Dolutegravir

>10%

Increased cholesterol and triglycerides (up to 17%)

1-10%

Increased lipase (1-8%)

Hyperglycemia (<1-7%)

Increased creatinine kinase (3-4%)

Increased AST (2-3%)

Insomnia (<1-3%)

Increased ALT (2%)

Increased bilirubin (<1-2%)

Headache (<1-2%)

GI disorders (<2%)

Fatigue (<2%)

Hepatitis (<2%)

Myositis (<2%)

Renal impairment (<2%)

Pruritus (<2%)

Nausea (<1-1%)

<1%

Abnormal dreams

Dizziness

Diarrhea

Rash

Vertigo

Postmarketing Reports

Arthralgia

Myalgia

• Tivicay^®

Dolutegravir is a prescription medication used to treat human immunodeficiency virus (HIV) infection in adults and children who are at least 12 years of age and weigh at least 88 lb (40 kg). Dolutegravir does not cure HIV. Dolutegravir belongs to a group of drugs called HIV integrase inhibitors. These work by decreasing the amount of HIV in your blood and increasing the number of immune cells that help fight infections in your body.

This medication comes as a tablet to take by mouth once or twice a day with or without food.

Common side effects include trouble sleeping and headache.

You should not use this medication if you are allergic to dolutegravir or if you are also taking dofetilide (Tikosyn).

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

• liver disease, especially hepatitis B or C.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant. 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 dolutegravir 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.

Taking this medication will not prevent you from passing HIV to other people. Do not have unprotected sex or share razors or toothbrushes. Talk with your doctor about safe ways to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Avoid taking the following medicines within 6 hours before or 2 hours after you take dolutegravir:

• antacids or laxatives that contain calcium, magnesium, or aluminum (such as Amphojel, Di-Gel Maalox, Milk of Magnesia, Mylanta, Pepcid Complete, Rolaids, Rulox, Tums, and others), or the ulcer medicine sucralfate (Carafate);

• buffered medicine;

• vitamin or mineral supplements that contain calcium or iron.

In the U.S.

• Tivicay

Available Dosage Forms:

• Tablet

Therapeutic Class: Antiretroviral Agent

Pharmacologic Class: Dolutegravir

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.
• Fever.
• Muscle or joint pain.
• Mouth sores.
• Eye irritation.
• Shortness of breath.
• Feeling very tired or weak.
• Change in body fat.
• This medicine may help the immune system work. If you have an infection that you did not know you had, it may show up when you take dolutegravir. Tell your doctor right away if you notice any signs of infection like fever, sore throat, weakness, cough, or shortness of breath after you start this medicine.

HIV-1 infection, treatment: Children and Adolescents: Oral:

Treatment naive or treatment-experienced integrase strand transfer inhibitor (INSTI)-naive:

30 to <40 kg: 35 mg once daily

≥40 kg: 50 mg once daily

Treatment naive or treatment-experienced INSTI-naive when coadministered with carbamazepine, efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir or rifampin:

30 to <40 kg: 35 mg twice daily

≥40 kg: 50 mg twice daily

HIV-1 nonoccupational postexposure prophylaxis (nPEP) (off-label use): Adolescents ≥13 years (≥40 kg): Refer to adult dosing.

Take 2 hours before or 6 hours after cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. Alternatively, dolutegravir and supplements containing calcium or iron can be taken together with food.

Viral load, CD4 count, lipid profile; liver aminotransferases (baseline and during therapy); monitor for hypersensitivity

Applies to dolutegravir: oral tablet

General

Discontinuation due to side effects was reported in 2% of therapy-naive patients, 2% of therapy-experienced integrase strand transfer inhibitor (INSTI)-naive patients, and 3% of therapy-experienced INSTI-experienced patients.[Ref]

Gastrointestinal

Very common (10% or more): Diarrhea (up to 16%), nausea (up to 15%)
Common (1% to 10%): Elevated lipase, abdominal pain, abdominal discomfort, flatulence, upper abdominal pain, vomiting[Ref]

Grade 2 and Grade 3 to 4 elevations in lipase were reported in up to 8% and up to 3% of therapy-naive patients, respectively. Elevated lipase was reported in 8% of therapy-experienced INSTI-experienced patients.[Ref]

Metabolic

Common (1% to 10%): Hyperglycemia
Frequency not reported: Fasted lipid values increased (including cholesterol, HDL cholesterol, LDL cholesterol, triglycerides), redistribution/accumulation of body fat (including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, "cushingoid appearance")[Ref]

Grade 2 and Grade 3 hyperglycemia were reported in up to 7% and up to 1% of therapy-naive patients, respectively. Hyperglycemia and elevated cholesterol were reported in 12% and 8% of therapy-experienced INSTI-experienced patients, respectively.

Redistribution/accumulation of body fat has been reported with antiretroviral therapy; causality has not been established.[Ref]

Psychiatric

Common (1% to 10%): Insomnia, abnormal dreams[Ref]

Hepatic

Grade 2 and Grade 3 to 4 elevations in AST were reported in up to 3% and up to 2% of therapy-naive patients, respectively. Grade 2 and Grade 3 to 4 elevations in ALT were reported in 2% and up to 2% of therapy-naive patients, respectively. Grade 2 and Grade 3 to 4 elevations in total bilirubin were reported in up to 2% and less than 1% of therapy-naive patients, respectively. Elevated ALT and AST were reported in 8% and 6% of therapy-experienced INSTI-experienced patients, respectively.

The rates of AST and ALT abnormalities were higher patients coinfected with hepatitis B and/or C virus. ALT abnormalities (Grade 2 to 4) in hepatitis B and/or C coinfected patients compared with HIV monoinfected patients were reported in 16% versus 2% with 50 mg once a day and 8% versus 7% with 50 mg twice a day.

Liver chemistry elevations consistent with immune reconstitution syndrome were reported in some patients with hepatitis B and/or C at the start of dolutegravir therapy, especially when antihepatitis therapy was stopped.[Ref]

Common (1% to 10%): Elevated AST, elevated ALT, elevated total bilirubin, hepatitis
Frequency not reported: Liver chemistry elevations consistent with immune reconstitution syndrome[Ref]

Musculoskeletal

Grade 2 and Grade 3 to 4 elevations in creatine kinase were reported in up to 3% and up to 4% of therapy-naive patients, respectively.[Ref]

Common (1% to 10%): Elevated creatine kinase, myositis[Ref]

Hematologic

Grade 2 and Grade 3 to 4 reductions in total neutrophils were reported in up to 3% and 2% of therapy-naive patients, respectively. Hematology laboratory abnormality (Grade 3 to 4) was reported in 2% of therapy-experienced INSTI-experienced patients, with neutropenia (1%) reported most often.[Ref]

Common (1% to 10%): Decreased total neutrophils, hematology laboratory abnormality[Ref]

Nervous system

Very common (10% or more): Headache (up to 14%)
Common (1% to 10%): Dizziness[Ref]

Dermatologic

Common (1% to 10%): Pruritus, rash (includes rash, generalized rash, macular rash, maculopapular rash, pruritic rash, drug eruption)[Ref]

Renal

Increased serum creatinine occurred due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. Increased serum creatinine was reported within the first 4 weeks of therapy and remained stable through 24 to 48 weeks. A mean change of 0.11 mg/dL (range of -0.6 to 0.62 mg/dL) was reported after 48 weeks of therapy in therapy-naive patients.[Ref]

Common (1% to 10%): Renal impairment
Frequency not reported: Increased serum creatinine (due to inhibition of tubular secretion of creatinine)[Ref]

Other

Common (1% to 10%): Fatigue[Ref]

Hypersensitivity

Uncommon (0.1% to 1%): Hypersensitivity reactions (characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury)[Ref]

Immunologic

Uncommon (0.1% to 1%): Immune reconstitution syndrome, autoimmune disorders in the setting of immune reconstitution (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome)[Ref]

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

12 years or older, weighing at least 40 kg:
Therapy-naive or therapy-experienced INSTI-naive patients: 50 mg orally once a day

With concomitant efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin: 50 mg orally twice a day

Comments:
-Safety and efficacy not established in patients younger than 12 years or weighing less than 40 kg.
-Safety and efficacy not established in INSTI-experienced patients with documented or clinically suspected resistance to other INSTIs (raltegravir, elvitegravir).

Therapy-naive or therapy-experienced INSTI-naive patients:
Mild, moderate, or severe renal dysfunction: No adjustment recommended.

INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance):
Mild or moderate renal dysfunction: No adjustment recommended.
Severe renal dysfunction: Caution recommended; loss of therapeutic effect and resistance to this drug or other concomitant antiretroviral agents may occur with decrease in dolutegravir levels.