Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Ranbaxy Pharmaceuticals (Pty) Ltd, 14 Lautre Road, Stormill, Ext.1, Roodepoort, 1724, South Africa
Safety and efficacy of the individual active ingredients in various antiretroviral combination regimens with similar dosages as contained in Telatri have been established in clinical studies for the treatment of HIV patients. However, safety and efficacy of the fixed-drug combination as in Telatri for the treatment of HIV have not been established in clinical studies.
The complete package inserts of the other medicines used in this combination should be consulted before initiation of therapy.
Combination antiretroviral therapy, including Telatri has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia.
Combination antiretroviral therapy, including Telatri, has also been associated with the redistribution/accumulation of body fat, including central obesity, dorso-cervical fat, enlargement (buffalo hump), peripheral wasting, facial wasting and breast enlargement in HIV patients.
A higher risk of lipodystrophy has been associated with individual factors such as older age, and with medicine related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Fasting serum lipids and blood glucose levels should be monitored. Lipid disorders should be managed as clinically appropriate. Patients with evidence of lipodystrophy should also have a thorough cardiovascular risk assessment.
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), including components of Telatri. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Patients receiving Telatri may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by doctors experienced in the treatment of patients with HIV associated diseases.
Patients must be advised that treatment with Telatri, have not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions must continue to be used.
Lactic acidosis, usually associated with hepatic steatosis, including fatal cases, has been reported with the use of nucleoside analogues, such as in Telatri. Early symptoms (symptomatic hyperlactataemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), nonspecific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness). Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure or renal failure.
Lactic acidosis generally occurs after a few or several months of treatment. Treatment with nucleoside analogues should be discontinued in the setting of symptomatic hyperlactataemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.
Suspicious biochemical features include mild raised transaminases, raised lactate dehydrogenase (LDH) and/or creatine kinase.
In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal <2 mmol/l) and responds as follows:
The above lactate values may not be applicable to paediatric patients.
Diagnosis of lactic acidosis is confirmed by demonstrating metabolic acidosis with an increased anion gap and raised lactate level. Therapy should be stopped in any acidotic patient with a raised lactate level.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of Telatri alone or in combination, in the treatment of HIV infection. Most cases were women.
Caution should be exercised when administering Telatri to patients with known risk factor for liver disease.
Treatment with Telatri should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity. Caution should be exercised when administering nucleoside analogues as contained in Telatri to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicines and alcohol). Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk. Patients at increased risk should be followed closely. However, cases have also been reported in patients with no known risk factors.
There are no study results demonstrating the effect of Telatri on clinical progression of HIV-1.
Nucleoside and nucleotide analogues as contained in Telatri 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 postnatally to nucleoside analogues. The main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactataemia, hyperlipidaemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms.
Pancreatitis has been observed in some patients receiving lamivudine, as in Telatri. It is unclear whether this is due to lamivudine or to underlying HIV disease. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of Telatri until diagnosis of pancreatitis is excluded.
In patients with moderate to severe renal impairment, the terminal half-life of Telatri is increased due to the decreased clearance (see section 4.3).
Use of Telatri can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis).
The safety and efficacy of Telatri has not been established in patients with significant underlying liver disorders. Patients with pre-existing liver dysfunction including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.
Telatri is a combination product and the dose of the individual components cannot be altered. Tenofovir and lamivudine are principally eliminated by the kidney. Telatri is not recommended for patients with creatinine clearance <80 ml/min or patients who require haemodialysis. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphataemia) has been reported with the use of tenofovir disoproxil fumarate in clinical practice. Careful monitoring of renal function (serum creatinine and serum phosphate) is therefore recommended before taking Telatri.
Since Telatri is primarily eliminated by the kidneys, co-administration of Telatri with medicines that reduce renal function or compete for active tubular secretion may increase serum concentrations of Telatri and/or increase the concentrations of other renally eliminated medicines. Some examples include, but not limited to adefovir dipivoxil, cidofovir, aciclovir, valaciclovir, ganciclovir and valganciclovir.
Renal safety with tenofovir has only been studied to a very limited degree in adult patients with impaired renal function (creatinine clearance <80 ml/min).
It is recommended that renal function (creatinine clearance and serum phosphate) is assessed in all patient prior to initiating therapy with tenofovir disoproxil fumarate and that it is also monitored every four weeks during the first year of tenofovir disoproxil fumarate therapy, and then every three months. In patients at risk for renal impairment, including patients who have previously experienced renal events while receiving adefovir dipivoxil, consideration should be given to more frequent monitoring of renal function.
Use of tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic medicine (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2). If concomitant use of tenofovir disoproxil fumarate and nephrotoxic medicines is unavoidable, renal function should be monitored weekly.
Tenofovir disoproxil fumarate has not been clinically evaluated in patients receiving medicines which are secreted by the same renal pathway, including the transport proteins human organic anion transporter (hOAT) 1 and 3 or MRP 4 (e.g. cidofovir, a known nephrotoxic medicine). These renal transport proteins may be responsible for tubular secretion and in part, renal elimination of tenofovir and cidofovir. Consequently, the pharmacokinetics of these medicines, which are secreted by the same renal pathway including transport proteins hOAT 1 and 3 or MPR 4, might be modified if they are co-administered. Unless clearly necessary, concomitant use of these medicines which are secreted by the same renal pathway is not recommended, but if such use is unavoidable, renal function should be monitored weekly.
Telatri should be avoided with concurrent or recent use of a nephrotoxic medicine. Patients at risk of, or with a history of, renal dysfunction and patients receiving concomitant nephrotoxic substances should be carefully monitored for changes in serum creatinine and phosphorus.
Telatri should be avoided in antiretroviral experienced patients with HIV-1 harbouring the K65R mutation.
Decreases in bone mineral density of spine and changes in bone biomarkers from baseline are significantly greater with tenofovir disoproxil fumarate as contained in Telatri. Decreases in bone mineral density of the hip are significantly greater. Clinically relevant bone fractures are reported. If bone abnormalities are suspected then appropriate consultation should be obtained. Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk of osteopenia.
Telatri may cause a reduction in bone mineral density. The effects of tenofovir disoproxil fumarate-associated changes in bone mineral density on long-term bone health and future fracture risk are currently unknown.
Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained. Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy.
Telatri is not indicated for the treatment of chronic HBV infection. The safety and efficacy of Telatri has not been established for the treatment of patients co-infected with HBV and HIV.
Patients with chronic hepatitis B or C and treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. Medical practitioners should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with hepatitis B virus (HBV). In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant package insert for these medicines.
Patients with chronic hepatitis B or C treated with Telatri are at an increased risk for severe and potentially fatal hepatic adverse reactions. Doctors should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with hepatitis B virus (HBV).
Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients. In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy.
Acute exacerbations of hepatitis have been reported in patients after the discontinuation of hepatitis B therapy. Post-treatment exacerbations are usually associated with rising HBV DNA, and the majority appears to be self-limited. However, severe exacerbations, including fatalities, have been reported. Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B therapy. If appropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation. Liver flares are especially serious, and sometimes fatal in patients with decompensation liver disease.
In HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (cART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Immune reconstitution inflammatory syndrome (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 Anti-Retroviral 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, atypical mycobacterial infections, cytomegalovirus retinitis, pneumocystis jirovecii (carinii) pneumonia, and cryptococcal meningitis. Appropriate treatment of the opportunistic disease should be instituted or continued and ART continued. Inflammatory manifestations generally subside after a few weeks. 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, Guillain-Barre Syndrome, Polymyositis) have also been reported as IRIS reactions; however, the reported time to onset is more variable and these events may occur many months after initiation of the treatment.
Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Hypersensitivity reactions have been reported with integrase inhibitors, including dolutegravir and were characterised by rash, constitutional findings and sometimes, organ dysfunction, including liver injury. Discontinue dolutegravir and other suspect medicines immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping treatment with dolutegravir or other suspect medicines after the onset of hypersensitivity may result in a life-threatening reaction.
Safety and effectiveness in paediatric patients and patients < 18 years of age have not been established.
Clinical studies did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
The likelihood of interactions is low due to the limited metabolism and plasma protein binding and almost complete renal clearance. Zidovudine plasma levels are not significantly altered when coadministered with lamivudine. Zidovudine has no effect on the pharmacokinetics of lamivudine. Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when the two medicines are used concurrently. Lamivudine is therefore not recommended to be used in combination with zalcitabine. Administration of trimethoprim, a constituent of co-trimoxazole causes an increase in lamivudine plasma levels. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary. Lamivudine has no effect on the pharmacokinetics of co-trimoxazole. The possibility of interactions with other medicines administered concurrently should be considered, particularly when the main route is renal.
No medicine interaction studies have been conducted using Telatri. As Telatri contains tenofovir disoproxil fumarate and lamivudine, any interactions that have been identified with these individual medicines may occur with Telatri. Important medicine interaction information for Telatri is summarised in Tables 3, 4 and 5. The medicine interactions described are based on studies conducted with tenofovir disoproxil fumarate or lamivudine as individual medicines, or are potential medicines interactions. While the tables include potentially significant interactions, they are not all inclusive. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450 mediated interactions involving tenofovir with other medicines is low.
An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40% increase in lamivudine exposure at therapeutic doses. This does not require dose adjustment unless the patient also has renal impairment. Administration of co-trimoxazole with the lamivudine/zidovudine combination in patients with renal impairment should be carefully assessed.
Tenofovir, as in Telatri, is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. Co-administration of Telatri with medicines that are eliminated by active tubular secretion may increase serum concentrations of either tenofovir or the co-administered medicines due to competition for this elimination pathway. Medicines that decrease renal function may also increase serum concentrations of tenofovir, as in Telatri.
Tenofovir has been evaluated in healthy volunteers in combination with abacavir, adefovir dipivoxil, atazanavir, didanosine, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone, oral contraceptives and ribavirin. Tables 3 and 4 summarise pharmacokinetic effects of coadministered medicine on tenofovir pharmacokinetics and effects of tenofovir on the pharmacokinetics of co-administered medicine.
When administered with multiple doses of tenofovir, the Cmax and AUC of didanosine 400 mg increase significantly. The mechanism of this interaction is unknown.
When didanosine 250 mg enteric-coated capsules were administered with tenofovir, systemic exposures to didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasting conditions.
Table 2. Medicine Interactions: Changes in pharmacokinetic parameters for tenofovir1 in the presence of coadministered medicines:
| Co-administered medicine | Dose of Co- administered Medicine (mg) | N | % Change of Tenofovir Pharmacokinetic Parameters2 (90% CI) | ||
|---|---|---|---|---|---|
| Cmax | AUC | Cmin | |||
| Abacavir | 300 once | 8 | ↔ | ↔ | NC |
| Adefovir dipivoxil | 10 once | 22 | ↔ | ↔ | ↔ |
| Atazanavir | 400 once daily x 14 days | 33 | ↑ 14 (↑ 8 to ↑ 20) | ↑ 24 (↑ 21 to ↑ 28) | ↑ 22 (↑ 15 to ↑ 30) |
| Didanosine (enteric coated) | 400 once | 25 | ↔ | ↔ | ↔ |
| Didanosine (buffered) | 250 or 400 once daily x 7 days | 14 | ↔ | ↔ | ↔ |
| Efavirenz | 600 once daily x 14 days | 29 | ↔ | ↔ | ↔ |
| Emtricitabine | 200 once daily x 7 days | 17 | ↔ | ↔ | ↔ |
| Indinavir | 800 three times daily x 7 days | 13 | ↑ 14 (↓ 3 to ↑ 33) | ↔ | ↔ |
| Lamivudine | 150 twice daily x 7 days | 15 | ↔ | ↔ | ↔ |
| Lopinavir/Ritonavir | 400/100 twice daily x 14 days | 24 | ↔ | ↑ 32 (↑ 25 to ↑ 38) | ↑ 51 (↑ 37 to ↑ 66) |
1 Patients received tenofovir DF 300 mg once daily
2 Increase = ↑; Decrease = ↓; No effect = ↔; NC= Not calculated
Following multiple dosing to HIV-negative patients receiving either chronic methadone maintenance therapy, oral contraceptives, or single doses of ribavirin, steady state tenofovir pharmacokinetics were similar to those observed in previous studies, indicating a lack of clinically significant medicines interactions between these medicines and tenofovir disoproxil fumarate.
Table 3. Medicine Interactions: Changes in pharmacokinetic parameters for co-administered medicines in the presence of tenofovir:
| Co-administered medicine | Dose of Co- administered Medicine (mg) | N | % Change of Co- administered Medicine Pharmacokinetic Parameters1 (90% Cl) | ||
|---|---|---|---|---|---|
| Cmax | AUC | Cmin | |||
| Abacavir | 300 once | 8 | ↑ 122 (↑ 1 to ↑ 26) | ↔ | N/A |
| Adefovir dipivoxil | 10 once | 22 | ↔ | ↔ | N/A |
| Efavirenz | 600 mg once daily x 14 days | 30 | ↔ | ↔ | ↔ |
| Emtricitabine | 200 mg once daily x 7 days | 17 | ↔ | ↔ | ↔ |
| Indinavir | 800 mg three times daily x 7 days | 12 | ↑ 14 (↓ 3 to ↑ 33) | ↔ | ↔ |
| Lamivudine | 150 mg twice daily x 7 days | 15 | ↔ | ↔ | ↔ |
| Lopinavir/Ritonavir | 400/100 mg twice daily x 14 days | 21 | ↔ | ↔ | ↔ |
| Methadone2 | 40-110 once daily x 14 days3 | 13 | ↔ | ↔ | ↔ |
| Oral contraceptives4 | Ethinyl oestradiol/Norgestimate (Ortho-Tricyclen) Once daily x 7 days | 20 | ↔ | ↔ | ↔ |
| Ribavirin | 600 once | 22 | ↔ | ↔ | N/A |
| Ritonavir | Lopinavir/Ritonavir 400/100 twice daily x 14 days | 24 | ↔ | ↔ | ↔ |
| Atazanavir5 | 400 once daily x 14 days | 29 | ↔ | ↔ | ↔ |
| Atazanavir5 | Atazanavir/Ritonavir 300/100 once daily x 42 days | 10 | ↑ 28 (↑ 50 to ↑ 5) | ↑ 25 (↑ 42 to ↑ 3) | ↑ 236 (↑ 46 to ↑ 10) |
1 Increase = ↑; Decrease = ↓; No effect = ↔; NA = Not applicable
2 R-(active), S- and total methadone exposures were equivalent when dosed alone or with tenofovir as tenofovir disoproxil fumarate 300 mg.
3 Individual patients were maintained on their stable methadone dose. No pharmacodynamics alterations (opiate toxicity or withdrawal signs or symptoms) were reported.
4 Ethinyl oestradiol and 17-deacetyl norgestimate (pharmacologically active metabolite) exposures were equivalent when dosed alone or with tenofovir as tenofovir DF 300 mg.
5 REYATAZ US Prescribing Information (Bristol-Myers Squibb)
6 In HIV-infected patients, addition of tenofovir disoproxil fumarate to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2, 3 and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone.
Tenofovir disoproxil fumarate should not be administered concomitantly with other medicines containing tenofovir disoproxil fumarate or tenofovir alafenamide.
Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil fumarate with medicines that reduce renal function or compete for active tubular secretion via transport proteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir and/or the co-administered medicines.
Use of tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic medicines. Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see section 4.4).
Tacrolimus can affect renal function, close monitoring is recommended when it is co-administered with tenofovir disoproxil fumarate.
Interactions between tenofovir disoproxil fumarate and other medicines are listed in Table 4 below.
Table 4. Interactions between tenofovir disproxil fumarate and other medicines:
| Medicines by therapeutic area (dose in mg) | Effect on medicine levels mean percent change in AUC, Cmax, Cmin | Recommendations on co- administration with 245 mg tenofivir disoproxil (as fumarate) |
|---|---|---|
| Anti-infectives | ||
| Anitretrovirals | ||
| Protease Inhibitors (PIs) | ||
| Darunavir/Ritonavir (300 mg/100 mg twice daily / 300 mg OD) | Darunavir: No significant effect on darunavir/ritonavir Tenofovir: AUC: ↑ 22% Cmin: ↑ 37% | No dose adjustment is recommended. The increased exposure of tenofovir could potentiate tenofovir adverse events, including renal disorders. Renal function should be closely monitored. |
| Hepatitis C virus medicines | ||
| Ledipasvir/Sofosbuvir (90 mg/400 mg once daily) + Atazanavir/Ritonavir (300 mg/100 mg once daily) + Emtricitabine/Tenofovir disoproxil fumarate (200 mg/300 mg once daily)1 | Ledipasvir: AUC: ↑ 96% Cmax: ↑ 68% Cmin: ↑ 118% Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↑ 42% Atazanavir: AUC: ↔ Cmax: ↔ Cmin: ↑ 63% Ritonavir: AUC: ↔ Cmax: ↔ Cmin: ↑ 45% Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↔ Cmax: ↑ 47% Cmin: ↑ 47% | Increased plasma concentrations of tenofovir resulting from co- administration of tenofovir disoproxil fumarate, ledipasvir/sofosbuvir and atazanavir/ritonavir may increase adverse reactions related to tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with ledipasvir/sofosbuvir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been reported. The combination should be used with caution with frequent renal monitoring, if other alternatives are not available. |
| Ledipasvir/Sofosbuvir (90 mg/400 mg once daily) + Darunavir/Ritonavir (800 mg/100 mg once daily) + Emtricitabine/Tenofovir disoproxil fumarate (200 mg / 300 mg once daily)1 | Ledipasvir: AUC: ↔ Cmax: ↔ Cmin: ↔ Sofosbuvir: AUC: ↓ 27% Cmax: ↓ 37% GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Darunavir: AUC: ↔ Cmax: ↔ Cmin: ↔ Ritonavir: AUC: ↔ Cmax: ↔ Cmin: ↑ 48% Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 50% Cmax: ↑ 64% Cmin: ↑ 59% | Increased plasma concentrations of tenofovir resulting from co- administration of tenofovir disoproxil fumarate, ledipasvir/sofosbuvir and darunavir/ritonavir may increase adverse reactions related to tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with ledipasvir/sofosbuvir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been reported. The combination should be used with caution with frequent renal monitoring, if other alternatives are not available. |
| Ledipasvir/Sofosbuvirv(90 mg/400 mg once daily) + Efavirenz/Emtricitabine/ Tenofovir disoproxil fumarate (600 mg/200 mg/300 mg once daily) | Ledipasvir: AUC: ↓ 34% Cmax: ↓ 34% Cmin: ↓ 34% Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Efavirenz: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 98% Cmax: ↑ 79% Cmin: ↑ 163% | No dose adjustment is recommended. The increased exposure of tenofovir could potentiate adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders. Renal function should be closely monitored. |
| Ledipasvir/Sofosbuvir (90 mg/400 mg once daily) + Emtricitabine/Rilpivirine/ Tenofovir disoproxil fumarate (200 mg/25 mg/300 mg once daily) | Ledipasvir: AUC: ↔ Cmax: ↔ Cmin: ↔ Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Rilpivirine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 40% Cmax: ↔ Cmin: ↑ 91% | No dose adjustment is recommended. The increased exposure of tenofovir could potentiate adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders. Renal function should be closely monitored. |
| Ledipasvir/Sofosbuvir (90 mg/400 mg once daily) + Dolutegravir (50 mg once daily) + Emtricitabine/Tenofovir disoproxil fumarate (200 mg/300 mg once daily) | Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072AUC: ↔ Cmax: ↔ Cmin: ↔ Ledipasvir: AUC: ↔ Cmax: ↔ Cmin: ↔ Dolutegravir AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 65% Cmax: ↑ 61% Cmin: ↑ 115% | No dose adjustment is recommended. The increased exposure of tenofovir could potentiate adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders. Renal function should be closely monitored. |
| Sofosbuvir/Velpatasvir (400 mg/100 mg once daily) + Atazanavir/Ritonavir (300 mg mg once daily./100 mg once daily) + Emtricitabine/Tenofovir disoproxil fumarate (200 mg/300 mg once daily) | Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↑ 42% Velpatasvir: AUC: ↑ 142% Cmax: ↑ 55% Cmin: ↑ 301% Atazanavir: AUC: ↔ Cmax: ↔ Cmin: ↑ 39% Ritonavir: AUC: ↔ Cmax: ↔ Cmin: ↑ 29% Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↔ Cmax: ↑ 55% Cmin: ↑ 39% | Increased plasma concentrations of tenofovir resulting from co- administration of tenofovir disoproxil fumarate, sofosbuvir/velpatasvir and atazanavir/ritonavir may increase adverse reactions related to tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with sofosbuvir/velpatasvir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established. The combination should be used with caution with frequent renal monitoring. |
| Sofosbuvir/Velpatasvir (400 mg/100 mg once daily) + Darunavir/Ritonavir (800 mg q.d./100 mg once daily) + Emtricitabine/Tenofovir disoproxil fumarate (200 mg/300 mg once daily) | Sofosbuvir: AUC: ↓28% Cmax: ↓ 38% GS-33100722: AUC: ↔ Cmax: ↔ Cmin: ↔ Velpatasvir: AUC: ↔ Cmax: ↓ 24% Cmin: ↔ Darunavir: AUC: ↔ Cmax: ↔ Cmin: ↔ Ritonavir: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 39% Cmax: ↑ 55% Cmin: ↑ 52% | Increased plasma concentrations of tenofovir resulting from co- administration of tenofovir disoproxil fumarate, sofosbuvir/velpatasvir and darunavir/ritonavir may increase adverse reactions related to tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with sofosbuvir/velpatasvir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established. The combination should be used with caution with frequent renal monitoring. |
| Sofosbuvir/Velpatasvir (400 mg/100 mg once daily) + Lopinavir/Ritonavir (800 mg/200 mg once daily) + Emtricitabine/Tenofovir disoproxil fumarate (200 mg/300 mg once daily) | Sofosbuvir: AUC: ↓ 29% Cmax: ↓ 41% GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Velpatasvir: AUC: ↔ Cmax: ↓ 30% Cmin: ↑ 63% Lopinavir: AUC: ↔ Cmax: ↔ Cmin: ↔ Ritonavir: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↔ Cmax: ↑ 42% Cmin: ↔ | Increased plasma concentrations of tenofovir resulting from co- administration of tenofovir disoproxil fumarate, sofosbuvir/velpatasvir and lopinavir/ritonavir may increase adverse reactions related to tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with sofosbuvir/velpatasvir and a pharmacokinetic enhancer (e.g. ritonavir or cobicistat) has not been established. The combination should be used with caution with frequent renal monitoring. |
| Sofosbuvir/Velpatasvir (400 mg/100 mg once daily) + Raltegravir (400 mg twice daily) + Emtricitabine/Tenofovir disoproxil fumarate (200 mg/300 mg once daily) | Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Velpatasvir: AUC: ↔ Cmax: ↔ Cmin: ↔ Raltegravir: AUC: ↔ Cmax: ↔ Cmin: ↓ 21% Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 40% Cmax: ↑ 46% Cmin: ↑ 70% | No dose adjustment is recommended. The increased exposure of tenofovir could potentiate adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders. Renal function should be closely monitored. |
| Sofosbuvir/Velpatasvir (400 mg/100 mg once daily) + Efavirenz/Emtricitabine/ Tenofovir disoproxil fumarate (600 mg/200 mg/300 mg once daily) | Sofosbuvir: AUC: ↔ Cmax: ↑ 38% GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Velpatasvir: AUC: ↓ 53% Cmax: ↓ 47% Cmin: ↓ 57% Efavirenz: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 81% Cmax: ↑ 77% Cmin: ↑ 121% | Concomitant administration of sofosbuvir/velpatasvir and efavirenz is expected to decrease plasma concentrations of velpatasvir. Co-administration of sofosbuvir/velpatasvir with efavirenz-containing regimens is not recommended. |
| Sofosbuvir/Velpatasvir (400 mg/100 mg once daily) + Emtricitabine/Rilpivirine/ Tenofovir disoproxil fumarate (200 mg/25 mg/300 mg once daily) | Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Velpatasvir: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Rilpivirine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 40% Cmax: ↑ 44% Cmin: ↑ 84% | No dose adjustment is recommended. The increased exposure of tenofovir could potentiate adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders. Renal function should be closely monitored. |
| Sofosbuvir (400 mg once daily) + Efavirenz/Emtricitabine/ Tenofovir disoproxil fumarate (600 mg/200 mg/300 mg once daily) | Sofosbuvir: AUC: ↔ Cmax: ↓ 19% GS-3310072: AUC: ↔ Cmax: ↓ 23% Efavirenz: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↔ Cmax: ↑ 25% Cmin: ↔ | No dose adjustment is required. |
1 Data reported from simultaneous dosing with ledipasvir/sofosbuvir. Staggered administration (12 hours apart) provided similar results.
2 The predominant circulating metabolite of sofosbuvir.
There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil was reportedly co-administered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (ritonavir boosted), methadone, ribavirin, rifampicin, tacrolimus or the hormonal contraceptive norgestimate/ethinyl oestradiol.
The likelihood of metabolic interactions is low due to limited metabolism and plasma protein binding and almost completed renal clearance.
Zidovudine plasma levels are not significantly altered when co-administered with Telatri. Zidovudine has no effect on the pharmacokinetics of Telatri.
Co-administration of zidovudine results in a 13% increase in zidovudine exposure and a 28% increase in peak plasma levels. This is not considered to be of significance to patient safety and therefore no dosage adjustments are necessary.
Telatri may inhibit the intracellular phosphorylation of zalcitabine when the two medicines are used concurrently. Telatri is therefore not recommended to be used in combination with zalcitabine.
Administration of trimethoprim, a constituent of co-trimoxazole causes an increase in Telatri plasma levels. Unless the patient has renal impairment, no dosage adjustment of Telatri is necessary. Telatri has no effect on the pharmacokinetics of co-trimoxazole. Administration of co-trimoxazole with the Telatri in patients with renal impairment should be carefully assessed.
The possibility of interactions with other medicines administered concurrently should be considered, particularly when the main route is renal.
The co-administartion of Telatri with etravine (ETR) is not recommended unless the patient is also receiving concomitant atrazanivir + ritonavir (ATV + RTV), lopinavir + ritonavir (DRV + RTV).
Other medicines (e.g. ranitidine, cimetidine) are eliminated only in part by active renal secretion via the organic cationic transport system and were reported not to interact with lamivudine. The nucleoside analogues (e.g. didanosine) like zidovudine, are not eliminated by this mechanism and are unlikely to interact with lamivudine. Due to similarities, lamivudine should not be administered concomitantly with other cytidine analogues, such as emtricitabine.
In vitro lamivudine inhibits the intracellular phosphorylation of cladribine leading to a potential risk of cladribine loss of efficacy in case of combination in the clinical setting. Some of the reported clinical findings also support a possible interaction between lamivudine and cladribine. Therefore, the concomitant use of lamivudine with cladribine is not recommended. Lamivudine metabolism does not involve CYP3A, making interactions with medicines metabolised by this system (e.g. PIs) unlikely.
Co-administration of sorbitol solution (3.2 g, 10.2 g, 13.4 g) with a single 300 mg dose of lamivudine oral solution resulted in a reported dose-dependent decreases of 14%, 32%, and 36% in lamivudine exposure (AUC∞) and 28%, 52%, and 55% in the Cmax of lamivudine in adults. When possible, avoid chronic co-administration of Telatri with medicines containing sorbitol or other osmotic acting poly-alcohols or monosaccharide alcohols (e.g. xylitol, mannitol, lactitol, maltitol). Consider more frequent monitoring of HIV-1 viral load when chronic co-administration cannot be avoided.
Rifampicin decreases blood levels of dolutegravir. A supplementary dose of dolutegravir should be given to patients taking Telatri.
There is evidence that the concentration of isoniazid is increased by dolutegravir, as contained in Telatri.
Telatri should not be co-administered with polyvalent cation-containing antacids. Telatri is recommended to be administered 2 hours before or 6 hours after these medicines.
Metformin concentrations may be increased by Telatri. Metformin is contra-indicated in patients taking Telatri (see section 4.3).
Effect of Dolutegravir on the Pharmacokinetics of other medicines:
In vitro, dolutegravir reported no direct, or weak inhibition (IC50 >50 µM) of the enzymes cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate glucuronosyl transferase (UGT)1A1 or UGT2B7, or the transporters Pgp, BCRP, OATP1B1, OATP1B3, OCT1 or MRP2.
In vitro, dolutegravir did not induce CYP1A2, CYP2B6 or CYP3A4. In vivo, dolutegravir reportedly did not have an effect on midazolam, a CYP3A4 probe. Based on reported data, dolutegravir is not expected to affect the pharmacokinetics of medicines that are substrates of these enzymes or transporters (e.g., reverse transcriptase and protease inhibitors, opioid analgesics, antidepressants, statins, azole antifungals (such as fluconazole, itraconazole, clotrimazole), proton pump inhibitors (such as esomeprazole, lansoprazole, omeprazole), anti-erectile dysfunction medicines (such as sildenafil, tadalafil, vardenafil), aciclovir, valaciclovir, sitagliptin, adefovir).
In reported medicine interaction studies, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following: tenofovir, methadone, efavirenz, lopinavir, atazanavir, darunavir, etravirine, fosamprenavir, rilpivirine, telaprevir and oral contraceptives containing norgestimate and ethinyl estradiol.
In vitro, dolutegravir reportedly inhibited the renal organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter (MATE) 1. In vivo, a 10-14% decrease of creatinine clearance (secretory fraction is dependent on OCT2 and MATE-1 transport) was reported in patients. Dolutegravir may increase plasma concentrations of medicines in which excretion is dependent upon OCT2 or MATE-1 (dofetilide, metformin) (see Table 5: Medicine Interactions – other medicines).
In vitro, dolutegravir was reported to inhibit the renal uptake transporters, organic anion transporters (OAT1) and OAT3. Based on the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibition of OAT1 is unlikely. Inhibition of OAT3 has not been reported to be studied in vivo. Dolutegravir may increase plasma concentrations of medicines in which excretion is dependent upon OAT3.
Effect of other medicines on the Pharmacokinetics of dolutegravir:
Dolutegravir is reported to be eliminated mainly through metabolism by UGT1Al. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP; therefore medicines that induce those enzymes may theoretically decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir.
Co-administration of dolutegravir and other medicines that inhibit: UGT1A11 UGT1A3, UGT1A9, CYP3A4, and/or Pgp may increase dolutegravir plasma concentration (Table 5).
Efavirenz, nevirapine, rifampicin and tipranavir in combination with ritonavir each reduced the plasma concentrations of dolutegravir significantly and require dolutegravir dose adjustment to 50 mg twice daily.
Etravirine also reduced plasma concentrations, but the effect of etravirine was mitigated by coadministration of the CYP3A4 inhibitors lopinavir/ritonavir, darunavir/ritonavir and is expected to be mitigated by atazanavir/ritonavir. Therefore no dolutegravir dose adjustment is necessary when coadministered with etravirine and either lopinavir/ritonavir, darunavir/ritonavir, or atazanavir/ritonavir. Another inducer, fosamprenavir in combination with ritonavir decreased plasma concentrations of dolutegravir but does not require a dosage adjustment of dolutegravir. Caution is warranted and clinical monitoring is recommended when these combinations are given in INI-resistant patients (see Table 5: HIV-1 Antiviral Medicines).
A medicine interaction study with the UGTlA1 inhibitor, atazanavir, did not result in a clinically meaningful increase in the plasma concentrations of dolutegravir. Tenofovir, ritonavir, lopinavir/ritonavir, darunavir/ritonavir, rilpivirine, bocepravir, telaprevir, prednisone, rifabutin, and omeprazole had no or a minimal effect on dolutegravir pharmacokinetics, therefore no dolutegravir dose adjustment is required when co-administered with these medicines.
Table 5. Medicine Interactions:
| Concomitant Medicine Class: Medicine Name | Effect on Concentration of dolutegravir or Concomitant Medicine | Clinical Comment |
|---|---|---|
| HIV-1 Antiviral medicines | ||
| Non-nucleoside Reverse Transcriptase Inhibitor: Etravirine (ETR) | Dolutegravir ↓ AUC ↓ 71 % Cmax ↓ 52 % Cτ ↓ 88 % ETR ↔ | Etravirine decreased dolutegravir plasma concentration, which may result in loss of virologic response and possible resistance to dolutegravir. Dolutegravir should not be used with etravirine without co-administration of atazanavir/ritonavir darunavir/ritonavir or lopinavir/ritonavir. |
| Non-nucleoside Reverse Transcriptase Inhibitor: Efavirenz (EFV) | Dolutegravir ↓ AUC ↓ 57 % Cmax ↓ 39 % Cτ ↓ 75 % EFV ↔ | Efavirenz decreased dolutegravir plasma concentrations. The recommended dose of dolutegravir is 50 mg twice daily when co- administered with efavirenz. Alternative combinations that do not include efavirenz should be used where possible in INI-resistant patients. |
| Non-nucleoside Reverse Transcriptase Inhibitor: Nevirapine | Dolutegravir ↓ | Co-administration with nevirapine has the potential to decrease dolutegravir plasma concentration due to enzyme induction and has not been studied. Effect of nevirapine on dolutegravir exposure is likely similar to or less than that of efavirenz. The recommended dose of dolutegravir is 50 mg twice daily when co-administered with nevirapine. Alternative combinations that do not include nevirapine should be used where possible in INI- resistant patients. |
| Rilpivirine | Dolutegravir ↔ AUC ↑ 12 % Cmax ↑ 13 % Cτ ↑ 22 % Rilpivirine ↔ | No dose adjustment is necessary. |
| Protease Inhibitor: Atazanavir (ATV) | Dolutegravir ↑ AUC ↑ 91 % Cmax ↑ 50 % Cτ ↑ 180 % ATV ↔ | Atazanavir increased dolutegravir plasma concentration. No dose adjustment is necessary. |
| Protease Inhibitor: Atazanavir/ritonavir (ATV + RTV) | Dolutegravir ↑ AUC ↑ 62 % Cmax ↑ 33 % Cτ ↑ 121 % ATV ↔ RTV ↔ | Atazanavir/ritonavir increased dolutegravir plasma concentration. No dose adjustment is necessary. |
| Protease Inhibitor: Tipranavir/ritonavir (TPV+RTV) | Dolutegravir ↓ AUC ↓ 59 % Cmax ↓ 47 % Cτ ↓ 76 % TPV ↔ RTV ↔ | Tipranavir/ritonavir decreases dolutegravir concentrations. The recommended dose of dolutegravir is 50 mg twice daily when co-administered with tipranavir/ritonavir. Alternative combinations that do not include tipranavir/ritonavir should be used where possible in INI resistant patients. |
| Protease Inhibitor: Fosamprenavir/ ritonavir (FPV+RTV) | Dolutegravir ↓ AUC ↓ 35 % Cmax ↓ 24 % Cτ ↓ 49 % FPV ↔ RTV ↔ | Fosamprenavir/ritonavir decreases dolutegravir concentrations, but based on limited data, did not result in decreased efficacy in Phase Ill studies. No dose adjustment is necessary in INI-naive patients. Alternative combinations that do not include fosamprenavir/ritonavir should be used where possible in INI resistant patients. |
| Protease Inhibitor: Nelfinavir | Dolutegravir ↔ | This interaction has not been studied. Although an inhibitor of CYP3A4, based on data from other inhibitors, an increase is not expected. No dose adjustment is necessary. |
| Protease Inhibitor: Lopinavir/ritonavir (LPV + RTV) | DTG ↔ AUC ↔ Cmax ↔ Cτ ↔ | Lopinavir/ritonavir did not change dolutegravir plasma concentration to a clinically relevant extent. No dose adjustment is necessary. |
| Protease Inhibitor: Darunavir/ritonavir (DRV + RTV) | Dolutegravir ↓ AUC ↓ 32 % Cmax ↓ 11 % Cτ ↓ 38 % DRV ↔ RTV ↔ | Darunavir/ritonavir did not change dolutegravir plasma concentration to a clinically relevant extent. No dose adjustment is necessary. |
| Nucleoside Reverse Transcriptase Inhibitor: Tenofovir (TDV) | Dolutegravir ↔ TDV ↔ | Tenofovir did not change dolutegravir plasma concentration to a clinically relevant extent. No dose adjustment is necessary. |
| Protease Inhibitor: Lopinavir/ritonavir + Etravirine (LPV /RTV + ETR) | Dolutegravir ↔ AUC ↑ 10 % Cmax ↑ 7 % Cτ ↑ 28 % LPV ↔ RTV ↔ ETR ↔ | Lopinavir/ritonavir and etravirine did not change dolutegravir plasma concentration to a clinically relevant extent. No dose adjustment is necessary. |
| Protease Inhibitor: Darunavir/ritonavir + Etravirine (DRV/RTV + ETR) | Dolutegravir ↓ AUC ↓ 25 % Cmax ↓ 12 % Cτ ↓ 36 % DRV ↔ RTV ↔ | Darunavir/ritonavir and etravirine did not change dolutegravir plasma concentration to a clinically relevant extent. No dose adjustment is necessary. |
| Other Antiviral medicines | ||
| Telaprevir | Dolutegravir ↑ AUC ↑ 25 % Cmax ↑ 19 % Cτ ↑ 37 % Telaprevir ↔ (historical controls) (inhibition of CYP3A enzyme) | No dose adjustment is necessary |
| Boceprevir | Dolutegravir ↔ AUC ↑ 7 % Cmax ↑ 5 % Cτ ↑ 8 % Boceprevir ↔ (historical controls) | No dose adjustment is necessary. |
| Daclatasvir | Dolutegravir ↔ AUC ↑ 33 % Cmax ↑ 29 % Cτ ↑ 45 % Daclatasvir ↔ | Daclatasvir did not change dolutegravir plasma concentration to a clinically relevant extent. Dolutegravir did not change daclatasvir plasma concentration. No dose adjustment is necessary. |
| Other medicines | ||
| Dofetilide Pilsicainide | Dofetilide ↑ Pilsicainide ↑ | Co-administration of dolutegravir has the potential to increase dofetilide or pilsicainide plasma concentration via inhibition of OCT2 transporter; co-administration has not been studied. Dofetilide or pilsicainide co- administration with dolutegravir is contra- indicated due to the potential life-threatening toxicity caused by high dofetilide or pilsicainide concentration (see section 4.3). |
| Oxcarbazepine Phenytoin Phenobarbital Phenobarbitone Carbamazepine St. John’s wort | Dolutegravir ↓ | Co-administration may decrease dolutegravir plasma concentration and has not been studied. Co-administration with these metabolic inducers should be avoided. |
| Azole anti-fungal medicines Ketoconazole Fluconazole Itraconazole Posaconazole Voriconazole | Dolutegravir ↔ | No dose adjustment is necessary. Based on data from other CYP3A4 inhibitors, a marked increase is not expected. |
| Antacids containing polyvalent cations (e.g., Mg, AI or Ca) | Dolutegravir ↓ AUC ↓ 74 % Cmax ↓ 72 % C24 ↓ 74 % | Co-administration of antacids containing polyvalent cations decreased dolutegravir plasma concentration. Dolutegravir is recommended to be administered 2 hours before or 6 hours after taking antacid products containing polyvalent cations. |
| Calcium supplements | Dolutegravir ↓ AUC ↓ 39 % Cmax ↓ 37 % C24 ↓ 39 % | Dolutegravir is recommended to be administered 2 hours before or 6 hours after taking products containing calcium, or alternatively, administer with food. |
| Iron supplements | Dolutegravir ↓ AUC ↓ 54 % Cmax ↓ 57 % C24 ↓ 56 % | Dolutegravir is recommended to be administered 2 hours before or 6 hours after taking products containing iron, or alternatively, administer with food. |
| Multivitamin | Dolutegravir ↓ AUC ↓ 33 % Cmax ↓ 35 % C24 ↓ 32 % (Complex binding to polyvalent ions) | Multivitamins should be taken well separated in time from the administration of dolutegravir (minimum 2 hours after or 6 hours before). |
| Corticosteroids Prednisone | Dolutegravir ↔ AUC ↑ 11 % Cmax ↑ 6 % Cτ ↑ 17 % | No dose adjustment is necessary. |
| Metformin | Metformin ↑ | Co-administration of dolutegravir increased metformin plasma concentration. Metformin is contraindicated in patients taking dolutegravir (see section 4.3). |
| Antimycobacterials Rifabutin | Dolutegravir ↔ AUC ↓ 5 % Cmax ↑ 16 % Cτ ↓ 30 % (induction of UGT1A1 and CYP3A enzymes) | No dose adjustment is necessary. |
| Antimycobacterials Rifampicin | Dolutegravir ↓ AUC ↓ 54 % Cmax ↓ 43 % Cτ ↓72 % | Rifampicin decreased dolutegravir plasma concentration. The recommended dose of dolutegravir is 50 mg twice daily when co- administered with rifampicin. Alternatives to rifampicin should be used where possible for INI resistant patients. |
| Oral contraceptives (Ethinyl estradiol (EE) and Norelgestromin (NGMN) | Effect of Dolutegravir: EE ↔ AUC ↑ 3 % Cmax ↓ 1 % Cτ ↑ 2 % Effect of Dolutegravir: NGMN ↔ AUC ↓ 2 % Cmax ↓ 11 % Cτ ↓ 7 % | Dolutegravir did not change ethinyl estradiol and norgestromin plasma concentrations to a clinically relevant extent. No dose adjustment of oral contraceptives is necessary when co- administered with dolutegravir. |
| Methadone | Effect of dolutegravir: Methadone ↔ AUC ↓ 2 % Cmax ↔ 0 % Cτ ↓ 1 % | Dolutegravir did not change methadone plasma concentrations to a clinically relevant extent. No dose adjustment of methadone is necessary when co-administered with dolutegravir. |
Abbreviations: ↑ =increase; ↓ = decrease; ↔ = no significant change; AUC =area under the concentration versus time curve; Cmax =maximum observed concentration, Ct =concentration at the end of dosing interval.
Interaction studies have only been reported to be performed in adults.
Women of childbearing potential should be counselled about the potential risk of neural tube defects with dolutegravir (see below), including consideration of using effective contraceptive measures. Perform pregnancy testing before initiation of Telatri in women of childbearing potential to exclude inadvertent (unintentional) use of Telatri 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.
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.
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 new born was 33 hr compared to 14 hr in the adults. There is insufficient information on the effects of dolutegravir in neonates/infants.
Lamuvidine passes into breast milk. It is unknown whether tenofovir passes into breast milk. HIV infected women should not breastfeed their babies in order to avoid transmission of HIV to the baby.
There are no data on the effects of dolutegravir on human male or female fertility. Animal studies indicate no effects of dolutegravir on male or female fertility.
Telatri may affect the ability to drive and use machines. Patients should ensure that they do not engage in driving or using machines until they know how Telatri affects them.
| Body System | Lamivudine | Tenofovir Disoproxil Fumarate | Dolutegravir |
|---|---|---|---|
| Blood and lymphatic systems disorders | Less frequent: Neutropenia; anaemia, thrombocytopenia Frequency unknown: pure red cell aplasia | ||
| Immune system disorders | Frequency unknown: Autoimmune disorders (Graves' disease) (see section 4.4). Less frequent: Angioedema | Less frequent: Allergic reaction, angioedema | Less Frequent: Hypersensitivity; Immune Reconstitution syndrome |
| Metabolism and nutrition disorders | Frequent: Hyperlactataemia Less frequent: Lactic acidosis; lipodystrophy (redistribution/ accumulation of body fat) (see section 4.4). Frequency unknown: weight increase | Frequent: Hypophosphataemia, lipodystrophy, weight loss Less frequent: Lactic Acidosis, hypokalaemia Frequency unknown: weight increase | |
| Psychiatric disorders | Frequent: Insomnia, Depression, Anxiety Less Frequent: Suicidal ideation or suicide attempt (particularly in patients with a pre- existing history of depression or psychiatric illness) | ||
| Nervous system disorders | Frequent: Headache; insomnia Less frequent: Peripheral neuropathy (or paraesthesia), late onset neurological disorders in children exposed in utero. | Frequent: Dizziness, headache, depression, insomnia, peripheral neuropathy, anxiety | Frequent: Headache, Dizziness, Abnormal dreams |
| Respiratory, Thoracic and mediastinal disorders | Frequent: Cough, nasal symptoms | Frequent: Pneumonia Frequency unknown: Dyspnoea | |
| Gastrointestinal disorders | Frequent: Nausea, vomiting; upper abdominal pain or cramps; diarrhoea Less frequent: Pancreatitis; elevations in serum amylase | Frequent: Abdominal pain; anorexia; dyspepsia; flatulence; diarrhoea; vomiting, nausea Less frequent: Increased amylase; pancreatitis | Frequent: Nausea; Diarrhoea Less Frequent: Vomiting; flatulence; upper abdominal pain Frequency not known: Abdominal pain; abdominal discomfort |
| Hepatobiliary disorders | Less frequent: Transient rises in liver enzymes (AST, ALT); hepatitis | Less frequent: Increased liver enzymes; hepatitis, hepatic steatosis | Frequency not known: Hepatitis |
| Skin and subcutaneous tissue disorders | Frequent: Rash; alopecia | Frequent: Rash (pruritis, maculopapular rash, urticarial, vesiculobullous rash, pustular rash), sweating | Frequent: Rash; pruritus |
| Musculoskeletal and connective tissue disorders | Frequent: arthralgia, muscle disorders Less frequent: rhabdomyolysis, decrease in bone mineral density, osteopenia, fractures Frequency unknown: Osteonecrosis (see section 4.4). | Frequent: Arthralgia, myalgia Less frequent: Rhabdomyolysis, muscular weakness, osteomalacia (manifested as bone pain and infrequently contributing to fractures), myopathy Frequency unknown: Osteonecrosis (see section 4.4) | Less Frequent: Arthralgia; Myalgia |
| Renal and urinary disorders | Frequent: Renal insufficiency; renal failure; proximal tubulopathy; proteinuria; increases creatinine; acute tubular necrosis; nephrogenic diabetes insipidus. Less frequent: acute renal failure, nephritis (including acute interstitial nephritis) Frequency unknown: Fanconi syndrome | ||
| General disorders and administration site conditions | Frequent: fatigue, malaise, fever | Frequent: Asthenia, pain, fever, back pain, chest pain | Frequent: Fatigue |
| Investigations | Frequency unknown: levels of blood lipids and glucose may increase | Frequent: Grade 3 and 4 laboratory abnormalities in total cholesterol, triglyceride, creatine kinase, haematuria, neutrophil, urine glucose and serum glucose. Frequency unknown: Levels of blood lipids and glucose may increase. | Frequent: Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) elevations; Creatine phosphokinase (CPK) elevations Frequency unknown: increase in serum creatinine and total bilirubin (without clinical jaundice) |
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8
Not applicable.
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