Lamivudine, Tenofovir disoproxil and Doravirine

Doravirine has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). It is not known whether the exposure to doravirine will increase in patients with severe hepatic impairment. Therefore, caution is advised when doravirine/lamivudine/tenofovir disoproxil is administered to patients with severe hepatic impairment.

All patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy.

Severe acute exacerbations of hepatitis B (e.g., liver decompensated and liver failure) have been reported in patients who are co-infected with HIV-1 and HBV, and have discontinued lamivudine or tenofovir disoproxil. Patients who are co-infected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with doravirine/lamivudine/tenofovir disoproxil. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

There are no or limited amount of data from the use of doravirine in pregnant women. A large amount of data on pregnant women (more than 3 000 outcomes from first trimester) taking the individual active component lamivudine in combination with other antiretrovirals indicates no malformative toxicity. A moderate amount of data on pregnant women (between 300-1 000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with tenofovir disoproxil.

Antiretroviral pregnancy registry: To monitor maternal-foetal outcomes in patients exposed to antiretroviral medicinal products while pregnant, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients in this registry.

Animal studies with doravirine do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

Animal studies with tenofovir disoproxil do not indicate direct or indirect harmful effects of tenofovir disoproxil with respect to reproductive toxicity.

Animal studies with lamivudine showed an increase in early embryonic deaths in rabbits but not in rats. Placental transfer of lamivudine has been shown to occur in humans. Lamivudine may inhibit cellular DNA replication. The clinical relevance of this finding is unknown.

As a precautionary measure, it is preferable to avoid the use of doravirine/lamivudine/tenofovir disoproxil during pregnancy.

It is unknown whether doravirine is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of doravirine in milk.

Lamivudine has been identified in breast-fed newborns/infants of treated women. Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breast-fed infants of mothers treated for HIV are very low (<4% of maternal serum concentrations) and progressively decrease to undetectable levels when breast-fed infants reach 24 weeks of age. There are no data available on the safety of lamivudine when administered to babies less than three months old.

Tenofovir is excreted in human milk. There is insufficient information on the effects of tenofovir in newborns/infants.

Because of the potential for HIV-1 transmission and the potential for serious adverse reactions in breast-feeding infants, mothers should be instructed not to breast-feed if they are receiving doravirine/lamivudine/tenofovir disoproxil.

Fertility

No human data on the effect of doravirine/lamivudine/tenofovir disoproxil on fertility are available. Animal studies do not indicate harmful effects of doravirine, lamivudine, or tenofovir disoproxil on fertility at exposure levels higher than the exposure in humans at the recommended clinical dose.

Doravirine/lamivudine/tenofovir disoproxil combination may have a minor influence on the ability to drive and use machines. Patients should be informed that fatigue, dizziness, and somnolence have been reported during treatment with doravirine/lamivudine/tenofovir disoproxil. This should be considered when assessing a patient’s ability to drive or operate machinery.

Summary of the safety profile

In phase 3 clinical trials with doravirine plus 2 nucleoside analogue reverse transcriptase inhibitors (NRTIs), the most frequently reported adverse reactions were nausea (4%) and headache (3%).

Tabulated summary of adverse reactions

The adverse reactions with doravirine plus 2 NRTIs from Phase 3 clinical trials (DRIVE FORWARD, DRIVE SHIFT and DRIVE AHEAD) are listed below by body system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 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), or very rare (<1/10,000).

Tabulated summary of adverse reactions associated with doravirine/lamivudine/tenofovir disoproxil:

^* This adverse reaction was not identified as an adverse reaction associated with doravirine from the Phase 3 clinical studies (DRIVE-FORWARD, DRIVE-AHEAD, DRIVE-SHIFT), but is included in this table as an adverse reaction based on the Summary of Product Characteristics of 3TC and/or TDF. The highest frequency category reported in the 3TC or TDF Summary of Product Characteristics is used.
^† This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally
associated with tenofovir disoproxil in the absence of this condition.
¹ insomnia includes: insomnia, initial insomnia and sleep disorder.
² depression includes: depression, depressed mood, major depression, and persistent depressive disorder.
³ anxiety includes: anxiety and generalised anxiety disorder.
⁴ abdominal pain includes: abdominal pain, and abdominal pain upper.
⁵ abdominal discomfort includes: abdominal discomfort, and epigastric discomfort.
⁶ faeces soft includes: faeces soft and abnormal faeces.
⁷ gastrointestinal motility disorder includes: gastrointestinal motility disorder, and frequent bowel movements.
⁸ rash includes: rash, rash macular, rash erythematous, rash generalised, rash maculo-papular, rash papular, and urticarial.
⁹ alanine aminotransferase increased includes: alanine aminotransferase increased andhepatocellular injury.

Immune reactivation syndrome

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Lactic acidosis

Cases of lactic acidosis have been reported with tenofovir disoproxil alone or in combination with other antiretrovirals. Patients with predisposing factors such as patients with decompensated liver disease, or patients receiving concomitant medicinal products known to induce lactic acidosis are at increased risk of experiencing severe lactic acidosis during tenofovir disoproxil treatment, including fatal outcomes.

Paediatric population

The safety of doravirine/lamivudine/tenofovir disoproxil was evaluated in 45 HIV-1 infected virologically suppressed or treatment-naïve paediatric patients 12 to less than 18 years of age through Week 48 in an open-label trial (IMPAACT 2014 (Protocol 027)). The safety profile in paediatric subjects was similar to that in adults.