Dolutegravir

Registered South African indications:

• Human immunodeficiency virus (HIV) infection

Contraindications

South African recommendations

Film-coated tablets

• Hypersensitivity to dolutegravir or any of the inactive ingredients
• Combination with dofetilide and pilsicainide
• Moderate and severe hepatic impairment
• Metformin is contraindicated in patients taking dolutegravir

Dispersible tablets

• Hypersensitivity to dolutegravir or to any of the excipients
• Combination with dofetilide and pilsicainide
• Severe hepatic impairment (Child-Pugh grade C)
• First trimester of pregnancy

Recommendations in other jurisdictions

Film-coated tablets

• Hypersensitivity to the active substance or to any of the excipients
• Medicinal products with narrow therapeutic windows that are substrates of organic cation transporter 2 (OCT2), including but not limited to fampridine (also known as dalfampridine)

Cautions

• Second and third trimester of pregnancy (odt) (South African recommendations)
• Pregnancy (fct) (South African recommendations)
• Pregnancy (Recommendations in other jurisdictions)
• Breastfeeding
• Mild hepatic impairment (fct) (South African recommendations)
• Mild to moderate hepatic impairment (odt) (South African recommendations)
• Hepatic impairment (Recommendations in other jurisdictions)
• Elderly
• Integrase class resistance
• Hepatitis B co-infection

Forms avail. in SA and covered in this monograph: fct, dsp

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Dolutegravir therapy should be initiated by a medical practitioner experienced in the management of HIV infection

Human immunodeficiency virus (HIV) infection (Additional agents required)
- Treatment-naïve and treatment-experienced and integrase inhibitor-naïve patients (in combination with other antiretroviral agents)

• Oral (fct): 50mg, dly without food

- Without resistance to the integrase class

• Oral (dsp): 30mg, dly with or without food

- Integrase inhibitor resistance documented or clinically suspected (in combination with other antiretroviral agents)

• Oral (fct): 50mg, 12hrly without food
• Oral (dsp): 30mg, 12hrly with or without food

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The decision to use dolutegravir dispersible tablets 10mg for such patients should be informed by the integrase resistance pattern

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The bioavailability of film-coated tablets and dispersible tablets is not comparable therefore they must not be used as direct replacements. For example, the recommended adult dose for film-coated tablets is 50mg versus 30mg for dispersible tablets. Patients changing between film-coated and dispersible tablets should follow the dosing recommendations that are specific for the formulation

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If the patient misses a dose of dolutegravir dispersible tablets, the patient should take the dose as soon as possible, providing the next dose is not due within 4 hours. If the next dose is due within 4 hours, the patient should not take the missed dose and simply resume the usual dosing schedule

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The dispersible tablets may be swallowed whole with drinking water or dispersed in drinking water. When dispersed, the amount of water will depend on the number of tablets prescribed. The tablet should not be chewed cut or crushed

Forms avail. in SA and covered in this monograph: dsp

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Dolutegravir therapy should be initiated by a medical practitioner experienced in the management of HIV infection

Human immunodeficiency virus (HIV) infection (Additional agents required)
- Without resistance to the integrase class

The recommended dose is determined according to weight and age and is presented in the table below

Age	Body weight (kg)	Dose: Oral (dsp)
<4 weeks	<3	Not established for use
≥4 weeks	3-<6	5mg, dly
<6 months	6-<10	10mg, dly
≥6 months	6-<10	15mg, dly
	10-<14	20mg, dly
	14-<20	25mg, dly
	≥20	30mg, dly

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Dolutegravir dispersible tablets can be taken with or without food

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The dispersible tablets may be swallowed whole with drinking water or dispersed in drinking water. When dispersed, the amount of water will depend on the number of tablets prescribed. The tablet should not be chewed cut or crushed

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In patients infected with HIV-1 with resistance to the integrase class: There are insufficient data to recommend a dose for dolutegravir dispersible tablets in integrase inhibitor resistant adolescents, children and infants

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If the patient misses a dose of dolutegravir dispersible tablets, the patient should take the dose as soon as possible, providing the next dose is not due within 4 hours. If the next dose is due within 4 hours, the patient should not take the missed dose and simply resume the usual dosing schedule

Consult HIV/infectious disease specialists prior to any decisions related to ARV regimen termination/switch

 Pregnancy

South African recommendations

Film-coated tablet

• First trimester: Caution; positive evidence of risk
• Second and third trimester: Caution
• Use of dolutegravir during pregnancy was associated with a small increase in the prevalence of neural tube defects (0.19%) compared to non-dolutegravir regimens (0,11%). Most neural tube defects occur within the first 4 weeks of embryonic development after conception (approximately 6 weeks after the last menstrual period)
• If a pregnancy is confirmed in the first trimester while on dolutegravir, the benefits and risks of continuing dolutegravir versus switching to another antiretroviral regimen should be discussed with the patient, taking the gestational age and the critical time period of neural tube defect development into account
• Dolutegravir may be used during the second and third trimester of pregnancy when the expected benefit outweighs the potential risk to the foetus. Dolutegravir was shown to cross the placenta in humans, leading to significant exposure to the foetus, but the implications of such exposure are not yet known
• Women of childbearing potential / Contraception in males and females: Women of childbearing potential should be counselled about the potential risk of neural tube defects with dolutegravir, including consideration of using effective contraceptive measures. Perform pregnancy testing before initiation of dolutegravir in women of childbearing potential to exclude inadvertent (unintentional) use of dolutegravir during the first trimester of pregnancy. If a woman plans pregnancy, the benefits and the risks of starting or continuing treatment with dolutegravir versus using another antiretroviral regimen should be discussed with her

Dispersible tablet

• First trimester: Contraindicated
• Second and third trimester: Caution
• Use of dolutegravir at the time of conception was associated with a small increase in the prevalence of neural tube defects (0.19%) compared to non-dolutegravir regimens (0.11%)
• Most neural tube defects occur within the first 4 weeks of embryonic development after conception (approximately 6 weeks after the last menstrual period)
• If a pregnancy is confirmed in the first trimester while on dolutegravir, the benefits and risks of continuing dolutegravir versus switching to another antiretroviral regimen should be discussed with the patient, taking the gestational age and the critical time period of neural tube defect development into account
• Dolutegravir may be used during the second and third trimester of pregnancy when the expected benefit outweighs the potential risk to the foetus
• Dolutegravir was shown to cross the placenta in humans, leading to significant exposure to the foetus, but the implications of such exposure are not yet known
• Women of childbearing potential should be counseled about the potential risk of neural tube defects with dolutegravir, including consideration of using effective contraceptive measures
• Perform pregnancy testing before initiation of dolutegravir dispersible tablets in women of childbearing potential to exclude inadvertent use of dolutegravir dispersible tablets during the first trimester of pregnancy
• If a woman plans pregnancy, the benefits and the risks of starting or continuing treatment with dolutegravir versus using another antiretroviral regimen should be discussed with her

Recommendations in other jurisdictions

Film-coated tablet

• First trimester: Caution; positive evidence of risk
• Second and third trimester: Caution
• Human experience from a birth outcome surveillance study in Botswana shows a small increase of neural tube defects; 7 cases in 3,591 deliveries (0.19%; 95% CI 0.09%, 0.40%) to mothers taking dolutegravir-containing regimens at the time of conception compared to 21 cases in 19,361 deliveries (0.11%: 95% CI 0.07%, 0.17%) to women exposed to non-dolutegravir regimens at the time of conception
• The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live births (0.05-0.1%)
• Most neural tube defects occur within the first 4 weeks of embryonic development after conception (approximately 6 weeks after the last menstrual period)
• If a pregnancy is confirmed in the first trimester while on dolutegravir, the benefits and risks of continuing dolutegravir versus switching to another antiretroviral regimen should be discussed with the patient taking the gestational age and the critical time period of neural tube defect development into account
• Data analysed from the Antiretroviral Pregnancy Registry do not indicate an increased risk of major birth defects in over 600 women exposed to dolutegravir during pregnancy but are currently insufficient to address the risk of neural tube defects
• In animal reproductive toxicity studies, no adverse development outcomes, including neural tube defects, were identified
• Dolutegravir was shown to cross the placenta in animals
• More than 1000 outcomes from exposure during second and third trimester of pregnancy indicate no evidence of increased risk of foeto/neonatal toxicity
• Dolutegravir may be used during the second and third trimester of pregnancy when the expected benefit justifies the potential risk to the foetus
• Women of childbearing potential (WOCBP) should be counseled about the potential risk of neural tube defects with dolutegravir, including consideration of effective contraceptive measures
• If a woman plans pregnancy, the benefits and the risks of continuing treatment with dolutegravir should be discussed with the patient

Breastfeeding

South African recommendations

Film-coated tablet

• Caution; not recommended
• HIV infected women should not breast feed their infants in order to avoid transmission of HIV or follow appropriate guidelines
• Dolutegravir is excreted in human breast milk, and there is significant exposure to the neonate/infants due to slow elimination; the half-life of dolutegravir in the newborn was 33 hr compared to 14 hr in the adults. There is insufficient information on the effects of dolutegravir in neonates/infants

Dispersible tablet

• Caution; not recommended
• HIV-infected women should not breastfeed their infants in order to avoid transmission of HIV or follow appropriate guidelines. Dolutegravir is excreted in human breast milk in small amounts
• There is insufficient information on the effects of dolutegravir in neonates/infants

Recommendations in other jurisdictions

Film-coated tablet

• Caution; not recommended
• Dolutegravir is excreted in human milk in small amounts. There is insufficient information on the effects of dolutegravir in neonates/infants
• It is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV

Renal Impairment

• No dose adjustment recommended

Hepatic Impairment

South African recommendations

Film-coated tablet

• Mild (Child-Pugh class A): No dose adjustment recommended 
• Moderate to severe (Child-Pugh class B & C): Contraindicated 

Dispersible tablet

• Mild to moderate (Child-Pugh class A & B): No dose adjustment recommended
• Severe (Child-Pugh class C): Contraindicated

Recommendations in other jurisdictions

Film-coated tablet

• Mild to moderate (Child-Pugh class A & B): No dose adjustment recommended
• Severe (Child-Pugh class C): Caution; no information available

Elderly

• Caution; no dose adjustment recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Dizziness
• Insomnia
• Abnormal dreams
• Depression
• Suicidal ideation
• Suicide attempt
• Fatigue

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Flatulence
• Upper abdominal pain
• Abdominal pain
• Abdominal discomfort

Hepatobiliary Disorders

• Hepatitis
• Elevated alanine aminotransferase 
• Elevated aspartate aminotransferase 

Endocrine and Metabolic Disorders

• Elevated creatine phosphokinase

Musculoskeletal Disorders

• Arthralgia
• Myalgia

Skin and Subcutaneous Tissue Disorders

• Rash
• Pruritus

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity 
• Immune Reconstitution Syndrome 

• Dofetilide
• Pilsicainide
• Fampridine (also known as dalfampridine)
• CYP3A4 inhibitors
• CYP3A4 inducers
• Non-nucleoside reverse transcriptase inhibitors
• Protease inhibitors
• Antiviral agents
• Antiarrhythmics
• Anticonvulsants
• St. John's wort
• Antacids
• Calcium supplements
• Iron supplements
• Multivitamin
• Metformin
• Rifampicin

None routine. Specific cases may require

• Hepatic function
• Renal function

Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid integration which is essential for the HIV replication cycle.

Oral dispersible tablet 10mg

• Odinsti dispersible tablets

Tablet 50mg

• Dalimune (Cipla)
• Dolutegravir Mylan (Mylan)
• Hetvir 50 (Hetero Drugs South Africa)
• Myltega (Mylan)
• Novalute (Novagen Pharma)
• Olegra (Aurobindo) 
• Stigra (Emcure Pharmaceuticals)
• Tegem (Emcure Pharmaceuticals)
• Tivicay (GSK) originator