Primigyn

Dinoprostone.

Primigyn gel contains 0.5 mg dinoprostone BP per 3 g gel in a syringe with a catheter for endocervical application.
Primigyn is a translucent gel for endocervical application containing 0.5 mg dinoprostone [prostaglandin E2 (PGE2)] as an active ingredient in 3 g gel.
Chemical name: Dinoprostone, prostaglandin E2, PGE2.
Molecular formula: C₂₀H₃₂O₅.
Molecular weight: 352.46508 g/mol.

Pharmacology: Mechanism of Action: Primigyn gel contains dinoprostone, a naturally occurring form of PGE2. It is applied endocervically and is used extensively for ripening and dilatation of an unfavorable cervix. Since it is a synthetic analog of PGE2, its mechanisms of action is similar to the one exhibited by the naturally occurring PGE2. The human cervix is a complex and heterogeneous organ which undergoes extensive biochemical and structural changes during pregnancy and parturition. Cervical ripening serves as a prelude to the onset of labor and eventual delivery. It is an inflammatory process in which there is collagen remodeling resulting in cervical softening, effacement and dilatation just before active labor. Prostaglandin E2 (PGE2) plays an incontrovertible role in the process of cervical ripening and induction of labor. It is produced continuously during pregnancy by the myometrium, cervix, fetal membranes and placenta. Furthermore, production is increased in late pregnancy, which facilitates cervical ripening and induction of labor. The increased PGE2 in the cervix at term is suggested to increase the activity of collagenase and proteases which dissolve collagen bundles in the cervix, increase hyaluronic acid levels, increase submucosal water content and change the physical properties of the cervix, ultimately making the cervix soft, elastic and dilated PGE2 also stimulates the production of PGF2 which sensitizes the myometrium to oxytocin, and therefore may stimulate contractions of the gravid uterus and induce labor. Since PGE2 also stimulates smooth muscles of the gastrointestinal tract, it may cause nausea, vomiting and diarrhea.
Clinical trials: Among all the routes of prostaglandin administration available for cervical ripening ad labor induction, endocervical PGE2 is a valuable option due to increased efficacy and low incidence of side effects associated with it.
Primigyn, an endocervical PGE2 gel, is used extensively for preinduction cervical ripening and labor induction. This is based on a repertoire of clinical trials which attest the significant efficacy and safety of endocervical PGE2 gel in cervical ripening and induction of labor. A randomized clinical trial evaluated the efficacy and safety of PGE2 endocervical gel (0.5 mg in 2-2.5 ml gel base) for preinduction cervical ripening prior to oxytocin induction. The study involved 538 women at term with low Bishop score (i.e., S4) who were treated with either PGE2 endocervical gel 12 hours prior to labor induction with oxytocin (PGE2 endocervical gel group) or with oxytocin induction alone (control group). During the 12- hour ripening period, patients in PGE2 endocervical group compared with control group achieved significant improvement in Bishop score which translated into high rate of labor (47.4% vs 9.6%, P < 0.001; figure 1). Deliveries without oxytocin occurred in 25.4% patients in the PGE2 endocervical gel group and in only 4.9% patients in the control group (figure 1). Endocervical application of PGE2 gel also reduced the time between induction, delivery and the duration of oxytocin administration. Equivalent maternal and fetal outcomes and incidence of complications denoted safety of PGE2 endocervical gel for cervical ripening of an unfavorable cervix. Similarly, another open randomized clinical trial yet again demonstrated that endocervical application of PGE2 gel in pregnant women at term with low Bishop score is significantly effective in cervical ripening and labor induction. The study women (n=100) were randomized into two groups: PGE2 endocervical gel group who were treated with PGE2 endocervical (0.5 mg in 2.5 ml gel) 12 hours before oxytocin labor induction, and control group who received oxytocin infusion alone. Notably, Bishop score progressed at least 3 points in 92% women in the PGE2 endocervical gel group whereas the mean Bishop score in the control group increased insignificantly. During the 12-hour ripening period before oxytocin induction, 32% women in the PGE2 endocervical gel group and 6% women in the control group delivered (figure 2). Of the remaining women who underwent oxytocin induction, the first induction attempt was successful in 64% women in the PGE2 endocervical gel group and 57% women in the control group (figure 2). Cesarean section rate was also lower in the former group compared with the latter (10% and 12%, respectively, figure 2). The safety ofpGE2 endocervical gel was reflected by no serious maternal or fetal side effects.
A multicentric prospective, randomized trial corroborated the aforementioned findings by showing a single application of PGE2 endocervical gel (0.5 mg in 2.5 ml gel) 12 hours prior to oxytocin induction in women at term with low Bishop score to achieve successful initial induction in 83% of patients compared to 58% success in non-primed controls (figure 3).
The researchers also noted that the induction delivery interval was shorter in the PGE2 endocervical gel group compared with the control group (median times 9.0 vs 11.3 hours. Additionally, the rate of cesarean section was lower in the former group than the latter (16% vs 21%, respectively).
It was concluded that the endocervical PGE2 gel application is an effective and well-tolerated method of cervical ripening prior to oxytocin induction in term pregnant women with unfavorable cervices.' The endocervical application of PGE2 gel has also been found to be more efficacious than PGE2 vaginal tablets. A randomized double­ blind study compared the efficacy and safety of endocervical PGE2 gel (0.5 mg of PGE2 in 3 g of the gel; PGE2 endocervical gel group) for preinduction cervical ripening with PGE2 vaginal tablets (2.0 mg tablet; PGE2 vaginal tablet group) and placebo treatment (placebo group) in at term, nulliparous women with low Bishop score. The overall success was defined as a progression in Bishop score of at least 3 points within 12 hours. While 55% women in PGE2 endocervical gel group achieved success, only 37% in PGE2 vaginal tablet group and 20% in the placebo group documented success(figure 4), Even in women with very unfavorable cervices (Bishop score 0-2), PGE2 endocervical gel maintained its superiority over its comparators ; the success rates were 75%, 15% and 0%, respectively, A very low incidence of side effects attested the safety of PGE2 endocervical gel. Similar comparisons between PGE2 endocervical gel and PGE2 vaginal gel have revealed the former formulation s to be more effective than the latter in achieving cervical ripeness. When compared with intravaginal misoprostol (PGEl) for labor induction, although the two methods are equally effective in achieving active labor and delivering within 24 hours, it is noteworthy that PGE2 endocervical gel is more safe due to lower incidence of uterine hyperstimulation and tachysystole. Overall, based on the tangible evidence it may be summated that endocervical application of PGE2 gel is an efficacious and well tolerated method to facilitate cervical ripening in pregnant women at term with unfavorable cervices for labor induction. (See Figures 1, 2, 3, and 4).

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Pharmacokinetics: Absorption: Time taken to reach the maximum concentration (T_max) 0.5 to 0.75 hours, maximum concentration (C_max) 484 pg/mL.
Metabolism: Primigyn is rapidly metabolized in the cervical tissues by oxidative pathways.
Elimination: Half-life (t_½) 2.5-5 minutes. The metabolic products are excreted by the kidneys in the urine.

Primigyn is indicated for the cervical ripening and dilatation of unfavorable cervices in at-term pregnant women for labor induction.
Cervical favorability can be assessed via Bishop score (see Table).
A score of ≤6 indicates an unfavorable cervix which warrants cervical ripening prior to labor induction. See table.

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Overdosage of Primigyn may be expressed by uterine hypercontractility and uterine hypertonicity. However, since PGE2-induced hyperstimulation is transient in nature, conservative strategies such as change in maternal position and administration of oxygen to the mother are effective in relieving hyperstimulation in most cases. Beta-adrenergic drugs to treat hyperstimulation may be required in a few cases.

Use of Primigyn is not recommended in: Patients with hypersensitivity to prostaglandins; Patients in whom oxytocic agents are contraindicated, such as: Patients with history of cesarean section or major uterine surgery; Patients with cephalopelvic disproportion; Patients with history of difficult labor and/or traumatic delivery Grand multiparae with previous term pregnancies; Patients with non-vertex presentation; Patients with hyperactive or hypertonic uterine patterns; Patients with fetal distress where delivery is not imminent; Patients in whom surgical intervention is warranted; Patients in whom vaginal delivery is not indicated, such as, those with herpes genitalis, unexplained vaginal bleeding during pregnancy, vasa previa or placenta previa.

Primigyn should be administered by experienced healthcare providers and in hospital settings with appropriate obstetrical care facilities. Placement of Primigyn should be endocervical, just below the level of the internal orifice of the uterus (internal os) and not in the extra-amniotic space to avoid uterine hyperstimulation. Uterine activity, fetal status, cervical dilatation and effacement should be carefully monitored for early identification of any undesirable effects, such as hypertonic myometrial contractions and fetal distress. Use with caution in patients with acute pelvic inflammatory disease, ruptured membranes, asthma, glaucoma, cardiac disease, renal or hepatic impairment and pulmonary disease. Since prostaglandins augment the action of oxytocin on the gravid uterus, the uterine activity should be carefully monitored when oxytocin is use d subsequent to Primigyn for labor induction.
The risk of uterine rupture should be considered if hypertonic myometrial contractions develop after Primigyn placement.
There is increased risk of post-partum disseminated intravascular coagulation in women aged 30 years or older, those with complications during pregnancy and those with a gestational age over 40 weeks.
Primigyn placement may result in inadvertent disruption and subsequent embolization of antigenic tissue. It rarely causes the development of the anaphylactoid syndrome of pregnancy

Extensive use of Primigyn has not revealed any serious adverse reaction.
The patients may occasionally experience benign effects such as nausea, vomiting, diarrhea, vaginal irritation, abdominal pain, back pain, headache, and dizziness.
Development of intrapartum fetal bradycardia and uterine contractile abnormalities with or without fetal distress have also been reported.

Since Primigyn may potentiate uterine response to other oxytocic agents, their concomitant use should be avoided. Generally, a gap of 6-12 hours is recommended in patients who require oxytocin induction following preinduction ripening with Primigyn.

Primigyn should be stored in the refrigerator between 2°C to 8°C. Of special note, it should not be frozen

Drugs Acting on the Uterus

G02AD02 - dinoprostone ; Belongs to the class of prostaglandins. Used to induce abortion or augment labour and to minimize blood loss from the placental site.

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