Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: LeBasi Pharmaceuticals (Pty) Ltd, San Domenico Building, Unit 6, Ground Floor, 10 Church Street, Durbanville, 7551
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Use in women with unknown or positive HIV status.
The DapiRing is not always effective in preventing HIV-1 infection. The time to onset of risk reduction after initial insertion or following reinsertion after the ring has been expelled or removed and not immediately replaced, is unknown.
The healthcare professional should perform a risk assessment to identify the most suitable prevention option(s) tailored to the woman’s individual situation. The DapiRing should only be used as part of an overall HIV-1 infection prevention strategy, including the use of other HIV-1 prevention measures, which include consistent and correct condom use and regular testing for other sexually transmitted infections.
The DapiRing is used locally in the vagina and only reduces the risk of HIV-1 infection in women by vaginal intercourse.
The DapiRing should not be removed prior to, during or after vaginal sexual intercourse.
The DapiRing should only be used in women confirmed to be HIV-1 negative, as per applicable local HIV testing guidelines. Women should be re-confirmed to be HIV-negative at frequent intervals (e.g. at least every 3 months) while using the DapiRing (see section 4.3).
Continued use of the DapiRing in the presence of HIV-1 infection could lead to the selection of viral mutations associated with non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. Therefore, if clinical symptoms consistent with acute viral infection are present and recent (<1 month) exposure to HIV-1 is suspected, the use of the DapiRing should be delayed or stopped for at least one month and HIV-negative status should be confirmed before initiating or continuing the use of the DapiRing. Importance of adherence to product use Women using the DapiRing should be counselled to strictly adhere to the recommended continuous use of the ring and to replace it every 28 days.
Women using the DapiRing should be counselled to strictly adhere to the recommended continuous use of the ring and to replace it every 28 days.
Study data suggest that HIV-1 risk reduction is correlated with adherence to product use. If women do not adhere to using the product, there is no reduction in HIV-1 infection risk. Dapivirine concentrations in vaginal fluid decline rapidly following removal of the ring.
It is not known whether continued use of the DapiRing in women with unrecognised lower genital tract infections could potentially result in an increased risk of developing pelvic inflammatory disease. Therefore, early detection and appropriate treatment of genital infection (including STIs) in women using the DapiRing is considered important, as well as consideration given to treatment of sexual partners.
Concomitant use of vaginally administered antimicrobial products to treat vulvovaginal infections that have not been studied in clinical trials of DapiRing is not recommended (see section 4.5).
No data are available on the effect of vaginal practices, including dry sex practices, on the safety and efficacy of the DapiRing. Therefore, concomitant use of such practices with the DapiRing is not recommended.
Due to the low systemic exposure to dapivirine in women using the DapiRing, which does not exceed 2 ng/mL (see section 5.2), the risk of systemic medicine interactions is considered low and medicine interaction studies were focused on medicines potentially co-administered locally in the vagina.
In vitro studies have indicated that the main metabolic pathways for dapivirine are oxidation and glucuronidation mediated by CYP450 and UGT enzymes, respectively). In vaginal tissue, CYP450, but not UGT enzyme activity was detected (see section 5.2). Dapivirine inhibited several CYP450 and UGT enzymes (see section 5.2), and therefore there is the potential for interactions, specifically in the vaginal tissues, with co-administered vaginal medicines that are metabolised by these enzymes.
Due to the low systemic concentrations, dapivirine is not expected to affect the pharmacokinetics of oral hormonal contraceptives and therefore, it is expected that dapivirine will not interfere with the efficacy and safety of co-administered oral hormonal contraceptives.
Co-administration of a single vaginal dose of 1 200 mg miconazole, administered as an oil-based formulation in a vaginal capsule, with the DapiRing was evaluated in a single clinical trial. Under these circumstances miconazole concentrations in vaginal fluids were approximately 6-fold higher and miconazole concentrations in plasma were 4-fold higher following co-administration. While these changes are explained by the inhibitory potential of dapivirine towards the metabolism of miconazole (via CYP3A4), these changes are not considered clinically relevant.
During the first few days following co-administration, dapivirine vaginal fluid levels were approximately 2 to 3-fold lower than levels observed in the absence of miconazole. Plasma concentrations of dapivirine did not change significantly. The underlying mechanisms are not fully resolved and clinical relevance is unclear. Even so, women should be advised to use additional preventive measures against HIV, when co-treated with vaginal miconazole.
Co-administration of clotrimazole administered as a (water-based) vaginal cream (50 mg/day clotrimazole) for 7 days with the DapiRing was evaluated in a single clinical trial. Dapivirine exposure in vaginal fluid was 20% higher during co-administration with clotrimazole. Dapivirine plasma exposure was similar with or without co-administration of clotrimazole. After repeated application of clotrimazole cream for 7 days, systemic exposure of clotrimazole in the presence of dapivirine was approximately 33% higher, whereas vaginal fluid concentrations were similar to levels observed when clotrimazole was used alone. These increases are not expected to be clinically relevant.
The concurrent use of the DapiRing and clotrimazole was well-tolerated. However, due to methodological problems limiting the reliability of the pharmacokinetic results for both drugs, concurrent use of these products should be undertaken with caution.
No data are available on the concomitant administration of other vaginally administered products, including metronidazole and clindamycin. No data are available on concomitant use of other vaginal rings, such as contraceptive vaginal rings or diaphragms. Concomitant use of the DapiRing with such products is not recommended.
The DapiRing can be used with condoms and both should be used during vaginal sexual intercourse.
Clinical data show that the use of the DapiRing does not affect the failure rate of male condoms, including slippage or breakage, or have an effect on the safety, tolerability, acceptability and user experience of male condoms.
Clinical data show that the use of the DapiRing does not affect the failure rate of female condoms, including slippage, breakage, misdirection or invagination, and has no effect on safety, tolerability and acceptability of female condoms.
The DapiRing should remain in the vagina during menses and can be used with tampons. Women should be careful not to accidentally remove the ring when removing a tampon. Dapivirine vaginal fluid concentrations decreased up to 4-fold during menses but increased again thereafter and achieved concentrations consistent with the “no menses” group in a clinical trial by end of menses.
The use of tampons generally resulted in a 2-fold decrease of dapivirine in vaginal fluid concentrations during menses. As the clinical relevance of the reduced vaginal dapivirine levels during menses and tampon use is unclear, women should be advised to use additional preventive measures against HIV during menses.
Ring removal during menses resulted in marked reductions in dapivirine concentrations in vaginal fluid, therefore continued use of the ring during menses is important.
Contact with vaginal fluids, and blood during menses, may change the colour of the ring during use. Such discolouration does not affect the mechanism of action in which DapiRing protects against HIV-1 infection during vaginal sex.
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of the DapiRing 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 DapiRing (see section 5.3). 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 DapiRing. 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.
There are no clinical data on the effect of the DapiRing 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 DapiRing (see section 5.3).
The DapiRing has no or negligible influence on the ability to drive and use machines.
The most commonly reported adverse reactions (i.e. reported by ≥5% of participants in the DapiRing group) were:
The adverse reactions observed in the clinical trials with the DapiRing, are listed below (Table 1) 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).
Table 1. Tabulated summary of adverse reactions associated with the DapiRing, based on pooled Phase II/III clinical trials:
| System Organ Class | Very Common | Common | Uncommon | Rare |
|---|---|---|---|---|
| Infections and infestations | Urinary tract infection | Vulvovaginitis Cervicitis | Cystitis | |
| Gastrointestinal disorders | Abdominal pain lower | Abdominal discomfort | ||
| Renal and urinary disorders | Dysuria | Pollakiuria Bladder pain | Micturition urgency | |
| Reproductive system and breast disorders | Vaginal discharge Vulvovaginal pruritus Pelvic pain | Vaginal odour Cervix erythema Vulvovaginal discomfort Vulvovaginal pain Cervical discharge Cervix ecchymosis Pelvic discomfort Vaginal erosion Cervix oedema Uterine cervical erosion Cervix petechiae | Genital itching Genital discomfort Vulval abrasion | |
| General disorders and administration site conditions | Suprapubic pain Application site discomfort | Application site pain | ||
| Injury, poisoning and procedural complications | Vaginal laceration |
The safety of the DapiRing 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.
The safety of the DapiRing 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 DapiRing group and 23 participants to the placebo ring group. The DapiRing 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.
Reporting suspected adverse reactions after authorisation of DapiRing is important. It allows continued monitoring of the benefit/risk balance of DapiRing. Healthcare 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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