Dolutegravir/ Lamivudine

Registered South African indications:

• Human immunodeficiency virus type 1 (HIV-1) infection

Contraindications
South African manufacturer recommendations

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Severe renal impairment (CrCl<50ml/min due to the lamivudine component)
• Severe hepatic impairment
• Coadministration with dofetilide and pilsicainide

International manufacturer recommendations

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Coadministration with medicinal agents with narrow therapeutic windows, that are substrates of organic cation transporter (OCT2), including but not limited to fampridine (also known as dalfampridine)

Cautions
South African manufacturer recommendations

• Pregnancy
• Breastfeeding
• Renal impairment (CrCl≥50ml/min)
• Mild to moderate (Child-Pugh grade A or B) hepatic impairment
• Elderly
• Known risk factors for hepatic disease
• Significant underlying hepatic disorders
  - Non-alcoholic fatty hepatic disease (hepatic steatosis)
  - Chronic hepatitis B or C (See additional prescribing points)
  - Advanced hepatic disease or cirrhosis
• Low CD4 counts
• Advanced HIV disease and/or long-term exposure to combination antiretroviral therapy (cART)
• HIV negative infants exposed in utero and/or post-natally to nucleoside analogues
• Coadministration with other medicinal agents which contains lamivudine or dolutegravir (See additional prescribing points)

International manufacturer recommendations

• Pregnancy
• Women of childbearing potential
• Breastfeeding
• Renal impairment
• Severe (Child-Pugh grade C) hepatic impairment
• Elderly
• Pre-existing hepatic dysfunction
  - Chronic active hepatitis
  - Chronic hepatitis B or C
• Pre-existing history of depression or psychiatric illness
• Severe immune deficiency at the time of institution of combination antiretroviral therapy (CART)
• Risk factors for osteonecrosis
  -Advanced HIV disease
  - Long-term exposure to CART
• HIV negative infants exposed in utero and/or post-natally to nucleoside analogue

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

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Human immunodeficiency virus (HIV type‑1) infection
- Naïve, treatment-experienced, and integrase inhibitor naïve patients with no known or suspected resistance to either antiretroviral component

Dolutegravir/ Lamivudine
50/300 (mg)

• Oral (tab): 1 tab, dly

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

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Dolutegravir/ lamivudine is a fixed-dose tablet and should not be prescribed for patients requiring dosage adjustments, such as those with CrCl<50ml/min

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Separate preparation of dolutegravir is available where a dose adjustment is required due to interactions

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For patients with integrase inhibitor resistance, dolutegravir/ lamivudine is not recommended. In this case, refer to the dolutegravir tablet product information

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Dolutegravir/ lamivudine is for oral administration and should be swallowed whole

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Dolutegravir/ lamivudine can be taken with or without food

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International manufacturer recommendations

Human immunodeficiency virus type 1 (HIV-1) infection 
- With no known or suspected resistance to the integrase inhibitor class, or lamivudine

Dolutegravir/ Lamivudine
50/300 (mg)

• Oral (tab):≥40kg: 1 tab, dly

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Should be prescribed by physicians experienced in the management of HIV infection

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Separate preparation of dolutegravir is available where a dose adjustment is indicated due to drug-drug interactions. In these cases, refer to the individual product information for dolutegravir

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Missed doses: If a dose is missed, dolutegravir/ lamivudine should be taken as soon as possible, providing the next dose is not due within 4 hours. If the next dose is due within 4 hours, the missed dose should not be taken and simply resume the usual dosing schedule

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Dolutegravir/ lamivudine is for oral administration

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Dolutegravir/ lamivudine can be taken with or without food

Paed. forms avail. and covered in this monograph: tab

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

• Not established for use in children below 18 years

International manufacturer recommendations

Human immunodeficiency virus type 1 (HIV-1) infection 
- With no known or suspected resistance to the integrase inhibitor class, or lamivudine

Dolutegravir/ Lamivudine
50/300 (mg)

• Younger than 12 years:<40kg: Not established for use
• 12 years and older:≥40kg: See adult dosage

Pregnancy
South African manufacturer recommendations

• 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/ lamivudine, the benefits and risks of continuing dolutegravir/ lamivudine 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/ lamivudine 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
• There have been reports of mild and transient elevations in serum lactate levels due to mitochondrial dysfunction in neonates and infants exposed in utero or peri-partum to nucleoside reverse transcriptase inhibitors such as lamivudine. There have also been reports of developmental delay, seizures and other neurological disorders. However, a causal relationship between these events and lamivudine exposure in utero and peri-partum has not been established
• Lamivudine was associated with findings in animal reproductive toxicity studies

International manufacturer recommendations

• Caution
• The safety and efficacy of a dual regimen has not been studied in pregnancy
• 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/ lamivudine, the benefits and risks of continuing dolutegravir/ lamivudine 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 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. Dolutegravir/ lamivudine may be used during the second and third trimester of pregnancy when the expected benefit justifies the potential risk to the foetus
• A large amount of data on the use of lamivudine in pregnant women (more than 5200 outcomes from first trimester) indicates no malformative toxicity
• Animal studies showed lamivudine may inhibit cellular DNA replication. The clinical relevance of these findings is unknown
• Mitochondrial dysfunction: Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues 
• Women of childbearing potential should be counselled 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/ lamivudine should be discussed with the patient

Breastfeeding
South African manufacturer recommendations

• Caution; not recommended 
• HIV infected women should not breastfeed their infants in order to avoid transmission of HIV or follow appropriate guidelines
• Both dolutegravir and lamivudine, are secreted 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 hours compared to 14 hours in the adults
• There is insufficient information on the effects of dolutegravir in neonates/infants
• Lamivudine is excreted in human milk at similar concentrations to those found in serum

International manufacturer recommendations

• Caution; not recommended 
• Dolutegravir is excreted in human milk in small amounts
• There is insufficient information on the effects of dolutegravir in neonates/infants
• Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breastfed infants of mothers treated for HIV are very low (<4% of maternal serum concentrations) and progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. There are no data available on the safety of lamivudine when administered to babies less than three months old
• It is recommended that HIV infected women do not breastfeed their infants under any circumstances in order to avoid transmission of HIV

Fertility 

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

Renal Impairment 
South African manufacturer recommendations

• CrCl≥50ml/min: Caution; dose adjustment recommended 
  Whilst no dosage adjustment of dolutegravir is necessary in patients with renal impairment, a dose reduction of lamivudine is required due to decreased clearance
• CrCl<50ml/min: Contraindicated 

International manufacturer recommendations

• CrCl≥50ml/min: Caution; no dose adjustment recommended 
  No dose adjustment is required in patients with mild renal impairment
• CrCl<50ml/min: Caution, not recommended 

Hepatic Impairment
South African manufacturer recommendations

• Mild to moderate (Child-Pugh grade A or B): Caution; no dose adjustment recommended 
  No dosage adjustment is necessary unless accompanied by renal impairment
• Severe (Child-Pugh grade C): Contraindicated 

International manufacturer recommendations

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

Elderly 
South African manufacturer recommendations

• Caution; no dose adjustment recommended 
  There are limited data on the use of dolutegravir/ lamivudine in patients aged 65 years and older. However, there is no evidence that elderly patients require a different dose than younger adult patients. When treating elderly patients, consideration needs to be given to greater frequency of decreased hepatic and renal function, haematological abnormalities and concomitant medicines or disease

International manufacturer recommendations

• Caution; no dose adjustment recommended 

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Dizziness
• Somnolence
• Peripheral neuropathy
• Paraesthesia
• Depression
• Anxiety
• Insomnia
• Abnormal dreams
• Suicidal ideation
• Suicide attempt
• Fatigue

Gastrointestinal Disorders 

• Nausea and vomiting
• Diarrhoea
• Flatulence
• Abdominal pain/discomfort
• Pancreatitis

Hepatobiliary Disorders 

• Increased alanine aminotransferase 
• Increased aspartate aminotransferase 
• Hepatitis
• Acute hepatic failure
• Increased bilirubin

Endocrine and Metabolic Disorders 

• Lactic acidosis
• Increased weight
• Increased serum lipids
• Increased blood glucose

Musculoskeletal Disorders 

• Arthralgia
• Muscle disorders
  - Myalgia
• Rhabdomyolysis
• Osteonecrosis

Skin and Subcutaneous Tissue Disorders 

• Rash
• Pruritus
• Alopecia
• Angioedema

Immune, Blood and Lymphatic System Disorders 

• Neutropenia
• Anaemia
• Thrombocytopenia
• Pure red cell aplasia
• Hypersensitivity (See additional prescribing points)
  - Rash
  - Severe liver effects
• Increased creatine phosphokinase
• Increased amylase 
•  Autoimmune disorders 
  - Graves' disease
  - Autoimmune hepatitis
• Immune reconstitution syndrome

• Medicinal agents in which excretion is dependent upon organic cation transporters (OCT2) and/or multi-antimicrobial extrusion protein (MATE1)
• Emtricitabine
• Fampridine (also known as dalfampridine)
• Metformin
• Etravirine without boosted protease inhibitors
• Efavirenz
• Nevirapine
• Tipranavir and ritonavir
• Rifampicin
• Carbamazepine
• Phenobarbital
• Phenytoin
• Oxcarbazepine
• Cladribine
• Sorbitol
• Magnesium/aluminium-containing antacids
• Calcium supplements (fasted intake)
• Iron supplements (fasted intake)
• Multivitamins containing calcium, iron and magnesium (fasted intake)

Other interactions

• Sorbitol
• Osmotic-acting poly-alcohols or monosaccharide alcohols
• Xylitol
• Mannitol
• Lactitol
• Maltitol
• St. John's wort

(See additional prescribing points for recommendations concerning coadministration)

• Hepatitis B (prior to initiation)
• Viral load
• CD4 count
• Renal function (baseline and during therapy)
• Hepatic function (baseline and during therapy)
   - Liver aminotransferases
  - Bilirubin
• Blood glucose 
• Lipid profile
• Weight 

 Specific cases may require

• Pregnancy status
• New-onset or worsening haematologic toxicity (in patients with CrCl<50ml/minute) (periodically and as clinically indicated)
  - Neutropenia
  - Anaemia

Additional observations

• Signs or symptoms of
  - Hypersensitivity reactions
  - Lactic acidosis

Coadministration with other medicinal agents

• The recommended dose of dolutegravir is 50mg twice daily when coadministered with rifampicin, carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St. John's wort, etravirine (without boosted protease inhibitors), efavirenz, nevirapine, or tipranavir/ritonavir
• Dolutegravir/ lamivudine should not be coadministered with polyvalent cation-containing antacids. Polyvalent cation-containing antacids are recommended to be taken 2 hours after or 6 hours before dolutegravir/ lamivudine
• When taken with food, dolutegravir/ lamivudine and supplements or multivitamins containing calcium, iron or magnesium can be taken at the same time. If dolutegravir/ lamivudine is administered under fasting conditions, supplements or multivitamins containing calcium, iron or magnesium are recommended to be taken 2 hours after or 6 hours before dolutegravir/ lamivudine
• Dolutegravir increased metformin concentrations. A dose adjustment of metformin should be considered when starting and stopping coadministration of dolutegravir/ lamivudine with metformin, to maintain glycaemic control. Metformin is eliminated renally and, therefore, it is of importance to monitor renal function when co-treated with dolutegravir/ lamivudine. This combination may increase the risk for lactic acidosis in patients with moderate renal impairment (stage 3a CrCl 45–59ml/min) and a cautious approach is recommended. Reduction of the metformin dose should be highly considered
• The combination of dolutegravir/ lamivudine with cladribine is not recommended
• Dolutegravir/ lamivudine should not be taken with any other medicinal product containing dolutegravir, lamivudine or emtricitabine, except where a dose adjustment of dolutegravir is indicated due to drug-drug interactions

Hypersensitivity reactions

• Hypersensitivity reactions have been reported with dolutegravir and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Dolutegravir/ lamivudine and other suspect medicinal products should be discontinued immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, 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)
• Clinical status including liver aminotransferases and bilirubin should be monitored. Delay in stopping treatment with dolutegravir/ lamivudine or other suspect active substances after the onset of hypersensitivity may result in a life-threatening allergic reaction

Lactic acidosis/hyperlactataemia

• Lamivudine, which is an active constituent of dolutegravir/ lamivudine, can cause potentially fatal lactic acidosis as a consequence of mitochondrial dysfunction. Clinical features include nausea, abdominal pain, dyspnoea, fatigue and weight loss
• The venous lactate level (normal 2mmol/l) and the serum bicarbonate level in patients with suspicious symptoms and biochemistry should be measured and handled as follows:
• Lactate 2-5mmol/l with minimum symptoms: switch to medicines that are less likely to cause lactic acidosis
• Lactate 5-10mmol/l with symptoms and/or reduced standard bicarbonate: Change NRTIs and change treatment option. Once lactate has settled, use medicines that are less likely to cause lactic acidosis. Other possible causes such as sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis and hyperthyroidism should be excluded
• Lactate >10mmol/l: Stop all therapy (80% mortality)
• Caution should be exercised when treating patients with known risk factors for liver disease. Treatment with dolutegravir/ lamivudine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity

Co-infection with hepatitis B or C

• Patients with chronic hepatitis B or C and treated with antiviral therapy are at an increased risk of developing severe and potentially fatal hepatic adverse reactions. Medical practitioners should refer to the current HIV treatment guidelines for the optimal management of HIV infection in patients coinfected with hepatitis B virus (HBV)
• Dolutegravir/ lamivudine contains lamivudine which is active against hepatitis B. Dolutegravir however lacks such activity. Lamivudine monotherapy is generally not considered an adequate treatment for hepatitis B, since the risk for hepatitis B resistance development is high. An additional antiviral medicine is therefore needed if dolutegravir/ lamivudine is used in HBV co-infected patients
• Patients co-infected with HIV and HBV who discontinue dolutegravir/ lamivudine should be closely monitored with both clinical and laboratory follow-up after stopping treatment. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation
• Aspartate transaminase and alanine transaminase abnormalities, as well as liver chemistry elevations consistent with immune reconstitution syndrome, may be increased in patients coinfected with hepatitis B and/or C that are treated with dolutegravir/ lamivudine. If there is worsening liver disease in these patients, temporary or permanent discontinuation of treatment must be considered

Immune reconstitution inflammatory syndrome (IRIS)

• IRIS is an immunopathological response resulting from the rapid restoration of pathogen specific immune responses to pre-existing antigens combined with immune dysregulation, which occurs shortly after starting combination antiretroviral therapy (cART). Typically, such reaction presents by paradoxical deterioration of opportunistic infections being treated or with unmasking of an asymptomatic opportunistic disease, often with an atypical inflammatory presentation
• IRIS usually develops within the first three months of initiation of ART and occurs more commonly in patients with low CD4 counts. Common examples of IRIS reactions to opportunistic diseases are tuberculosis, cytomegalovirus retinitis, pneumocystis jiroveci pneumonia, mycobacterium avium infection, and cryptococcal meningitis
• Appropriate treatment of the opportunistic disease should be instituted or continued, and ART continued. Severe cases may respond to glucocorticoids, but there is only limited evidence for this in patients with tuberculosis IRIS. Autoimmune disorders (such as Graves’ disease) have also been reported as IRIS reactions; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment

Opportunistic infections

• Patients receiving dolutegravir/ lamivudine should be advised that they may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close observation by healthcare professionals experienced in the treatment of patients with associated HIV disease. Regular monitoring of viral load and CD4 counts needs to be done

Risk of HIV transmission to others

• Patients should be advised that current antiretroviral therapy, including dolutegravir/ lamivudine, does not prevent the risk of transmission of HIV to others through sexual contact or blood

Lipodystrophy and metabolic abnormalities

• Combination antiretroviral therapy has been associated with body fat redistribution including central obesity, dorso-cervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and elevated serum lipid and glucose levels in HIV patients
• Clinical examination should include evaluation for physical signs of fat redistribution. Patients with evidence of lipodystrophy should have a thorough cardiovascular risk assessment

Osteonecrosis

• Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported, particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (cART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement

Pancreatitis

• Pancreatitis has been reported in patients receiving lamivudine which is an active constituent of dolutegravir/ lamivudine. It is uncertain whether this was due to treatment or underlying HIV disease. Pancreatitis should be considered if clinical symptoms like nausea, vomiting, and/or abdominal pain, or elevated biochemical markers indicative of pancreatitis occur. Therapy should be discontinued until pancreatitis is excluded

Weight and metabolic parameters

• The use of antiretroviral therapy may result in an increase in weight and blood lipid and glucose levels. Patients being treated with dolutegravir/ lamivudine should be advised to lead a healthy lifestyle and their lipid and glucose levels should be monitored

Mannitol precaution

• Dolutegravir/ lamivudine contains mannitol and may have a laxative effect

Dolutegravir inhibits human immunodeficiency virus (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 HIV replication cycle. Lamivudine, via its active metabolite 5'-triphosphates (TP) (an analogue for cytidine), inhibits reverse transcriptase of HIV-1 and HIV-2 through incorporation of the monophosphate form into the viral DNA chain, resulting in chain termination. Lamivudine triphosphate shows significantly less affinity for host cell DNA polymerases.

COMBINATION PREPARATIONS 

Dolutegravir/ Lamivudine

Tablet 50mg/300mg

• Lomida (Cipla Medpro) originator