Dapivirine

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of the dapivirine vaginal ring in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity that are relevant to use of the dapivirine vaginal ring. Although safety has not been established in pregnancy, the benefits of treatment should be considered for pregnant women at high risk of HIV infection, considering the subsequent risk of HIV transmission to the unborn child.

Dapivirine has been shown to be excreted in human milk. In one clinical study, dapivirine concentrations in breast milk from sixteen HIV-1 negative mothers who were lactating but not breast-feeding were 70% higher than in maternal plasma. However, since milk concentrations remained low (<1 420 pg/ml), infant exposure to dapivirine is anticipated to be low (below 1 µg/day).

No formal studies have been conducted in women who are breast-feeding.

There is insufficient information on the effects of dapivirine in newborns/infants. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from use of the dapivirine vaginal ring . The benefit of breast-feeding for the child and the benefit of reducing the risk of HIV-1 infection for the mother should be taken into account.

Fertility

There are no clinical data on the effect of the dapivirine vaginal ring on fertility. There are no data from animal fertility studies with vaginal administration of dapivirine.

Oral studies in rats have shown effects on fertility but only at exposure levels well in excess of maximum exposure resulting from human vaginal administration, indicating that this is of little relevance to use of the dapivirine vaginal ring .

The dapivirine vaginal ring has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most commonly reported adverse reactions (i.e. reported by ≥5% of participants in the dapivirine group) were:

• Urinary tract infection (15,2%)
• Vaginal discharge (7,1%)
• Vulvovaginal pruritus (6,5%)
• Vulvovaginitis (6,4%)
• Pelvic pain (6,2%)

Tabulated summary of adverse reactions

The adverse reactions observed in the clinical trials with the dapivirine, are listed below (Table) according to frequencies defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100) and rare (≥1/10 000 to <1/1,000).

Tabulated summary of adverse reactions associated with the dapivirine vaginal ring, based on pooled Phase II/III clinical trials:

Other special populations

Post-menopausal women

The safety of the dapivirine over a 12-week use period has been evaluated in one placebocontrolled trial in post-menopausal women (n=96; 45-65 years of age). In this trial the most commonly observed adverse drug reactions (ADRs) (assessed as product-related by the Investigator) that were reported in more than 2 participants in either treatment group were vaginal discharge, lower abdominal pain, urinary tract infection, vulvovaginitis, vaginal odour, vulvovaginal erythema and vulvovaginal pruritus. These ADRs are consistent with ADRs reported in trials of women of reproductive age. Additional ADRs included cervix ecchymosis, cervical petechiae, vaginal ecchymosis and vaginal spotting. These events are not unanticipated for the enrolled population.

Paediatric population

The safety of the dapivirine in adolescents aged 15-17 years was evaluated in a placebo-controlled trial. In total, 96 participants were enrolled and randomised: 73 participants to the dapivirine group and 23 participants to the placebo ring group. The dapivirine was well tolerated in adolescent females when inserted once every 4 weeks and used continuously for 24 weeks. The type and nature of adverse events reported were similar to those reported in trials conducted in women of reproductive age 18 years and older.