Source: Health Products Regulatory Authority (ZA) Revision Year: 2024 Publisher: Viatris Healthcare (Pty) Ltd, 4 Brewery Street, Isando, Kempton Park, 1600, Republic of South Africa
Safety and efficacy of the individual active ingredients in various antiretroviral combination regimens with similar dosages as contained in ACRIPTEGA have been established in clinical studies for the treatment of HIV patients. However, safety and efficacy of the fixed drug combination as in ACRIPTEGA for the treatment of HIV have not been established in clinical studies.
ACRIPTEGA can cause depression and suicidal ideation behaviour, particularly in patients with a pre-existing history of depression or psychiatric illness. Patients should inform their doctor if they notice any symptoms of depression during treatment.
The complete package inserts of the other medicines used in combination should be consulted before initiation of therapy.
Combination antiretroviral therapy, including ACRIPTEGA has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia.
Combination antiretroviral therapy, including ACRIPTEGA, 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.
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 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 can occur many months after initiation of treatment.
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 ACRIPTEGA. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Patients receiving ACRIPTEGA 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 antiretroviral ACRIPTEGA, 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 ACRIPTEGA. Early symptoms (symptomatic hyperlactataemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific 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 respond 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 ACRIPTEGA alone or in combination, in the treatment of HIV infection. Most cases were women.
Caution should be exercised when administering ACRIPTEGA to patients with known risk factors for liver disease.
Treatment with ACRIPTEGA 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 ACRIPTEGA 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.
Patients at increased risk should be followed closely.
There are no study results demonstrating the effect of ACRIPTEGA on clinical progression of HIV-1.
Nucleoside and nucleotide analogues as contained in ACRIPTEGA 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 ACRIPTEGA. 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 ACRIPTEGA until diagnosis of pancreatitis is excluded.
In patients with moderate to severe renal impairment, the terminal half-life of ACRIPTEGA is increased due to decreased clearance. The dose of ACRIPTEGA should therefore be adjusted (see section 4.2 Posology and method of administration).
Use of ACRIPTEGA can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis).
The safety and efficacy of ACRIPTEGA 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.
ACRIPTEGA is a combination product and the dose of the individual components cannot be altered. Tenofovir and lamivudine are principally eliminated by the kidney. ACRIPTEGA is not recommended for patients with creatinine clearance < 50 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 ACRIPTEGA.
Since ACRIPTEGA is primarily eliminated by the kidneys, co-administration of ACRIPTEGA with medicines that reduce renal function or compete for active tubular secretion may increase serum concentrations of ACRIPTEGA and/or increase the concentrations of other renally eliminated medicines. Some examples include, but are 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 patients 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 MRP 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.
ACRIPTEGA 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.
ACRIPTEGA 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 ACRIPTEGA. Decreases in bone mineral density of the hip are significantly greater. Clinically relevant bone fractures are reported.
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 monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk of osteopenia.
Reductions of bone mineral density (BMD) have been observed with tenofovir disoproxil in randomised controlled clinical trials of duration up to 144 weeks in HIV or HBV-infected patients (see section 4.8 Undesirable effects). These BMD decreases generally improved after treatment discontinuation.
In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen in patients treated with tenofovir disoproxil as part of a regimen containing a boosted protease inhibitor. Overall in view of the bone abnormalities associated with tenofovir disoproxil and the limitations of long-term data on the impact of tenofovir disoproxil on bone health and fracture risk, alternative treatment regimens should be considered for patients with osteoporosis or with a history of bone fractures.
Bone abnormalities such as osteomalacia which can manifest as persistent or worsening bone pain and, which can infrequently contribute to fractures may be associated with tenofovir disoproxil-induced proximal renal tubulopathy (see section 4.8 Undesirable effects).
ACRIPTEGA is not indicated for the treatment of chronic HBV infection. The safety and efficacy of ACRIPTEGA 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 inserts for these medicines.
Patients with chronic hepatitis B or C treated with ACRIPTEGA 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 decompensated 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. Typically, such reactions have been observed within the first few weeks or months of initiation of cART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii (carinii) pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Safety and effectiveness in paediatric patients and patients <18 years of age have not been established.
Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
ACRIPTEGA contains lactose. Patients with rare hereditary conditions of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency or glucose-galactose malabsorption should not take ACRIPTEGA.
ACRIPTEGA contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
The likelihood of interactions is low due to the limited metabolism as plasma protein binding and almost complete renal clearance.
Zidovudine plasma levels are not significantly altered when co-administered with Lamivudine. Zidovudine has no effect on the pharmacokinetics of lamivudine. Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when the two medicinal products 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 ACRIPTEGA. As ACRIPTEGA contains tenofovir disoproxil fumarate and lamivudine, any interactions that have been identified with these individual medicines may occur with ACRIPTEGA. Important medicine interaction information for ACRIPTEGA is summarised in Tables 1 and 2. The medicine interactions described are based on studies conducted with tenofovir disoproxil fumarate or lamivudine as individual medicines or are potential medicine 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 medicinal products is low.
An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40% increase in lamivudine exposed 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 ACRIPTEGA, is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. Co-administration of ACRIPTEGA 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 ACRIPTEGA.
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 1 and 2 summarise pharmacokinetic effects of co-administered 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 increased 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 fasted conditions.
Table 1. Medicine Interactions: Changes in Pharmacokinetic Parameters for Tenofovir1 in the Presence of Co-Administered Medicines:
| Co-administered Medicine | Dose of co-administered medicine (mg) | N | % change of Tenofovir Pharmacokinetic Parameters2 (90% Cl) | ||
|---|---|---|---|---|---|
| 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 subjects 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 medicine interactions between these medicines and tenofovir disoproxil fumarate.
Table 2. 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 Tenofovir Pharmacokinetic Parameters1 (90% Cl) | ||
|---|---|---|---|---|---|
| Cmax | AUC | Cmin | |||
| Abacavir | 300 once | 8 | ↑ 122 (↑ 1 to ↑ 26) | ↔ | NA |
| Adefovir dipivoxil | 10 once | 22 | ↔ | ↔ | NA |
| 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 | ↔ | ↔ | ↔ |
| Ribavarin | 600 once | 22 | ↔ | ↔ | NA |
| 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 subjects were maintained on their stable methadone dose. No pharmacodynamic 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.
Pharmacokinetic parameters (Mean ± SD) after a single 300 mg Oral dose of Lamivudine in 3 groups of Adults with varying degrees of Renal Function:
| Parameters | Creatinine Clearance Criterion (Number of Subjects) | ||
|---|---|---|---|
| >60 mL/min (n=6) | 10-30 mL/min (n=4) | <10 mL/min (n=6) | |
| Creatinine clearance (mL/min) | 111 ± 14 | 28 ± 8 | 6 ± 2 |
| Cmax (mcg/mL) | 2,6 ± 0,5 | 3,6 ± 0,8 | 5,8 ± 1,2 |
| AUC∞ (mcg/mL) | 11,0 ± 1,7 | 48,0 ± 19 | 157 ± 74 |
| C1/F (mL/min) | 464 ± 76 | 114 ± 34 | 36 ± 11 |
Pharmacokinetic Parameters (Geometric Mean [95% CI]) after Repeat Dosing of Lamivudine in 3 Paediatric Trials:
| Trial (Number of Subjects) | ||||||
|---|---|---|---|---|---|---|
| ARROW PK (n=35) | PENTA-13 (n=19) | PENTA-15 (n=17)a | ||||
| Age Range | 3-12 years | 2-12 years | 3-36 months | |||
| Formulation | Tablet | Solution and Tabletb | Solution | |||
| Parameter | Once Daily | Twice Daily | Once Daily | Twice Daily | Once Daily | Twice Daily |
| Cmax (mcg/mL) | 3,17 (2,76, 3,64) | 1,80 (1,59, 2,04) | 2,09 (1,80, 2,42) | 1,11 (0,96, 1,29) | 1,87 (1,65, 2,13) | 1,05 (0,88, 1,26) |
| AUC(0-24) (mcgmL) | 13,0 (11,4, 14,9) | 12,0 (10,7, 13,4) | 9,80 (8,64, 11,1) | 8,88 (7,67, 10,3) | 8,66 (7,46, 10,1) | 9,48 (7,89, 11,4) |
The likelihood of metabolic interactions is low due to limited metabolism and plasma protein binding and almost complete renal clearance.
Zidovudine plasma levels are not significantly altered when co-administered with ACRIPTEGA.
Zidovudine has no effect on the pharmacokinetics of ACRIPTEGA.
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.
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. ACRIPTEGA may inhibit the intracellular phosphorylation of zalcitabine when the two medicines are used concurrently. ACRIPTEGA is therefore not recommended to be used in combination with zalcitabine.
Administration of trimethoprim, a constituent of co-trimoxazole causes an increase in ACRIPTEGA plasma levels. Unless the patient has renal impairment, no dosage adjustment of ACRIPTEGA is necessary. ACRIPTEGA 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.
The co-administration of ACRIPTEGA with etravirine (ETR) is not recommended unless the patient is also receiving concomitant atazanavir + ritonavir (ATV + RTV), lopinavir + ritonavir (LPV + RTV) or darunavir + ritonavir (DRV +RTV) (see section 4.5 Interaction with other medicines and other forms of interaction).
Table 3. Medicine Interactions:
| Concomitant Medicine Class: Medicine Name | Effect on Concentration of TIVICAY or Concomitant Medicine | Clinical comment |
|---|---|---|
| HIV-1 Antiviral Agents | ||
| 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. ACRIPTEGA 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 contained in ACRIPTEGA 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 contained in ACRIPTEGA 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. |
| Protease inhibitor: Atazanavir (ATV) | Dolutegravir ↑ AUC ↑ 91% Cmax ↑ 49% Cτ ↑ 180% ATV ↔ | Atazanavir increased dolutegravir plasma concentrations. 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 in 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 contained in ACRIPTEGA 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 III studies. No dose adjustment is necessary in INI-naïve 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 ↔ LPV ↔ RTV ↔ | 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% | 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 Agents | ||
| 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 ACRIPTEGA is contra-indicated due to the potential life- threatening toxicity caused by high dofetilide or pilsicainide concentration (see section 4.3 Contraindications). |
| Oxcarbazepine Phenytoin Phenobarbital 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. |
| Antacids containing polyvalent cations (e.g., Mg, Al or Ca) | Dolutegravir ↓ AUC ↓ 74% Cmax ↓ 72% C24 ↓ 74% | Co-administration of antacids containing polyvalent cation decreased dolutegravir plasma concentration. ACRIPTEGA 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% | ACRIPTEGA 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% | ACRIPTEGA is recommended to be administered 2 hours before or 6 hours after taking products containing iron, or alternatively, administer with food. |
| Metformin | Metformin ↑ | Co-administration of dolutegravir increased metformin plasma concentration. |
| Rifampicin | Dolutegravir ↓ AUC ↓ 54% Cmax ↓ 43% Cτ↓ 72% | Rifampicin decreased dolutegravir plasma concentration. The recommended dose of dolutegravir contained in ACRIPTEGA 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 Norgestromin (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 ACRIPTEGA. |
| 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 ACRIPTEGA. |
Rifampicin decreases the blood levels of dolutegravir. A supplementary dose of dolutegravir should be given to patients taking ACRIPTEGA.
There is evidence that the concentration of isoniazid is increased by dolutegravir, as contained in ACRIPTEGA.
In vitro, ACRIPTEGA demonstrated no direct, or weak inhibition (IC50 >50 mM) 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, OATP1B3, OCT1 or MRP2.
In vitro, dolutegravir did not include CYP1A2, CYP2B6 or CYP3A4. In vivo, dolutegravir did not have an effect on midazolam, CYP3A4 probe. Based on these data, ACRIPTEGA 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 agents (such as sildenafil, tadalafil, vardenafil), acyclovir, valaciclovir, sitagliptin, adefovir).
In 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 inhibited the renal organic cation transporter 2 (OTC2). Based on this observation, ACRIPTEGA may increase plasma concentrations of medicines in which excretion is dependent upon OCTZ (dofetilide, metformin).
ACRIPTEGA should not be co-administered with polyvalent cation-containing antacids. ACRIPTEGA is recommended to be administered 2 hours before or 6 hours after these medicines (see section 4.5 Interaction with other medicines and other forms of interaction).
Metformin concentrations may be increased by ACRIPTEGA.
ACRIPTEGA should not be prescribed in women who plan to become pregnant. Woman of child-bearing age should not use ACRIPTEGA unless they are reliably using highly effect contraception. Treatment with ACRIPTEGA should not be initiated without a medically supervised negative pregnancy test. This test should be repeated at frequent intervals during treatment with ACRIPTEGA; and especially in the event that pregnancy is suspected.
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 ACRIPTEGA in women of childbearing potential to exclude inadvertent (unintentional) use of ACRIPTEGA 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.
ACRIPTEGA is contraindicated in pregnancy and lactation.
Tenofovir, dolutegravir and lamivudine were shown to cross the placenta in reproductive toxicity studies in animals. Late onset neurological disorders, including seizures, have been observed in children who have been exposed to nucleoside analogues such as tenofovir and lamivudine, (see Mitochondrial Dysfunction under (section 4.4 Special warnings and precautions for use).
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.
Mothers breastfeeding their infants should not use ACRIPTEGA. HIV infected women should not breastfeed their infants in order to avoid transmission of HIV or follow appropriate guidelines. Dolutegravir is excreted in human breast milk, and there is significant exposure to the neonate/infants due to slow elimination; the half-life of dolutegravir in the newborn was 33 hr compared to 14 hr in the adults. There is insufficient information on the effects of dolutegravir in neonates/infants.
Lamivudine is excreted in human milk at similar concentrations to those found in serum and tenofovir is excreted in breast milk. Lamivudine passes into breast milk.
Mothers taking ACRIPTEGA should not breastfeed their infants.
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.
ACRIPTEGA 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 ACRIPTEGA affects them.
ACRIPTEGA can have side effects.
Less frequent: depression
The following side effects have been reported during therapy for HIV disease with ACRIPTEGA tablets alone and in combination with other antiretrovirals.
Lamivudine:
Tabulated summary of adverse reactions
| Tabulated summary of adverse reactions to ACRIPTEGA and its individual components | |
|---|---|
| Frequency | Adverse reaction |
| Blood and lymphatic system disorders | |
| Less frequent | Neutropenia, anaemia, thrombocytopenia, pure red cell aplasia |
| Metabolism and nutrition disorders | |
| Frequent | Hyperlactataemia |
| Less frequent | Lactic acidosis, lipodystrophy (redistribution/accumulation of body fat) (see section 4.4 Special warnings and precautions for use) |
| Nervous system disorders | |
| Frequent | Headache, insomnia |
| Less frequent | Paraesthesia, peripheral neuropathy has been reported, although a causal relationship to treatment is uncertain, late onset neurological disorders in children exposed in utero |
| Gastrointestinal disorders | |
| Frequent | Nausea, vomiting, upper abdominal pain, diarrhoea |
| Less frequent | Pancreatitis, although a causal relationship to treatment is uncertain, rise in serum amylase |
| Hepato-biliary disorders | |
| Less frequent | Transient rises in liver enzymes (AST, ALT) |
| Skin and subcutaneous tissue disorders | |
| Frequent | Rash, alopecia |
| Musculoskeletal and connective tissue disorders | |
| Frequent | Arthralgia, muscle disorders |
| Less frequent | Rhabdomyolysis, decrease in bone mineral density, osteopenia, fractures |
| General disorders and administration site conditions | |
| Frequent | Fatigue, malaise, fever |
Tenofovir disoproxil fumarate:
| Tabulated summary of adverse reactions to ACRIPTEGA and its individual components | |
|---|---|
| Frequency | Adverse reaction |
| Immune system disorders | |
| Less frequent | Allergic reaction |
| Metabolism and nutrition disorders | |
| Frequency unknown | Hypophosphataemia, lactic acidosis |
| Respiratory, thoracic, and mediastinal disorders | |
| Frequency unknown | Dyspnoea |
| Gastrointestinal disorders | |
| Frequency unknown | Abdominal pain, increased amylase, pancreatitis |
| Hepato-biliary disorders | |
| Frequency unknown | Increased liver enzymes, hepatitis |
| Musculoskeletal and connective tissue disorders | |
| Frequent | Bone mineral density decreased |
| Less frequent | Rhabdomyolysis, muscular weakness, osteomalacia (manifested as bone pain and infrequently contributing to fractures), myopathy |
| Renal and urinary disorders | |
| Frequency unknown | Renal insufficiency, renal failure, acute renal failure, Fanconi syndrome, proximal tubulopathy, proteinuria, increased creatinine, acute tubular necrosis, nephrogenic diabetes insipidus |
Dolutegravir:
| Tabulated summary of adverse reactions to ACRIPTEGA and its individual components | |
|---|---|
| Frequency | Adverse reaction |
| Immune system disorders | |
| Less frequent | Hypersensitivity, immune reconstitution syndrome |
| Psychiatric disorders | |
| Frequent | Insomnia |
| Nervous system disorders | |
| Frequent | Headache, dizziness, abnormal dreams |
| Gastrointestinal disorders | |
| Frequent | Nausea, vomiting upper abdominal pain, diarrhoea, flatulence |
| Less frequent | Abdominal pain, abdominal discomfort |
| Hepato-biliary disorders | |
| Less frequent | Hepatitis |
| Skin and subcutaneous tissue disorders | |
| Frequent | Rash, pruritus |
| General disorders and administration site conditions | |
| Frequent | Fatigue |
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 requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.
Not applicable.
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