Drugs List

Therapeutic Indications

Uses

HIV infection-combined with other antiretrovirals

Administration

Can be taken with or without food. In the presence of integrase class resistance, dolutegravir should be taken with food to enhance exposure (particularly in patients with Q148 mutations).

Missed doses
Advise patient if a dose is missed to take the missed dose as soon as possible provided there are more than 4 hours until the next scheduled dose. If a dose has been missed and the next dose is due within 4 hours, advise the patient to avoid taking the missed dose and resume the normal dosing schedule.

Switching to different dosage forms
Dolutegravir dispersible tablets can be used in patients aged 4 weeks and above and weighing a least 3kg, or for patients whom film-coated tablets are not appropriate. Film-coated tablets are available for patients aged 6 years and above and weighing at least 14kg. Patients can change between formulations however the bioavailability of dispersible tablets and film-coated tablets is not comparable. Therefore they are not interchangeable on a mg per mg basis.

Contraindications

Infants weighing less than 3kg
Neonates
Breastfeeding

Precautions and Warnings

Children under 6 years
Children weighing less than 14kg
Hepatitis B
Hepatitis C
Pregnancy
Psychiatric disorder
Severe hepatic impairment

Treatment does not prevent risk of transmission of HIV
Advise ability to drive/operate machinery may be affected by side effects
HIV therapy: Must be used in combination with other antiretrovirals
Not all formulations are suitable for all age groups/body weights
Perform viral resistance testing before initiating therapy
Treatment should be initiated by doctor experienced in HIV management
Women childbearing potential: Discuss potential risk of neural tube defects
Different oral formulations are not interchangeable (not bioequivalent)
Autoimmune disorders can occur many months after initiation of treatment
Blood lipid and glucose levels may increase requiring treatment
Monitor for signs of osteonecrosis
Monitor hepatic function in patients with hepatic impairment
Monitor levels of hepatic enzymes and bilirubin
Advise patient to seek medical advice if joint aches or pain occur
Advise patient to seek medical advice if movement becomes difficult
Autoimmune diseases may occur during treatment
Inflammatory symptoms should be evaluated and treated appropriately
Neonate exposed in utero: Risk of neural tube defects
Risk of developing opportunistic infections
Advise patient to seek advice at first indications of pregnancy
Discontinue if drug-related rash or other hypersensitivity reactions occur
Not licensed for all indications in all age groups
Advise patient not to take St John's wort concurrently
Avoid antacids/mineral supplements 2 hrs after or 6 hrs before dose
Female: Ensure adequate contraception during treatment

Patients with limited treatment options who have mutations of Q148 plus, equal to or greater than 2 secondary mutations from G140 A/C/S, E138 A/K/T, L74I may be considered for treatment with a higher dose due to multi class resistance. Consider the integrase resistance pattern in these patients when using dolutegravir.

Hypersensitivity reactions have been reported with use of dolutegravir. These were characterised by rash, constitutional findings, organ dysfunction, including severe liver reactions. Dolutegravir should be discontinued immediately if signs or symptoms of hypersensitivity reactions develop. These hypersensitivity reactions can include, severe rash or rash accompanied by raised liver enzymes, fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, eosinophilia, angioedema. This list is not comprehensive. Monitor clinical status including liver aminotransferases and bilirubin. Delay in stopping treatment may result in a life-threatening allergic reaction.

When combination antiretroviral therapy is initiated in HIV-infected patients with severe immune deficiency, an inflammatory reaction to asymptomatic or residual opportunist pathogens may arise and can cause serious clinical conditions or aggravation of symptoms. Reactions are usually observed within the first few weeks or months after treatment initiation. Examples are cytomegalovirus retinitis, mycobacterial infections or Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treated appropriately.

Blood lipid and glucose levels may increase during antiretroviral therapy. This may be linked to disease control and lifestyle. Refer to established HIV treatment guidelines for monitoring and manage lipid and glucose level disorders as appropriate.

Pregnancy and Lactation

Pregnancy

Use dolutegravir with caution during pregnancy.

The manufacturer suggests dolutegravir should only be used during the second and third trimester of pregnancy if the expected benefit justifies the potential risk to the foetus.

The MHRA states that due to results from an observational study there is evidence of an increased risk of neural tube defects in babies born to mothers who became pregnant while taking dolutegravir. Most neural tube defects occur within the first 4 weeks of embryonic development after conception. If pregnancy is confirmed in the first trimester, the benefits and risks of continuing treatment or switching to another antiretroviral regimen should be discussed with the patient taking the gestational age and critical time period of neural tube defect development into account.

At the time of writing, there are limited data on the use of dolutegravir in pregnancy. The current data is currently insufficient to address the risk of neural tube defects.

Animal reproductive toxicity studies have shown dolutegravir to cross the placenta but have not shown dolutegravir to be teratogenic.

Lactation

Dolutegravir is contraindicated during breastfeeding.

In order to avoid HIV transmission, it is recommend that infants are not breastfed by HIV infected women.

It is not known if dolutegravir is excreted into human milk.

Animal studies have demonstrated that dolutegravir is excreted in milk. Lactating rats dosed with a single 50 mg/kg oral dose 10 days postpartum, dolutegravir was measured in milk concentrations typically higher than blood.

Side Effects

Abdominal discomfort
Abdominal pain
Acute hepatic failure
Anxiety
Arthralgia
Aspartate aminotransferase increased
Autoimmune disorders
Autoimmune hepatitis
Creatine phosphokinase increased
Depression
Diarrhoea
Dizziness
Dream abnormalities
Elevated blood glucose (transient)
Fatigue
Flatulence
Graves' disease
Headache
Hepatitis
Hypersensitivity reactions
Immune Reactivation/Reconstitution Syndrome
Increase in aminotransferase level
Insomnia
Myalgia
Nausea
Pruritus
Rash
Rise in blood lipids
Serum bilirubin increased
Suicidal tendencies
Vomiting
Weight gain

Presentation

Oral formulations containing dolutegravir as dolutegravir sodium.

Drugs List

Therapeutic Indications

Uses

HIV infection-combined with other antiretrovirals

Dosage

Adults

Children

Administration

Can be taken with or without food. In the presence of integrase class resistance, dolutegravir should be taken with food to enhance exposure (particularly in patients with Q148 mutations).

Missed doses
Advise patient if a dose is missed to take the missed dose as soon as possible provided there are more than 4 hours until the next scheduled dose. If a dose has been missed and the next dose is due within 4 hours, advise the patient to avoid taking the missed dose and resume the normal dosing schedule.

Switching to different dosage forms
Dolutegravir dispersible tablets can be used in patients aged 4 weeks and above and weighing a least 3kg, or for patients whom film-coated tablets are not appropriate. Film-coated tablets are available for patients aged 6 years and above and weighing at least 14kg. Patients can change between formulations however the bioavailability of dispersible tablets and film-coated tablets is not comparable. Therefore they are not interchangeable on a mg per mg basis.

Contraindications

Infants weighing less than 3kg
Neonates
Breastfeeding

Precautions and Warnings

Children under 6 years
Children weighing less than 14kg
Hepatitis B
Hepatitis C
Pregnancy
Psychiatric disorder
Severe hepatic impairment

Treatment does not prevent risk of transmission of HIV
Advise ability to drive/operate machinery may be affected by side effects
HIV therapy: Must be used in combination with other antiretrovirals
Not all formulations are suitable for all age groups/body weights
Perform viral resistance testing before initiating therapy
Treatment should be initiated by doctor experienced in HIV management
Women childbearing potential: Discuss potential risk of neural tube defects
Different oral formulations are not interchangeable (not bioequivalent)
Autoimmune disorders can occur many months after initiation of treatment
Blood lipid and glucose levels may increase requiring treatment
Monitor for signs of osteonecrosis
Monitor hepatic function in patients with hepatic impairment
Monitor levels of hepatic enzymes and bilirubin
Advise patient to seek medical advice if joint aches or pain occur
Advise patient to seek medical advice if movement becomes difficult
Autoimmune diseases may occur during treatment
Inflammatory symptoms should be evaluated and treated appropriately
Neonate exposed in utero: Risk of neural tube defects
Risk of developing opportunistic infections
Advise patient to seek advice at first indications of pregnancy
Discontinue if drug-related rash or other hypersensitivity reactions occur
Not licensed for all indications in all age groups
Advise patient not to take St John's wort concurrently
Avoid antacids/mineral supplements 2 hrs after or 6 hrs before dose
Female: Ensure adequate contraception during treatment

Patients with limited treatment options who have mutations of Q148 plus, equal to or greater than 2 secondary mutations from G140 A/C/S, E138 A/K/T, L74I may be considered for treatment with a higher dose due to multi class resistance. Consider the integrase resistance pattern in these patients when using dolutegravir.

Hypersensitivity reactions have been reported with use of dolutegravir. These were characterised by rash, constitutional findings, organ dysfunction, including severe liver reactions. Dolutegravir should be discontinued immediately if signs or symptoms of hypersensitivity reactions develop. These hypersensitivity reactions can include, severe rash or rash accompanied by raised liver enzymes, fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, eosinophilia, angioedema. This list is not comprehensive. Monitor clinical status including liver aminotransferases and bilirubin. Delay in stopping treatment may result in a life-threatening allergic reaction.

When combination antiretroviral therapy is initiated in HIV-infected patients with severe immune deficiency, an inflammatory reaction to asymptomatic or residual opportunist pathogens may arise and can cause serious clinical conditions or aggravation of symptoms. Reactions are usually observed within the first few weeks or months after treatment initiation. Examples are cytomegalovirus retinitis, mycobacterial infections or Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treated appropriately.

Blood lipid and glucose levels may increase during antiretroviral therapy. This may be linked to disease control and lifestyle. Refer to established HIV treatment guidelines for monitoring and manage lipid and glucose level disorders as appropriate.

Pregnancy and Lactation

Pregnancy

Use dolutegravir with caution during pregnancy.

The manufacturer suggests dolutegravir should only be used during the second and third trimester of pregnancy if the expected benefit justifies the potential risk to the foetus.

The MHRA states that due to results from an observational study there is evidence of an increased risk of neural tube defects in babies born to mothers who became pregnant while taking dolutegravir. Most neural tube defects occur within the first 4 weeks of embryonic development after conception. If pregnancy is confirmed in the first trimester, the benefits and risks of continuing treatment or switching to another antiretroviral regimen should be discussed with the patient taking the gestational age and critical time period of neural tube defect development into account.

At the time of writing, there are limited data on the use of dolutegravir in pregnancy. The current data is currently insufficient to address the risk of neural tube defects.

Animal reproductive toxicity studies have shown dolutegravir to cross the placenta but have not shown dolutegravir to be teratogenic.

Lactation

Dolutegravir is contraindicated during breastfeeding.

In order to avoid HIV transmission, it is recommend that infants are not breastfed by HIV infected women.

It is not known if dolutegravir is excreted into human milk.

Animal studies have demonstrated that dolutegravir is excreted in milk. Lactating rats dosed with a single 50 mg/kg oral dose 10 days postpartum, dolutegravir was measured in milk concentrations typically higher than blood.

Side Effects

Abdominal discomfort
Abdominal pain
Acute hepatic failure
Anxiety
Arthralgia
Aspartate aminotransferase increased
Autoimmune disorders
Autoimmune hepatitis
Creatine phosphokinase increased
Depression
Diarrhoea
Dizziness
Dream abnormalities
Elevated blood glucose (transient)
Fatigue
Flatulence
Graves' disease
Headache
Hepatitis
Hypersensitivity reactions
Immune Reactivation/Reconstitution Syndrome
Increase in aminotransferase level
Insomnia
Myalgia
Nausea
Pruritus
Rash
Rise in blood lipids
Serum bilirubin increased
Suicidal tendencies
Vomiting
Weight gain

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last full review date: December 2018

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 3rd edition (2015) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Summary of Product Characteristics: Tivicay 5mg dispersible tablets. ViiV Healthcare UK Ltd. Revised February 2022.

Summary of Product Characteristics: Tivicay 10mg, 25mg and 50mg film coated tablets. ViiV Healthcare UK Ltd. Revised February 2022.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 13 October 2022