Pragiola: composition and dosage form
The hard capsules come in five strengths: 25, 50, 75, 150 and 300 mg of pregabalin. That range is not there for variety but because the daily dose has to be built from very different combinations — from 25 mg in renal failure to 600 mg in neuropathic pain.
It is taken by mouth only, with food or independently of it. The daily dose is always split into two or three takings, and that rule does not change for any of the indications.
How Pragiola works
The target is not the one the name suggests. Pregabalin binds to an auxiliary subunit — the α2-δ protein — of the voltage-gated calcium channel in the central nervous system, and GABA receptors play no part in it, even though in chemical terms the substance remains a derivative of gamma-aminobutyric acid: (S)-3-(aminomethyl)-5-methylhexanoic acid.
Everything practical about the medicine follows from that. It is barely metabolised: less than 2% of the dose leaves in the urine as metabolites and the rest goes out through the kidneys unchanged. Pregabalin does not bind to plasma proteins and in vitro does not inhibit the metabolism of other medicines. It therefore has virtually no pharmacokinetic interactions, and the whole arithmetic of the dose rests on how the kidneys work.
Indications
There are three indications and they come from different fields of medicine. The first is the treatment of peripheral and central neuropathic pain in adults. The second is the treatment of partial seizures in adults as part of combination therapy, whether or not the seizures become secondarily generalised.
The third indication is generalised anxiety disorder in adults. Here the product information additionally requires regular review of whether treatment should continue. In children under 12 and adolescents aged 12–17 safety and efficacy have not been established and there are no dosing recommendations for them.
How to take it and dosage
The range is the same for all indications — 150 to 600 mg a day in two or three divided doses — and what differs is how fast the dose is built up. In neuropathic pain treatment starts at 150 mg a day, after 3–7 days, depending on tolerance and response, it rises to 300 mg, and after a further 7 days it goes if needed to the maximum of 600 mg. In epilepsy the starting dose is the same but the step is slower: 300 mg no sooner than after a week, 600 mg a week after that. In generalised anxiety disorder there are more steps: 150 mg, after a week 300 mg, after another week 450 mg and only then 600 mg. Stopping abruptly is not allowed in any indication — the dose is lowered gradually over at least a week.
For the kidneys the product information gives not a table of "mild, moderate, severe" but a calculation: creatinine clearance in ml/min equals 1.23 × [140 − age in years] × body weight in kg, divided by serum creatinine in µmol/l, and the result is multiplied by 0.85 for women. The dose then follows from that figure. With a clearance of 60 ml/min or more the regimen is the usual one: start at 150 mg, maximum 600 mg, two or three takings. From 30 to 60 ml/min, start at 75 mg with a maximum of 300 mg. From 15 to 30 ml/min, start at 25–50 mg with a maximum of 150 mg in one or two takings. Below 15 ml/min, start at 25 mg with a maximum of 75 mg once a day. Haemodialysis removes half the medicine in four hours, so dialysis patients are given a single dose on top of the daily one right after each session: 25 to 100 mg. With impaired liver function the dose need not change, and in older people it often has to be reduced — but again because of the kidneys.
Contraindications
There is one formal contraindication: hypersensitivity to pregabalin or to any excipient of the capsule. That section of the product information holds no other prohibitions.
This does not mean the medicine can be prescribed to anyone. Everything that in other product information would read as a ban has been moved here into the warnings: reduced renal function does not forbid treatment but changes the dose; past drug misuse, heart failure in older people, spinal cord injury and concurrent opioid use are all reasons for caution and monitoring rather than for refusal.
Special warnings and precautions
The commonest problem is dizziness and drowsiness, and in older people these end in falls and injuries. Loss of consciousness, confusion and mental disturbance have also been described, so the patient is advised to be careful until they know how the medicine affects them. The influence on driving is judged small to moderate, and until that is clear it is better not to return to the wheel, to machinery or to hazardous work.
| What has been noticed | How it is read |
|---|---|
| Swelling of the face, lips or upper airway | A sign of angioedema: the medicine is withdrawn at once |
| Blurred or double vision, narrowed visual field | Seen more often than with placebo in the trials; it usually settles as treatment goes on, and persistent problems may ease after withdrawal |
| Weight gain in a patient with diabetes | The doses of antidiabetic medicines may need revising |
| Breathlessness and oedema in an older person with heart disease | Cases of congestive heart failure have been described; symptoms may resolve after withdrawal |
| Constipation on opioid analgesia | The combination slows the lower bowel as far as obstruction; prevention is planned in advance |
| Raising the dose on one's own, seeking the medicine out | Misuse, tolerance and dependence have been described, particularly in people with that history |
Withdrawal stands apart. In some patients, after both short and long courses were stopped, insomnia, headache, nausea, anxiety, diarrhoea, a flu-like state, nervousness, depression, pain, sweating, dizziness and seizures appeared — a picture suggesting physical dependence, with frequency and severity depending on the dose. The patient has to be warned about this before treatment starts, not at the moment of stopping. Seizures, including status epilepticus and grand mal attacks, are possible both during treatment and shortly after it is stopped. In people taking antiepileptic medicines suicidal thoughts and behaviour have been described generally, and a meta-analysis of placebo-controlled trials showed a small increase in risk that cannot be ruled out for pregabalin. Renal failure, sometimes reversible after withdrawal, and encephalopathy have also been reported, the latter mainly in people with coexisting conditions that predispose to it. There are too few data on moving a patient to pregabalin monotherapy once seizures have been brought under control with a combination.
Drug interactions
Pregabalin has virtually no pharmacokinetic interactions, which is unusual for a medicine used so widely. In vivo studies found no clinically relevant influence either with phenytoin, carbamazepine, valproic acid, lamotrigine and gabapentin, or with lorazepam, oxycodone and ethanol. Population analysis showed that pregabalin clearance is not affected by oral antidiabetic medicines, diuretics, insulin, phenobarbital, tiagabine or topiramate. The medicine likewise does not affect oral contraceptives containing norethisterone and ethinylestradiol, nor they it.
The danger lies on a different plane — the pharmacodynamic one. Pregabalin can potentiate the effects of ethanol and lorazepam. In controlled studies repeated dosing together with oxycodone, lorazepam or ethanol had no appreciable effect on breathing, but after the medicine reached the market there were reports of respiratory failure and coma in patients taking it with other central nervous system depressants. With oxycodone the effect appears to be additive both for cognitive function and for gross motor skills. No specific studies of pharmacodynamic interactions were carried out in elderly volunteers, and all interactions were studied only in adults.
Pregnancy and breastfeeding
There are too few data on use in pregnant women, and animal studies showed reproductive toxicity; what the risk is in humans is unknown. The medicine is therefore not used in pregnancy unless the expected benefit to the mother clearly outweighs the risk to the fetus. The same uncertainty produces a requirement that is easy to overlook: women of childbearing age need effective contraception while on treatment.
Pregabalin passes into breast milk and its effect on the newborn and the infant is unknown, so the choice is between stopping feeding and stopping treatment, weighing the benefit of each. There are no clinical data on female fertility. In healthy men taking 600 mg a day, sperm motility was unchanged after three months, but in rats of both sexes an unfavourable effect on reproduction and development was found, and the clinical significance of those observations is unclear.
Adverse reactions
The trial programme covered more than 8,900 patients given pregabalin, over 5,600 of them in double-blind placebo-controlled studies. Dizziness and drowsiness were the commonest findings; overall the reactions were mild or moderate. Adverse events led 12% of those on the medicine to stop treatment against 5% on placebo, and the reason was most often that same dizziness and drowsiness. In patients with spinal cord injury the rate of reactions, especially nervous system ones, turned out higher — probably because effects add up with the other medicines such patients need.
- Very common: dizziness, drowsiness, headache.
- Common: ataxia, impaired coordination and balance, tremor, speech disturbance, forgetfulness and impaired memory, difficulty concentrating, paraesthesia, hypoaesthesia, sedation, lethargy; euphoria, confusion, disorientation, irritability, insomnia, reduced libido; blurred and double vision; vomiting, nausea, constipation, diarrhoea, flatulence, dry mouth; increased appetite; nasopharyngitis.
- Uncommon: syncope, stupor, loss of consciousness, myoclonus, dyskinesia, nystagmus, cognitive impairment; hallucinations, panic attacks, agitation, depression, aggression, depersonalisation, apathy; narrowed visual field, reduced visual acuity, eye pain and dryness; tachycardia, sinus bradycardia, first-degree atrioventricular block, congestive heart failure; low and raised blood pressure, hot flushes; breathlessness, cough, nosebleed; neutropenia, hypoglycaemia, loss of appetite.
- Rare: angioedema and allergic reactions, seizures, altered sense of smell, dysgraphia, loss of vision, keratitis, pupil dilatation, QT prolongation, sinus arrhythmia, pulmonary oedema, a feeling of tightness in the throat.
Some of the above may be linked not to the medicine but to the underlying illness or to other medicines taken — the product information says so separately. What is listed here is the commonest and the most significant reactions, not an exhaustive list.
Overdose
Drowsiness, confusion, agitation and restlessness — that is what was seen most often once overdoses began to be reported from everyday practice. Less often it came to seizures, and very rarely coma was described.
There is no specific antidote: treatment comes down to general supportive care and, if needed, haemodialysis. Dialysis does work here — half the medicine leaves the plasma in four hours — and in that respect a pregabalin overdose compares favourably with poisoning by substances that bind tightly to proteins.
How to get a prescription for Pragiola online
Pregabalin is a case where the dose is not chosen by eye: it is calculated from age, body weight and creatinine, and on dialysis a separate dose is added after every session. On top of that the medicine is among those for which misuse and dependence have been described, and stopping it has to be gradual. All of that makes prescribing a medical decision rather than a formality.
An online consultation is above all suited to continuing a regimen that has already been worked out. The questionnaire covers the indication, the current dose and the number of takings a day, age and body weight, the latest creatinine or the estimated clearance, dialysis, heart disease, diabetes, spinal cord injury, episodes of drug misuse, pregnancy or plans for one and the contraception used, and also opioid painkillers, benzodiazepines and other medicines that depress the nervous system. The doctor studies the answers and, where there are sufficient grounds, issues an electronic prescription that arrives as a code for a Polish pharmacy.
