Quinagolide
Quinagolide is a non-ergot-derived selective dopamine D2 receptor agonist used for the treatment of elevated levels of prolactin or hyperprolactinaemia. Hyperprolalctinaemia is associated with gonadal dysfunction, including infertility and reduced libido, as well as long-term complications such as osteoporosis 1. Newer dopamine receptor agonists such as quinagolide and Cabergoline are shown to effectively inhibit prolactin secretion with improved efficacy over Bromocriptine. These drugs are effective in patients who are intolerant or resistant to Bromocriptine. Quinagolide exists as a racemate and its relevant clinical activity is mediated predominantly by the (-) enantiomer. It is typically present in the hydrochloride salt form and is marketed as oral tablets under the brand name Norprolac contained as a racemate. Quinagolide is currently available in several countries including Canada, but not approved for treatment in the United States.
Mechanism of effect
Prolactin secretion from the lactotroph cells present in the anterior pituiatry gland is under tonic inhibitory control mediated by dopaminergic signalling via D2 receptors 5. Quinagolide selectively binds to D2 receptors expressed on the surface of lactotroph cells with high affinity which results in reduced adenylyl cyclase activity, reduced intracellular cyclic adenosine monophosphate and inhibited prolactin secretion. It also binds to D1 receptors but with low affinity and little clinical relevance 1.
Pharmacodynamic
Quinagolide achieves long-lasting reduction in prolactin levels in a dose-proportional effect via selectively targeting D2 receptors as an agonist. It potently suppresses both basal and stimulated serum prolactin levels by exerting a strong inhibitory effect on the secretion of the anterior pituitary hormone prolactin.
Pharmacokinetics
Absorption
The absorption of quinagolide is rapid and extensive with 95% of the dose absorbed after oral ingestion, however the absolute bioavailability is low (4 %) due to pre-systemic metabolism. The time to reach peak plasma concentration is 30-60 minutes. Prolactin-lowering effect of quinagolide at recommended therapeutic doses occurs within 2 hours after ingestion reaches a maximum within 4 to 6 hours and is maintained for at least 24 hours 7.
Volume of distribution
Approximate volume of distribution is 100L following a single oral admininstration. The parent drug and metabolites is predicted to be extensively distributed in the extravascular compartment with primary target organs being the liver, kidneys, salivary glands and pituitary Label.
Protein binding
Plasma protein binding is reported to be non-specific with an approximate ratio of 90%.
Metabolism
Quinagolide undergoes extensive first pass metabolism with sulfate and glucuronide conjugates being the major circulating metabolites. N-desethyl analogue is a biologically active metabolite while sulfate or glucuronide conjugates and N,N-didesethyl analogue are inactive metabolites.
Route of elimination
More than 95% of total dose is excreted as metabolites and the excretion via urine and feces is approximately equal. Renal elimination accounts for 50% of total elimination, where sulfate or glucuronide conjugates, N-desethyl and N,N-didesethyl analogues can be detected in the urine. Unconjugated forms of sulfate or glucuronide conjugates, N-desethyl and N,N-didesethyl analogues are excreted into feces, and fecal elimination accounts for 40% of the total elimination of the drug.
Half-life
The terminal half-life for parent drug is 11.5 hours following single dose and 17 hours at steady state.
ClearanceNot Available
Drug indications
Indicated for the treatment of hyperprolactinemia (idiopathic or originating from a prolactin-secreting pituitary microadenoma or macroadenoma).
Dosage
Adults:
It is important to take your medicine as directed by your doctor. The label on your medicine should tell you how much to take and when to take it. If it does not, or you are not sure, ask your doctor or pharmacist.
Elderly:
Take this medicine only if your doctor has decided that this is appropriate for you. Follow the instructions given to you very carefully.
The tablets should only be removed from the blister when it is time to take your medicine.
- Your treatment will normally begin with the ‘starter pack’ and you will take one 25 micrograms tablet daily (one light pink tablet) for the first three days (marked Day 1, Day 2 and Day 3 on the blister strip).
- This is followed by one 50 micrograms tablet daily (one very pale blue tablet) for the next three days (marked Day 4, Day 5 and Day 6 on the blister strip).
- From Day 7, the recommended dose is one 75 micrograms tablet daily (one whitish tablet). Most patients require a daily dose of 75 to 150 micrograms. Some patients require a daily dose of 300 micrograms or higher. Your doctor will tell you if you need a higher dose. You should not change the dose yourself.
Quinagolide should be taken once daily at bedtime preferably with a snack. Remove the tablet from the blister by pushing it through the foil and place it in your mouth. Swallow it with a mouthful of water.
If you take more Quinagolide than you should:
If you take more Quinagolide than you should, tell your doctor immediately or go to your nearest casualty department.
If you forget to take Quinagolide:
If you forget to take a dose, take it as soon as you remember. However, if you do not remember until it is nearly time for the next dose, take your next dose as usual and carry on as before. Do not take double doses to make up for a dose that you miss.
Drug contraindications
Hypersensitivity to the drug.
Impaired hepatic or renal function
during pregnancy
Side effects
Like all medicines, Quinagolide can have side effects. These are most common during the first few days of treatment and tend to go away on continuing treatment.
Very common side effects (affect more than 10 of every 100 patients treated):
Nausea
Vomiting
Headache
Dizziness
Tiredness
Common side effects (affect between 1 and 10 of every 100 patients treated):
Loss of appetite
Abdominal pain
Constipation or diarrhoea
Insomnia
Increased water retention
Flushing
Nasal congestion and a drop in blood pressure, which may result in fainting.
Rare side effects (affect between 1 and 10 of every 10,000 patients treated):
Somnolence (drowsiness or sleepiness).
Very rare side effects (affect less than 1 of every 10,000 patients treated):
Treatment with Quinagolide has been associated with a change in mental status, which is reversible when treatment is stopped.
Other side effects include:
Inability to resist the impulse, drive or temptation to perform an action that could be harmful to you or others, which may include:
strong impulse to gamble excessively despite serious personal or family consequences.
altered or increased sexual interest and behaviour of significant concern to you or to others, for example, an increased sexual drive.
binge eating (eating large amounts of food in a short time period) or compulsive eating (eating more food than normal and more than is needed to satisfy your hunger).
No interactions between NORPROLAC and other drugs have so far been reported. On theoretical grounds, a reduction of the prolactin-lowering effect could be expected when drugs (e.g. neuroleptic agents) with strong dopamine antagonistic properties are used concomitantly. As the potency of NORPROLAC for 5-HT1 and 5-HT2 receptors is some 100 times lower than that for D2 receptors, an interaction between NORPROLAC and 5-HT1a receptors is unlikely. However, care should be taken when using these medicaments concomitantly.
The tolerability of NORPROLAC may be reduced by alcohol.
Alerts
Fertility may be restored by treatment with NORPROLAC. Women of child-bearing age who do not wish to conceive should therefore be advised to practice a reliable method of contraception.
Since orthostatic hypotension may result in syncope, it is recommended to check blood pressure both lying and standing during the first days of therapy and following dosage increases.
In a few cases, including patients with no previous history of mental illness, treatment with NORPROLAC has been associated with the occurrence of acute psychosis, usually reversible upon discontinuation. Particular caution is required in patients who have had psychotic episodes in their previous history.
To date no data is available with the use of NORPROLAC in patients with impaired renal or hepatic function
NORPROLAC has been associated with somnolence. Other dopamine agonists can be associated with sudden sleep onset episodes, particularly in patients with Parkinson's disease. Patients must be informed of this and advised to exercise caution whilst driving or operating machines during treatment with NORPROLAC.
Patients who have experienced somnolence must not drive or operate machines. Furthermore, a reduction of dosage or termination of therapy may be considered
Pregnancy level
Animal data provide no evidence that NORPROLAC has any embryotoxic or teratogenic potential, but experience in pregnant women is still limited. In patients wishing to conceive, NORPROLAC should be discontinued when pregnancy is confirmed, unless there is a medical reason for continuing therapy. No increased incidence of abortion has been observed following withdrawal of the drug at this point.
If pregnancy occurs in the presence of a pituitary adenoma and NORPROLAC treatment has been stopped, close supervision throughout pregnancy is essential.
Breast feeding warning
Breast-feeding is usually not possible since NORPROLAC suppresses lactation. If lactation should continue during treatment, breast-feeding cannot be recommended because it is not known whether quinagolide passes into human breast milk.
Drug forms
Norprolac
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