Dolutegravir and Rilpivirine interacts in the following cases:
In patients with severe renal impairment or end-stage renal disease, dolutegravir/rilpivirine should be used with caution, as rilpivirine plasma concentrations may be increased secondary to renal dysfunction. No data are available in subjects receiving dialysis although haemodialysis or peritoneal dialysis are not expected to affect dolutegravir or rilpivirine exposure.
Dolutegravir/rilpivirine should be used with caution in patients with moderate hepatic impairment.
No data are available in patients with severe hepatic impairment (Child-Pugh score C); therefore dolutegravir/rilpivirine is not recommended in these patients.
No clinical data are available in patients with hepatitis B co-infection. Physicians should refer to current treatment guidelines for the management of HIV infection in patients co-infected with hepatitis B virus. Limited data is available in patients with hepatitis C co-infection. A higher incidence of liver chemistry elevations (Grade 1) were observed in patients treated with dolutegravir and rilpivirine co-infected with hepatitis C compared to those who were not co-infected. Monitoring of liver function is recommended in patients with hepatitis B and/or C co-infection.
Lower exposures of dolutegravir and rilpivirine were observed during pregnancy. In phase 3 studies, lower rilpivirine exposure, similar to that seen during pregnancy, has been associated with an increased risk of virological failure. The use of dolutegravir/rilpivirine during pregnancy is not recommended.
The safety and efficacy of a dual regimen has not been studied in pregnancy.
Human experience from a birth outcome surveillance study in Botswana shows a small increase of neural tube defects; 7 cases in 3,591 deliveries (0.19%; 95% CI 0.09%, 0.40%) to mothers taking dolutegravircontaining regimens at the time of conception compared to 21 cases in 19,361 deliveries (0.11%: 95% CI 0.07%, 0.17%) to women exposed to non-dolutegravir regimens at the time of conception.
The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live births (0.05-0.1%). Most neural tube defects occur within the first 4 weeks of embryonic development after conception (approximately 6 weeks after the last menstrual period).
Data analysed from the Antiretroviral Pregnancy Registry do not indicate an increased risk of major birth defects in over 600 women exposed to dolutegravir during pregnancy but are currently insufficient to address the risk of neural tube defects.
In animal reproductive toxicology studies with dolutegravir, no adverse development outcomes, including neural tube defects, were identified.
More than 1000 outcomes from exposure to dolutegravir during second and third trimester pregnancy indicate no evidence of increased risk of foetal/neonatal toxicity.
Dolutegravir crosses the placenta in humans. In pregnant women living with HIV, the median foetal umbilical cord concentration of dolutegravir was approximately 1.3-fold greater compared with the maternal peripheral plasma concentration.
There is insufficient information on the effects of dolutegravir on neonates.
Animal studies with rilpivirine do not indicate direct or indirect harmful effects with respect to reproductive toxicity.
It is unknown if rilpivirine is excreted in human milk. Available toxicological data in animals has shown excretion of rilpivirine in milk. Dolutegravir is excreted in human milk in small amounts (a median dolutegravir breast milk to maternal plasma ratio of 0.033 has been shown). There is insufficent information on the effects of dolutegravir in newborns/infants.
It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV.
There are no data on the effects of dolutegravir or rilpivirine on human male or female fertility. Animal studies indicate no clinically relevant effects on male or female fertility.
Women of childbearing potential should be counselled about the potential risk of neural tube defects with dolutegravir, including consideration of effective contraceptive measures.
If a woman plans pregnancy, the benefits and the risks of continuing treatment with dolutegravir/rilpivirine should be discussed with the patient.
Dolutegravir/rilpivirine has no or negligible influence on the ability to drive and use machines. Patients should be informed that fatigue, dizziness and somnolence have been reported during treatment with the components of dolutegravir/rilpivirine fixed-dose combination. The clinical status of the patient and the adverse reaction profile of dolutegravir/rilpivirine should be borne in mind when considering the patient’s ability to drive or operate machinery.
The most frequently reported adverse reactions with dolutegravir/rilpivirine (from clinical studies) were diarrhoea (2%) and headache (2%).
The most severe adverse reaction, related to the treatment with dolutegravir (from pooled Phase IIb and Phase III clinical studies), seen in an individual patient, was a hypersensitivity reaction that included rash and severe liver effects.
The sources of information for the safety database include 2 identical, randomised, open-label studies SWORD-1 and SWORD-2, pooled studies from individual components and post-marketing experience.
The adverse reactions considered at least possibly related to treatment with the components of dolutegravir/rilpivirine from clinical studies and post-marketing experience are listed in the table below by body system, organ class and frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), not known (cannot be estimated from the available data).
Tabulated list of adverse reactions to dolutegravir/rilpivirine based on clinical study and postmarketing experience with dolutegravir/rilpivirine fixed-dose combination and its individual components:
| System organ class (SOC) | Frequency category* | Adverse drug reactions |
|---|---|---|
| Blood and lymphatic systems disorders | common | decreased white blood cell count decreased haemoglobin decreased platelet count |
| Immune system disorders | uncommon | hypersensitivity |
| not known | immune reconstitution syndrome | |
| Metabolism and nutrition disorders | very common | increased total cholesterol (fasted) increased LDL cholesterol (fasted) |
| common | decreased appetite increased triglycerides (fasted) | |
| Psychiatric disorders | very common | insomnia |
| common | abnormal dreams depression sleep disorders depressed mood anxiety | |
| uncommon | suicidal ideation or suicide attempt (particularly in patients with a pre-existing history of depression or psychiatric illness), panic attack | |
| rare | completed suicide (particularly in patients with a preexisting history of depression or psychiatric illness) | |
| Nervous system disorders | very common | headache dizziness |
| common | somnolence | |
| Gastrointestinal disorders | very common | nausea increased pancreatic amylase diarrhoea |
| common | abdominal pain vomiting flatulence increased lipase abdominal discomfort upper abdominal pain dry mouth | |
| Hepatobiliary disorders | very common | increased transaminases (alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevations) |
| common | increased bilirubin | |
| uncommon | hepatitis | |
| rare | acute hepatic failure** | |
| Skin and subcutaneous tissue disorders | common | rash pruritus |
| Musculoskeletal and connective tissue disorders | uncommon | arthralgia myalgia |
| General disorders and administration site conditions | common | fatigue |
| Investigations | common | creatine phosphokinase (CPK) elevations, weight increased |
* Frequencies are assigned based on the maximum frequencies observed in the pooled SWORD studies or studies with the individual components
** This adverse reaction was identified through post-marketing surveillance for dolutegravir in combination with other ARVs. The frequency category of rare was estimated based on postmarketing reports.
Dolutegravir or rilpivirine have been associated with increases in serum creatinine occurring in the first week of treatment when administered with other antiretroviral medicinal products. Increases in serum creatinine occurred within the first four weeks of treatment with dolutegravir/rilpivirine and remained stable through 148 weeks. A mean change from baseline of 9.86 µmol/L (SD 10.4 µmol/L) was observed after 148 weeks treatment. These changes are related to inhibition of active transport, and are not considered to be clinically relevant as they do not reflect a change in glomerular filtration rate.
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.
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