dolutegravir

Dolutegravir is an antiretroviral medication used to treat human immunodeficiency virus type-1 (HIV-1) infection in adults and children.

Dolutegravir is used as a component of antiretroviral therapy (ART) regimen, which combines several antiretroviral drugs that work in different ways to prevent viral replication at different stages in the viral life cycle. HIV infection has no cure, but ART can effectively control viral growth and keep the infection under control.

HIV infects the immune system and eventually weakens it to the extent that the body is unable to defend itself effectively against even common infections. Without treatment, HIV infection in its later stages can progress to acquired immune deficiency syndrome (AIDS), with severe impairment of immune function.

HIV-1 is a retrovirus, whose genetic material is composed of only a single strand of ribonucleic acid (RNA). The virus infects T-cell, a type of immune cell and secretes an enzyme known as reverse transcriptase, converting into a double-stranded deoxyribonucleic acid (DNA). The viral DNA then releases another enzyme known as integrase, which enables it to integrate with the T-cell’s DNA, and proceeds to use the host DNA to replicate itself and infect other T-cells.

Dolutegravir is an integrase strand transfer inhibitor (INSTI), the latest class of drugs to be added to antiretroviral therapy. Dolutegravir works by preventing the integrase enzyme from transferring the viral DNA strand into the T-cell DNA strand. Without integrating with the T-cell DNA, HIV-1 cannot replicate itself and gets degraded. Dolutegravir is a second generation Integrase strand transfer inhibitor (INSTI) and has a high barrier to resistance, particularly when used as a first line therapy.

• Do not use in patients with previous hypersensitivity reactions to dolutegravir or any of its components
• Do not use concurrently with dofetilide, a drug used to treat irregular heart rhythms (arrhythmia). Dolutegravir can increase dofetilide effects which can cause life-threatening cardiac arrhythmia.
• Dolutegravir can cause injury to the liver including elevated liver enzymes, hepatitis and liver failure; patients with underlying hepatitis B or C are at higher risk for worsening of liver condition and reactivation of hepatitis B, particularly if anti-hepatitis therapy has been withdrawn; test patients before initiating dolutegravir therapy and monitor liver enzyme levels during therapy
• Dolutegravir can cause hypersensitivity reactions including skin reactions, fever, facial edema, difficulty breathing and organ dysfunction. Discontinue dolutegravir immediately if hypersensitivity reactions occur; delay may result in life-threatening reaction.
• Combination ART including dolutegravir can cause immune reconstitution syndrome; the immune system’s response to the drugs can reactivate indolent or residual opportunistic infections or trigger autoimmune disorders such as Graves’ disease, polymyositis, and Guillain-Barre syndrome
• Redistribution and accumulation of fat in the neck and abdominal regions, breast enlargement, facial wasting and peripheral wasting have been observed with ART; long-term consequences are not clear
• Dolutegravir use at conception and early pregnancy may increase the risk of neural tube defects in the fetus and may be associated with adverse pregnancy outcomes including preterm delivery, stillbirth and low birth weight:
  • Perform pregnancy testing in women of child-bearing potential before initiating therapy
  • Advise patients to use effective contraception during therapy
  • If pregnancy occurs during therapy, inform the patient about the potential risk to the fetus
  • Assess benefits and risks of continuing dolutegravir during pregnancy or switching to alternate HIV medicines
  • Discontinuing ART can increase viral load and risk of transmission to the child
  • Dolutegravir therapy may be considered during the second and third trimesters of pregnancy if the benefit outweighs the potential risk to the mother and the fetus
• Adult and pediatric formulations are not bioequivalent and not interchangeable on milligram-to-milligram basis. Dosage must be adjusted as per dosing recommendations when a pediatric patient is switched from one formulation to the other.

Common side effects of dolutegravir include:

• Increase in levels of serum lipase, the enzyme that breaks down lipids
• Increase in levels of triglycerides and cholesterol
• Increase in blood glucose levels (hyperglycemia)
• Elevation in liver enzymes ALT and AST
• Excessive bilirubin in blood (hyperbilirubinemia)
• Liver inflammation (hepatitis)
• Inflammation in muscles (myositis)
• Increase in serum creatinine phosphokinase
• Gastrointestinal symptoms including:
  • Abdominal distress or pain
  • Diarrhea
  • Gas (flatulence)
  • Nausea
  • Vomiting
• Insomnia
• Fatigue
• Headache
• Depression
• Suicidal ideation and tendencies
• Itching (pruritus)
• Kidney impairment
• Low blood count of neutrophil immune cells (neutropenia)

Less common side effects of dolutegravir include:

• Skin rash
• Hypersensitivity reactions
• Dizziness
• Vertigo
• Abnormal dreams
• Weight gain
• Toxicity to liver (hepatotoxicity)
• Liver failure
• Anxiety
• Muscle pain (myalgia)
• Joint pain (arthralgia)
• Immune reconstitution syndrome

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug.

Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Tablet (Tivicay)

• 10mg
• 25mg
• 50mg

Tablet for oral suspension (Tivicay PD)

• 5mg

Adult:

HIV Infection

• Indicated in combination with other ARTs
• INSTI indicated in patients who weigh 30 kg or more
• Treatment-naïve or treatment-experienced INSTI-naïve: 50 mg orally once a day
• INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance: 50 mg orally twice a day

Indicated in combination with rilpivirine

• To replace the current ART regimen in virologically suppressed patients (HIV-1 RNA less than 50 copies/mL) on a stable ART regimen for 6 months or longer with no history of treatment failure or known substitutions associated with resistance to dolutegravir or rilpivirine
• 50 mg orally once a day

Dosage Modifications

Coadministration with potent UGT1A or CYP3A inducers

• Treatment-naïve or treatment-experienced INSTI-naïve
• Potent UGT1A/CYP3A inducers (e.g., efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, rifampin)
• Increase dose to 50 mg orally twice a day

Hepatic impairment

• Mild-to-moderate hepatic impairment (Child-Pugh A or B): No dosage adjustment required
• Severe hepatic impairment (Child-Pugh C): Not recommended

Renal impairment

• Plasma concentrations were decreased in subjects with severe renal impairment
• No dosage adjustment required for treatment-naïve or treatment-experienced and INSTI-naïve patients with mild, moderate, or severe renal impairment or for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with mild or moderate renal impairment
• Severe renal impairment or for INSTI-experienced patients with resistance: Not recommended; decrease in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance

Dosing Considerations

• Dosage forms (i.e., Tivicay, Tivicay PD) are not bioequivalent or interchangeable
• Poor virologic response was observed in subjects treated with TIVICAY 50 mg twice daily with an INSTI-resistance Q148 substitution plus 2 or more additional INSTI-resistance substitutions, including L74I/M, E138A/D/K/T, G140A/S, Y143H/R, E157Q, G163E/K/Q/R/S, or G193E/R
• In patients with underlying hepatitis B or C, measure hepatic enzymes before initiating therapy and periodically thereafter
• Perform pregnancy testing before initiation in females of childbearing potential

Pediatric:

HIV Infection

Indicated in combination with other ARTs for treatment-naïve or treatment-experienced, but INSTI-naïve children aged 4 weeks or older who weigh 3 kg or more

Weight 3 to 14 kg

Tablets for oral suspension

• 3 to 6 kg: 5 mg orally once a day
• 6 to 10 kg: 15 mg orally once a day
• 10 to 14 kg: 20 mg orally once a day

Weight 14 kg or more

Tablets for oral suspension

• 14 to 20 kg: 25 mg orally once a day
• 20 kg or more: 30 mg orally once a day

Tablets

• 14 to 20 kg: 40 mg orally once a day
• 20 kg or more: 50 mg orally once a day

Dosage Modifications

• Coadministration with potent UGT1A or CYP3A inducers (e.g., efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, rifampin): Increase weight-based dose to twice daily

Dosing Considerations

• Dosage forms (i.e., Tivicay, Tivicay PD) are not bioequivalent or interchangeable
• Perform pregnancy testing before initiation of dolutegravir in females of childbearing potential

• There is no known specific treatment for dolutegravir overdose. Limited experience with single high doses of up to 250 mg in healthy individuals reveal no symptoms other than the listed side effects.
• Dolutegravir overdose is treated with symptomatic and supportive care.
• In case of overdose seek medical help immediately or contact Poison Control.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Severe interactions of dolutegravir include:
  • dofetilide
• Serious interactions of dolutegravir include:
  • aluminum hydroxide/magnesium carbonate
  • cabotegravir
  • carbamazepine
  • efavirenz
  • fosamprenavir
  • fosphenytoin
  • magnesium citrate
  • magnesium oxide
  • nevirapine
  • oxcarbazepine
  • phenobarbital
  • phenytoin
  • rifampin
  • tipranavir
• Moderate interactions of dolutegravir include:
  • aluminum hydroxide
  • calcium acetate
  • calcium carbonate
  • calcium citrate
  • dalfampridine
  • eslicarbazepine acetate
  • ferric maltol
  • ferrous fumarate
  • ferrous gluconate
  • ferrous sulfate
  • magnesium hydroxide
  • magnesium supplement
  • metformin
  • multivitamins
  • orlistat
  • selenium
  • sodium sulfate/magnesium sulfate/potassium chloride
  • sodium sulfate/potassium sulfate/magnesium sulfate
  • zinc
• Dolutegravir has no known mild interactions with other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There are no adequate and well-controlled studies of dolutegravir use in pregnant women; should be used only if clearly needed.
• Limited studies reveal an increase in neural tube defects in babies of women who became pregnant while taking dolutegravir, but not in women who started dolutegravir during pregnancy.
• Risk for neural tube defects is greatest in early stage of pregnancy; risk of neural tube defects may decrease with folic acid supplementation before conception and during pregnancy.
• Women on dolutegravir therapy should practice effective contraception.
• Pregnant women should not discontinue dolutegravir without consulting a healthcare professional; stopping treatment can cause the HIV infection to worsen and increase the risk of transmission to the fetus.
• Antiretroviral therapy is recommended for all pregnant women with HIV infection to improve health, keep the viral load low, and reduce the risk of transmission to the fetus. Therapy should be individualized after discussion with the patient, on the potential risks and benefits of treatment during pregnancy.
• It is not known whether dolutegravir is present in breast milk, affects milk production or has effects on the breastfed infant; animal studies show its presence in milk. Mothers with HIV infection should not breastfeed their infants to avoid the risk of transmission of HIV infection to the baby and the potential for adverse reactions in the infant from maternal dolutegravir therapy.
• A pregnancy exposure registry monitors pregnancy outcomes in women during pregnancy; healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

• Take dolutegravir exactly as prescribed
• Discontinue dolutegravir and seek medical help immediately if you develop:
  • Rash or other hypersensitivity reactions such as fever, muscle and joint aches, facial swelling or breathing difficulties
  • Signs of liver problems such as nausea, vomiting, yellowing of eyes/skin, pale-colored stools, tea-colored urine or sensitivity on the right side below ribs
• In some patients, initiation of dolutegravir therapy may reactivate symptoms of inflammation from previous infections because of the improved immune response, or trigger autoimmune disorders; notify your healthcare provider if you develop any infection or symptoms of autoimmune conditions
• Dolutegravir cannot cure HIV infection; continuous antiretroviral therapy is required to control HIV, decrease HIV-related illnesses and reduce the risk of progression to AIDS