7%), and elevated ALT (greater than 5 times ULN: up to 3.9%; greater than 10 times ULN: up to 1%) have been reported.[Ref]

Common (1% to 10%): Elevated total bilirubin, elevated AST, elevated ALT
Uncommon (0.1% to 1%): Hyperbilirubinemia, elevated GGT
Rare (0.01% to 0.1%): Toxic hepatitis, hepatic failure, hepatic cirrhosis
Very rare (less than 0.01%): Hepatic failure with allergic features
Frequency not reported: Hepatotoxicity (sometimes associated with rash and eosinophilia), cholestatic jaundice, portal vein thrombosis, hypertransaminasemia, jaundice[Ref]

Genitourinary

Common (1% to 10%): Bladder and urethral symptoms, urinary tract signs/symptoms, erection and ejaculation conditions and disorders, anogenital warts
Uncommon (0.1% to 1%): Proteinuria
Frequency not reported: Urinary abnormalities[Ref]

Cardiovascular

Common (1% to 10%): Vascular hypertensive disorders
Rare (0.01% to 0.1%): Angina pectoris
Frequency not reported: Postural/orthostatic hypotension, arrhythmia, unstable angina, acute cardiac failure, coronary artery disease, coronary artery occlusion, endocarditis, myocardial infarction, myocardial ischemia[Ref]

Oncologic

Common (1% to 10%): Skin neoplasms
Rare (0.01% to 0.1%): Malignant bile duct neoplasms/bile duct cancer, diffuse large B-cell lymphoma, Hodgkin's disease, metastases to bone, metastases to liver, metastases to peritoneum, esophageal carcinoma, nasopharyngeal carcinoma/cancer
Frequency not reported: Abdominal neoplasm, anal cancer, anaplastic large cell lymphomas (T- and null-cell types), endocrine neoplasms (malignant and unspecified), basal cell carcinoma, Bowen's disease, cholangiocarcinoma, lymphoma, squamous cell carcinoma, squamous cell carcinoma of skin, tongue neoplasm (unspecified malignant stage)[Ref]

Ocular

Common (1% to 10%): Conjunctivitis; ocular infections, inflammations, and associated manifestations
Frequency not reported: Abnormal vision, eye pain[Ref]

Renal

Uncommon (0.1% to 1%): Renal failure[Ref]

Immunologic

Frequency not reported: Immune reconstitution syndrome, autoimmune disorders in the setting of immune reconstitution (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome)[Ref]

Some side effects of maraviroc may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Summary of Use during Lactation

In the United States and other developed countries, HIV-infected mothers should generally not breastfeed their infants. No published information is available on the use of maraviroc during breastfeeding. In countries in which no acceptable, feasible, sustainable and safe replacement feeding is available, World Health Organization guidelines recommend that all women with an HIV infection who are pregnant or breastfeeding should be maintained on antiretroviral therapy for at least the duration of risk for mother-to-child transmission.Mothers should exclusively breastfeed their infants for the first 6 months of life; breastfeeding with complementary feeding should continue through at least 12 months of life up to 24 months of life.[1] The first choice regimen for nursing mothers is tenofovir, efavirenz and either lamivudine or emtricitabine. If these drugs are unavailable, alternative regimens include: 1) zidovudine, lamivudine and efavirenz; 2) zidovudine, lamivudine and nevirapine; or 3) tenofovir, nevirapine and either lamivudine or emtricitabine. Exclusively breastfed infants should also receive 6 weeks of prophylaxis with nevirapine.[2][3]

Drug Levels

Maternal Levels. Relevant published information was not found as of the revision date. Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Some case reports have suggested that antiretrovirals, including lamivudine, might cause hyperprolactinemia and galactorrhea in some patients,[14] although this has been disputed.[15] The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

References

1. Anon. Guideline: Updates on HIV and infant feeding: The duration of breastfeeding, and support from health services to improve feeding practices among mothers living with HIV. Geneva: World Health Organization. 2016. PMID: 27583316

2. World Health Organization. HIV and infant feeding: update. 2007. http://whqlibdoc.who.int/publications/2007/9789241595964_eng.pdf

3. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Geneva: World Health Organization. 2013. http://www.who.int/hiv/pub/guidelines/arv2013/en/

Substance Name

Maraviroc

CAS Registry Number

376348-65-1

Drug Class

Antiinfective Agents

Anti-HIV Agents

Antiviral Agents

Anti-Retroviral Agents

HIV Fusion Inhibitors