Dolutegravir/ Rilpivirine

Registered South African indications:

• Immunodeficiency virus-1 (HIV-1) infection

Contraindications
South African recommendations

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Pregnancy: First trimester  
• Peri- and pre-conception period
• Breastfeeding
• Moderate to severe hepatic impairment (Child-Pugh score B and C)
• Coadministration with: 
  - Non-nucleoside reverse transcriptase inhibitors (NNRTI’s)  e.g. delavirdine, efavirenz, etravirine, nevirapine
  - Carbamazepine, oxcarbazepine, phenobarbitone and phenytoin
  - Systemic dexamethasone (except as a single dose treatment)
  - Rifabutin, rifampicin and rifapentine (potent inducers of CYP3A enzymes)
  - Products containing St. John's wort (Hypericum perforatum)
  - Proton-pump inhibitors (PPIs)-lansoprazole, omeprazole, rabeprazole, pantoprazole and esomeprazole
  - Dofetilide
  - Pilsicainide
  - Fampridine (also known as dalfampridine)

Recommendations in other jurisdictions

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Coadministration with:
  - Fampridine (also known as dalfampridine)
  - Carbamazepine, oxcarbazepine, phenobarbital, phenytoin
  - Rifampicin, rifapentine
  - Proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole
  - Systemic dexamethasone, except as a single dose treatment
  - St John's wort (Hypericum perforatum)

Cautions
South African recommendations

• Pregnancy (second and third trimester) 
• Women of childbearing potential
• Elderly
• Supra-therapeutic doses (75mg and 300mg once daily)
• Baseline viral load >100000 HIV-1 RNA copies/ml
• Co-infection with hepatitis B and/or C
• Advanced HIV disease and/ or long-term exposure to combination antiretroviral therapy (cART)
• Galactose intolerance
• Total lactase deficiency 
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• Pregnancy
• Women of childbearing potential
• Breastfeeding
• Severe renal impairment or end-stage renal disease
• Moderate to severe hepatic impairment (Child-Pugh score B and C)
• Elderly
• Supra-therapeutic doses (75mg and 300mg once daily)
• Advanced HIV disease and/or long-term exposure to combination antiretroviral therapy (cART)
• Co-infection with hepatitis B and/or C
• Galactose intolerance
• Total lactase deficiency 
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

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

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

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

Immunodeficiency virus-1 (HIV-1) infection 
- In those who are virologically suppressed (HIV-1 RNA ˂50 copies/ml), for at least 6 months on a stable protease inhibitor (PI), integrase inhibitor (INI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) plus nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) based regimens, without known or suspected resistance to either antiretroviral component

Dolutegravir/ Rilpivirine
50/25 (mg)

• Oral (fct): 1 tab, dly

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Coadministration with any other non-nucleoside-analogue reverse transcriptase inhibitor (NNRTI) medicines is not recommended

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Patients using rifampicin: Rifampicin decreases the blood levels of dolutegravir

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Method of administration: Dolutegravir/ rilpivirine should be taken orally with food

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Indications and dosages registered in other jurisdictions

Dolutegravir/ rilpivirine should be prescribed by physicians experienced in the management of HIV infection

Immunodeficiency virus-1 (HIV-1) infection
- In adults who are virologically suppressed (HIV-1 RNA <50 copies/ml) on a stable antiretroviral regimen for at least 6 months with no history of virological failure and no known or suspected resistance to any non-nucleoside reverse transcriptase inhibitor or integrase inhibitor

Dolutegravir/ Rilpivirine
50/25 (mg)

• Oral (fct): 1 tab, dly

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Separate preparations of dolutegravir or rilpivirine are available in cases where discontinuation or dose adjustment of one of the active substances is indicated

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Missed doses: If the patient misses a dose of dolutegravir/ rilpivirine, the patient should take dolutegravir/ rilpivirine with a meal as soon as possible, providing the next dose is not due within 12 hours. If the next dose is due within 12 hours, the patient should not take the missed dose and simply resume the usual dosing schedule

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If a patient vomits within 4 hours of taking dolutegravir/ rilpivirine, another dolutegravir/ rilpivirine tablet should be taken with a meal. If a patient vomits more than 4 hours after taking dolutegravir/ rilpivirine, the patient does not need to take another dose of dolutegravir/ rilpivirine until the next regularly scheduled dose

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Method of administration: Dolutegravir/ rilpivirine must be taken orally with a meal. It is recommended that the film-coated tablet be swallowed whole with water and not be chewed or crushed

Not established for use in children

Pregnancy
South African recommendations

• Peri- and pre-conception period: Contraindicated
• First trimester: Contraindicated
• Second and third trimester: Caution; no evidence of risk in studies
• Safe use during pregnancy has not been established. The effect of dolutegravir on human pregnancy is unknown. In reproductive toxicity studies in animals, dolutegravir was shown to cross the placenta. Dolutegravir/ rilpivirine is contraindicated in peri, preconception period and the first trimester of pregnancy
• Treatment with dolutegravir/ rilpivirine should not be started without a medically/laboratory supervised negative pregnancy (urine and/or blood test, repeated at frequent intervals as needed. There is some evidence of neural tube defects with the use of dolutegravir, as contained in dolutegravir/ rilpivirine, if started at the time of conception or early pregnancy. Dolutegravir/ rilpivirine should not be prescribed to women who plan to become pregnant
• Rilpivirine in combination with a background regimen was evaluated in a clinical trial of 19 pregnant women during the second and third trimesters, and post-partum. The pharmacokinetic data demonstrated that total exposure (AUC) rilpivirine as a part of an antiretroviral regimen was approximately 30% lower during pregnancy compared with post-partum (6-12 weeks). Studies in rats and rabbits with rilpivirine have shown no evidence of relevant embryonic or foetal toxicity, effect on reproductive function, or teratogenicity
• Adequate contraception is recommended for women of childbearing potential when taking dolutegravir/ rilpivirine

Recommendations in other jurisdictions

• Caution; not recommended
• Lower exposures of dolutegravir and rilpivirine were observed during pregnancy. The use of dolutegravir/ rilpivirine during pregnancy is not recommended. The safety and efficacy of a dual regimen has not been studied in pregnancy. There are limited data from the use of rilpivirine in pregnant women
• 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)
• 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 toxicology studies with dolutegravir, 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 to dolutegravir during second and third-trimester pregnancy indicate no evidence of increased risk of foeto/neonatal toxicity
• Animal studies with rilpivirine do not indicate direct or indirect harmful effects with respect to reproductive toxicity
• Women of childbearing potential should be counselled about the potential risk of neural tube defects with dolutegravir (a component of dolutegravir/ rilpivirine), including consideration of effective contraceptive measures. If a woman plans pregnancy, the benefits and the risks of continuing treatment with dolutegravir/ rilpivirine should be discussed with the patient

Breastfeeding
South African recommendations

• Contraindicated  
• Safe use during breastfeeding has not been established. HIV-infected women should not breastfeed their infants in order to avoid transmission of HIV. It is expected that dolutegravir will be secreted into human milk. It is not known whether rilpivirine is secreted in human milk
• Because of both the potential for HIV transmission and the potential for adverse events in breastfeeding infants, mothers should be instructed not to breastfeed if they are receiving dolutegravir/ rilpivirine

Recommendations in other jurisdictions

• Caution; not recommended 
• It is unknown if rilpivirine is excreted in human milk. Available toxicological data in animals has shown excretion of rilpivirine in milk. Dolutegravir is excreted in human milk in small amounts. There is insufficient information on the effects of dolutegravir in newborns/infants
• It is recommended that HIV-infected women do not breastfeed their infants under any circumstances in order to avoid transmission of HIV

Fertility 
South African recommendations

• Animal studies indicate no effect of dolutegravir or rilpivirine on male or female fertility

Recommendations in other jurisdictions

• There are no data on the effects of dolutegravir or rilpivirine on human male or female fertility. Animal studies indicate no clinically relevant effects on male or female fertility

Renal Impairment
South African recommendations

• No dose adjustment recommended 

Recommendations in other jurisdictions

• Mild to moderate: No dose adjustment recommended 
• Severe renal impairment or end-stage renal disease: Caution; no dose adjustment recommended 
  The combination of dolutegravir/ rilpivirine with a strong CYP3A inhibitor should only be used if the benefit outweighs the risk. No data are available in subjects receiving dialysis although differences in pharmacokinetics are not expected in this population

Hepatic Impairment
South African  recommendations

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

Recommendations in other jurisdictions

• Mild (Child-Pugh score A): No dose adjustment recommended 
• Moderate (Child-Pugh score B): Caution; no dose adjustment recommended 
• Severe (Child-Pugh score C): Caution; not recommended 

Elderly

• Caution; no dose adjustment recommended 

Drugs in Sport

• Permitted - No warnings

Dolutegravir/ Rilpivirine
Central Nervous System Disorders

• Insomnia
• Abnormal dreams
• Depression
• Sleep disorders
• Depressed mood
• Anxiety
• Suicidal ideation or suicide attempt (particularly in patients with a pre-existing history of depression or psychiatric illness)
• Headache
• Dizziness 
• Somnolence
• Fatigue

Gastrointestinal Disorders 

• Nausea and vomiting
• Increased pancreatic amylase
• Diarrhoea
• Abdominal pain
• Flatulence
• Increased lipase
• Abdominal discomfort
  - Upper abdominal pain
• Dry mouth

Hepatobiliary Disorders 

• Increased alanine aminotransferase (ALT)
• Increased aspartate aminotransferase (AST)
• Increased bilirubin
• Hepatitis
• Acute hepatic failure

Endocrine and Metabolic Disorders 

• Increased total cholesterol (fasted)
• Increased low-density lipoprotein (LDL) cholesterol (fasted)
• Decreased appetite
• Increased triglycerides (fasted)

Musculoskeletal Disorders 

• Arthralgia
• Myalgia
• Increased creatine phosphokinase (CPK)

Skin and Subcutaneous Tissue Disorders 

• Rash
• Pruritus

Immune, Blood and Lymphatic System Disorders 

• Decreased white blood cell count
• Decreased haemoglobin
• Decreased platelet count
• Hypersensitivity
• Immune reconstitution syndrome

Dolutegravir
Central Nervous System Disorders

• Insomnia
• Headache
• Dizziness
• Abnormal dreams
• Fatigue 

Gastrointestinal Disorders 

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

Hepatobiliary Disorders 

• Hepatitis

Skin and Subcutaneous Tissue Disorders 

• Rash
• Pruritus

Immune, Blood and Lymphatic System Disorders 

• Hypersensitivity
• Immune reconstitution syndrome

Rilpivirine
Central Nervous System Disorders

• Depression
• Insomnia
• Abnormal dreams
• Sleep disorders
• Depressed mood
• Headache
• Dizziness 
• Somnolence
• Fatigue

Gastrointestinal Disorders 

• Nausea and vomiting
• Abdominal pain
• Abdominal discomfort
• Increased lipase

Hepatobiliary Disorders

• Increased aspartate aminotransferase (AST)
• Increased alanine aminotransferase (ALT)
• Increased bilirubin

Endocrine and Metabolic Disorders 

• Increased pancreatic amylase
• Increased total cholesterol (fasted)
• Increased low-density lipoprotein (LDL) cholesterol (fasted)
• Decreased appetite
• Increased triglycerides (fasted)

Skin and Subcutaneous Tissue Disorders 

• Rash

Immune, Blood and Lymphatic System Disorders 

• Decreased white blood cell count
• Decreased haemoglobin
• Decreased platelet count

Dolutegravir

• Fampridine (also known as dalfampridine)
• Medicinal agents in which excretion is dependent upon organic cation transporters (OCT2)
• Dofetilide
• Pilsicainide
• Metformin
• Rifampicin
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
• Etravirine (ETR)
• Efavirenz (EFV)
• Nevirapine
• Tipranavir/ ritonavir (TPV/ RTV)
• UGT1A1, UGT1A3, UGT1A9 inhibitors
• P-glycoprotein (P-gp) inhibitors
• CYP3A4 inhibitors
• Antacids containing polyvalent cations (e.g. magnesium, aluminium or calcium)
• Calcium supplements
• Iron supplements
• Carbamazepine
• Oxcarbazepine
• Phenobarbitone
• Phenytoin

Other interactions

• St John's wort (Hypericum perforatum)

Rilpivirine

• Fampridine (also known as dalfampridine)
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
• Delavirdine
• Efavirenz
• Etravirine
• Nevirapine

• CYP3A inducers 
• CYP3A inhibitors
• Agents that increase gastric pH
• Rifampicin
• Medicinal product with a known risk of Torsade de Pointes
• Carbamazepine
• Oxcarbazepine
• Phenobarbitone
• Phenytoin
• Dexamethasone (systemic)
• Famotidine
• Proton pump inhibitors
• Omeprazole
• Lansoprazole
• Rabeprazole
• Pantoprazole
• Esomeprazole
• Cimetidine
• Nizatidine
• Ranitidine
• Rifabutin
• Rifapentine
• Clarithromycin
• Erythromycin
• Troleandomycin
• Antacids (e.g. aluminium or magnesium hydroxide, calcium carbonate)

Other interactions

• St John's wort (Hypericum perforatum)

(See additional prescribing points for recommendations concerning coadministration)

• HIV viral load
• CD4 count
• Lipid profile
• Hepatic function

Specific cases may require

• Pregnancy status

Additional observations

• Signs of
  - Skin rash
  - Fever
  - Hypersensitivity reactions
• Signs and symptoms of infection

Coadministration with dolutegravir

• Etravirine decreased dolutegravir plasma concentrations, which may result in loss of virologic response and possible resistance to dolutegravir. Dolutegravir should not be used with etravirine without coadministration of atazanavir/ ritonavir, darunavir/ ritonavir or lopinavir/ ritonavir (South African recommendations)
• Efavirenz decreased dolutegravir plasma concentrations. Alternative combinations that do not include efavirenz should be used where possible in integrase inhibitor (INI)-resistant patients (South African recommendations)
• Coadministration of antacids containing polyvalent cations decreased dolutegravir plasma concentrations. Dolutegravir is recommended to be administered 4 hours before or 6 hours after taking antacid products containing polyvalent cations (South African recommendations)
• Calcium or iron supplements: Dolutegravir is recommended to be administered 4 hours before or 6 hours after taking products containing calcium or iron. Alternatively, administer with food
• Coadministration of dolutegravir increased metformin plasma concentrations. A dose adjustment of metformin should be considered when starting and stopping co-administration of dolutegravir/ rilpivirine with metformin, to maintain glycaemic control 

Coadministration with rilpivirine

• Concomitant use of rilpivirine with clarithromycin, erythromycin and troleandomycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered 
• Rilpivirine should not be used in combination with systemic dexamethasone as coadministration may cause significant decreases in rilpivirine plasma concentrations (induction of CYP3A enzymes). This may result in loss of therapeutic effect of rilpivirine. Alternatives should be considered, particularly for long-term use
• The combination of rilpivirine and H₂-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (gastric pH increase). H₂-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after dolutegravir/ rilpivirine
• The combination of rilpivirine and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (gastric pH increase). Antacids should only be administered either at least 2 hours before or at least 4 hours after dolutegravir/ rilpivirine

Mannitol and lactose monohydrate precaution (South African recommendations)

• Dolutegravir/ rilpivirine contains sugars/sweeteners such as mannitol and lactose monohydrate which may have a mild laxative effect

Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HV replication cycle. In vitro, dolutegravir dissociates slowly from the active site of the wild type integrase–DNA complex (t_1/2 71 hours). Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV. Rilpivirine activity is mediated by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β and γ. 

Film-coated tablet 50mg/25mg

• Daliduo (Cipla Medpro)