Dinoprostone

Registered South African indications:

• Cervical ripening (0.5mg gel)
• Induction of labour (1mg & 2mg gel)

Contraindications
South African manufacturer recommendations
0.5mg gel

• Hypersensitivity to the active ingredient or any of its excipients
• Patients in whom oxytocic agents are generally contraindicated or where prolonged contractions of the uterus are considered inappropriate, such as
  - History of caesarean section or major uterine surgery
  - Major degree of cephalopelvic disproportion may be present
  - History of difficult labour and/or traumatic delivery
  - Grand multiparae with six or more previous term pregnancies
  - Engagement of the head has not taken place
  - Obstetric conditions where either maternal or foetal benefit-risk ratio favours surgical intervention
• Ruptured membranes
• Unexplained vaginal bleeding/discharge and/or unexplained uterine bleeding during the pregnancy
• Non-vertex presentations
• Foetal heart rate pattern suggesting incipient foetal compromise

1mg & 2mg gel

• Hypersensitivity to the active ingredient or any of its excipients
• Grand multiparity (≥5 previous deliveries)
• Engagement of the head has not taken place
• Previous uterine surgery (e.g. caesarean section, hysterotomy or myomectomy)
• Cephalopelvic disproportion
• Foetal heart rate pattern suggests incipient foetal compromise
• Obstetric conditions where either maternal or foetal benefit/risk ratio favours surgical intervention
• Unexplained vaginal discharge and/or unexplained uterine or vaginal bleeding during current pregnancy

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Sensitivity to prostaglandins
• Renal impairment
• Hepatic impairment
• Patients in whom oxytocic agents are generally contraindicated or where prolonged contractions of the uterus are considered inappropriate, such as
  - History of caesarean section or major uterine surgery
  - Cephalopelvic disproportion
  - Foetal malpresentation
  - Clinical suspicion or definite evidence of pre-existing foetal distress
  - History of difficult labour and/or traumatic delivery
• History of, or existing, pelvic inflammatory disease, unless adequate prior treatment has been instituted
• Clinical suspicion or definite evidence of placenta praevia or unexplained vaginal bleeding during this pregnancy
• Active cardiac or pulmonary disease

Cautions
South African manufacturer recommendations
0.5mg gel

• Pregnancy
  - Multiple gestation
• Breastfeeding
• Renal impairment
• Hepatic impairment
• History of hypertonic uterine contractility or tetanic uterine contractions
• High-tone myometrial contractions
• Asthma or a history of asthma
• Glaucoma or raised intraocular pressure
• Compromised cardiovascular function
• High doses
• Prolonged treatment
• Ruptured chorioamniotic membranes
• Administration above the internal os level
• Risk factors for developing disseminated intravascular coagulation
  - Women 35 years or older
  - Complications during pregnancy
  - Gestational age over 40 weeks

1mg & 2mg gel

• Pregnancy
  - Multiple gestation
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Compromised cardiovascular function 
• Asthma
• Excessive uterine activity or unusual uterine pain
• Ruptured chorioamniotic membranes
• Glaucoma or raised intraocular pressure

International manufacturer recommendations

• Pregnancy
  - Multiple pregnancy
• Breastfeeding
• Contact with skin
• Asthma or a history of asthma
• Epilepsy or a history of epilepsy
• Glaucoma or raised intra-ocular pressure
• Compromised cardiovascular function 
• Hypertension
• Ruptured chorioamniotic membranes
• History of hypertonic uterine contractility or tetanic uterine contractions
• High-tone uterine contractions
• Prolonged treatment
• Risk factors for post-partum disseminated intravascular coagulation
  - Women 35 years or older
  - Complications during pregnancy
  - Gestational age over 40 weeks

Forms avail. in SA and covered in this monograph: gel

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Cervical ripening
- In-term or near-term pregnant women who have a single baby (or foetus) with a vertex presentation
0.5mg gel

• Endocervical (gel): 0.5mg, introduce the gel with the catheter provided into the cervical canal just below the level of the internal os

---

Dinoprostone is supplied as a translucent sterile gel preparation, in syringes with an accompanying catheter for endocervical application. After placement of the gel, the patient should remain in the dorsal position for 10-15 minutes to minimise gel leakage

---

Induction of labour
- At-term or near-term pregnant patients where there are no foetal or maternal contraindications
1mg & 2mg gel

• Intravaginal (gel): Initial: 1mg, placed in posterior fornix of the vaginal canal; Give a further 1-2mg after 6hrs if needed; Max: 3mg/24hrs

---

Second dose after 6 hours may be administered depending upon need; i.e. an absence of response to the initial 1mg dose indicates the 2mg dose should be given, while a 1mg dose would be suggested to augment an already present response to the initial dose

---

International manufacturer recommendations

Induction of labour
- When there are no foetal or maternal contraindications

Usage is restricted to qualified health care professionals and to hospitals and clinics with specialised obstetric units with facilities for continuous monitoring

In primigravida patients with unfavourable induction features (Bishop score of ≤4)

• Vaginal (gel):  Initial: 2mg, inserted high into posterior fornix of the vaginal canal; Give a further 1-2mg after 6hrs if needed; Max: 4mg/24hrs 

In other patients

• Vaginal (gel): Initial: 1mg, inserted high into posterior fornix of the vaginal canal; Give a further 1-2mg after 6hrs if needed; Max: 3mg/24hrs

---

In both groups of patients, a second dose may be administered after 6 hours as follows: 1mg should be used where uterine activity is insufficient for satisfactory progress of labour. 2mg may be used where response to the initial dose has been minimal

---

The recommended dose should not be exceeded, and the dosing interval should not be shortened as this increases the risk of uterine hyperstimulation, uterine rupture, uterine haemorrhage, foetal and neonatal death

---

The patient should remain recumbent for at least 30 minutes

No information available (South African manufacturer recommendations)
Not applicable (International manufacturer recommendations)

Pregnancy
South African manufacturer recommendations
0.5mg gel

• Caution
• Dinoprostone produced an increase in skeletal anomalies in rats and rabbits. Dinoprostone has been shown to be embryotoxic in rats and rabbits. Any dose that produces sustained increased uterine tone could put the embryo or foetus at risk
• Caution should also be exercised in the administration of oxytocic agents, including dinoprostone, for the induction of labour in patients with multiple gestation

1mg & 2mg gel

• Caution; no information available 
• Caution should be exercised in the administration of oxytocic agents, including dinoprostone, for the induction of labour in patients with multiple gestation

International manufacturer recommendations

• Caution
• Dinoprostone is only used during pregnancy, to induce labour. Dinoprostone should be used with caution in patients with multiple pregnancy

Breastfeeding
South African manufacturer recommendations
0.5mg gel

• Caution 
• Prostaglandins are excreted in breast milk at very low concentrations

1mg & 2mg gel

• Caution; no information available

International manufacturer recommendations

• Caution 
• Prostaglandins are excreted in breast milk. This is not expected to be a hazard given the circumstances in which dinoprostone is used

Fertility 

• No information available

Renal Impairment
South African manufacturer recommendations

• Caution; no dose adjustment recommended

International manufacturer recommendations

• Contraindicated

Hepatic Impairment
South African manufacturer recommendations

• Caution; no dose adjustment recommended

International manufacturer recommendations

• Contraindicated

Elderly

• Not indicated for use in geriatric patients 

Porphyria Information

• Probably not porphyrinogenic (PNP) 

Drugs in Sport

• Permitted - No warnings

Cardiovascular Disorders 

• Cardiac arrest
• Hypertension

Respiratory Disorders 

• Pulmonary amniotic fluid embolism
• Asthma
• Bronchospasm

Gastrointestinal Disorders 

• Diarrhoea
• Nausea and vomiting

Genitourinary Disorders

• Uterine contractile abnormalities (increase frequency, tone, or duration)
• Uterine hypertonus
• Uterine rupture
• Placental abruption
• Rapid cervical dilatation
• Uterine hypercontractility with/without foetal bradycardia
• Foetal distress/altered foetal heart rate (FHR)
• Warm feeling in vagina  
• Irritation
• Pain

Musculoskeletal Disorders 

• Back pain

Skin and Subcutaneous Tissue Disorders 

• Rash

Immune, Blood and Lymphatic System Disorders 

• Hypersensitivity reactions
• Anaphylactoid reactions
• Anaphylactic reactions
  - Anaphylactic shock
• Fever
• Post-partum disseminated intravascular coagulation

Others

• Foetal death
• Stillbirth
• Low Apgar score
  - Depressed neonates at birth (Apgar score <7)
• Neonatal death
• Neonatal distress

• Oxytocin (See additional prescribing points)
• Other oxytocic agents ​​​(See additional prescribing points)

• Foetal heart rate
• Uterine activity
• Progression of cervical dilation and effacement

Additional observations

• Signs of amniotic fluid embolism
  - Coma
  - Disseminated intravascular coagulation (evolving fibrinolysis)
  - Hypotension
  - Hypoxemia
  - Respiratory failure
  - Seizures

Coadministration with oxytocin and other oxytocic agents

• The response to oxytocin may be accentuated in the presence of exogenous prostaglandin therapy. Coadministration use with other oxytocic agents is not recommended. A dosing interval of at least 6 hours is recommended in case of oxytocin use is considered necessary following dinoprostone administration. If used in sequence, the patient's uterine activity should be carefully monitored

Special warnings and precautions for use (International manufacturer recommendations)

• Use the total contents of the syringe for one patient only. Discard after use. Use caution in handling the product to prevent contact with skin. Wash hands thoroughly with soap and water after administration
• As with any oxytocic agent, the risk of uterine rupture should be considered. Concomitant medication, maternal and foetal status should be taken into consideration in order to minimise the risk of uterine hyperstimulation, uterine rupture, uterine haemorrhage, foetal and neonatal death. Careful and regular monitoring of uterine activity and foetal heart rate should be conducted during use of dinoprostone. Patients who develop uterine hypertonus or hypercontractility, or in whom unusual foetal heart rate patterns develop, should be managed in a manner that addresses the welfare of the foetus and mother

The specific mechanism of action is not fully defined. Dinoprostone prostaglandin E2 (PGE2), administered endocervically, facilitates preinduction cervical softening (cervical maturation) in patients with unfavourable induction features. However, experimental data in humans demonstrates that PGE2 increases the volume of blood flow in the cervix similar to that observed in early stages of spontaneous labour. This data strongly suggests that endocervical administration of PGE2 affects cervical haemodynamics, thus leading to cervical maturation. In both laboratory animals and man, large doses of PGE2 can lower blood pressure, probably as a consequence of its effect on smooth muscle of the vascular system, and transient elevations of the body temperature have been observed. PGE2 is also capable of stimulating the smooth muscle of the gastrointestinal tract. (0.5mg gel)
Dinoprostone is a prostaglandin of the E series which induces myometrial contractions and promotes cervical ripening. (1mg & 2mg gel)

Gel (per 3g) 0.5mg

• Prepidil gel 0.5mg (Pfizer) originator

Gel (per 3g) 1mg

• Prandin E2 1mg (Pfizer) originator

Gel (per 3g) 2mg

• Prandin E2 2mg (Pfizer) originator