REGADEX Hard capsule Ref.[28042] Active ingredients: Pregabalin

Regadex 50 mg capsules contain Allura red AC (E129) which may cause allergic reactions.

Some diabetic patients who gain weight on pregabalin treatment may need to adjust hypoglycaemic medications.

There have been reports in the post-marketing experience of hypersensitivity reactions, including cases of angioedema. Pregabalin should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur.

Pregabalin treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall) in the elderly population. There have also been post-marketing reports of loss of consciousness, confusion and mental impairment. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medication.

In the post-marketing experience, transient visual blurring and other changes in visual acuity have been reported in patients treated with pregabalin. Discontinuation of pregabalin may result in resolution or improvement of these visual symptoms.

There are insufficient data for the withdrawal of concomitant antiepileptic medicinal products, once seizure control with pregabalin in the add-on situation has been reached, in order to reach monotherapy on pregabalin.

After discontinuation of short-term and long-term treatment with pregabalin, withdrawal symptoms have been observed in some patients. The following events have been mentioned: insomnia, headache, nausea, anxiety, hyperhidrosis, diarrhoea, flu syndrome, nervousness, depression, pain, sweating and dizziness. The patient should be informed about this at the start of the treatment.

Pregabalin is not known to be active at receptor sites associated with drugs of abuse. Cases of misuse and abuse have been reported in the post-marketing database. As with any CNS active drug, carefully evaluate patients for history of drug abuse and observe them for signs of pregabalin misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behaviour).

Concerning discontinuation of long-term treatment of pregabalin, there are no data of the incidence and severity of withdrawal symptoms in relation to duration of use and dosage of pregabalin.

Although the effects of discontinuation on the reversibility of renal failure have not been systematically studied, improved renal function following discontinuation or dose reduction of pregabalin has been reported.

There have been post-marketing reports of congestive heart failure in some patients receiving pregabalin. In short-term trials of patients without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral oedema and cardiovascular complications such as hypertension or congestive heart failure. Because there are limited data on severe congestive heart failure patients, pregabalin should be used with caution in these patients (see Section 4.8 Undesirable effects).

Treatment with pregabalin was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum values were 60 U/L for pregabalin-treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 2% of patients on pregabalin and 1% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three pregabalin-treated patients had events reported as rhabdomyolysis in pre-marketing clinical trials. The relationship between these myopathy events and pregabalin is not completely understood because the cases had documented factors that may have caused or contributed to these events. Regadex (pregabalin) should be discontinued if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur in the context of symptoms of myopathy.

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for pregabalin.

Therefore, patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

There is evidence from case reports, human studies, and animal studies associating pregabalin with serious, life-threatening, or fatal respiratory depression when co- administered with CNS depressants, including opioids, or in the setting of underlying respiratory impairment. When the decision is made to co-prescribe pregabalin with another CNS depressant, particularly an opioid, or to prescribe pregabalin to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating pregabalin at a low dose. The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including pregabalin).

There is more limited evidence from case reports, animal studies, and human studies associating pregabalin with serious respiratory depression, without co-administered CNS depressants or without underlying respiratory impairment. Patients with renal impairment might be at higher risk of experiencing this severe adverse reaction.

Since pregabalin is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of a dose recovered in urine as metabolites), does not inhibit drug metabolism in vitro, and is not bound to plasma proteins, it is unlikely to produce, or be subject to, pharmacokinetic interactions.

Accordingly, in in vivo studies no clinically relevant pharmacokinetic interactions were observed between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone or ethanol. Population pharmacokinetic analysis indicated that oral antidiabetics, diuretics, insulin, phenobarbital, tiagabine and topiramate had no clinically significant effect on pregabalin clearance.

Co-administration of pregabalin with the oral contraceptives norethisterone and/or ethinyl estradiol does not influence the steady-state pharmacokinetics of either substance. Pregabalin may potentiate the effects of ethanol and lorazepam. In controlled clinical trials, multiple oral doses of pregabalin co-administered with oxycodone, lorazepam, or ethanol did not result in clinically important effects on respiration. Pregabalin appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone.

In the post-marketing experience, there are reports of respiratory failure, and coma and deaths in patients taking pregabalin and other CNS depressant medications, including in patients who are substance abusers. There are post-marketing reports of events related to reduced lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) when pregabalin was co-administered with medications that have the potential to produce constipation, such as opioid analgesics.

No specific pharmacodynamic interaction studies were conducted in elderly volunteers.

Pregnancy

There are no adequate data on the use of pregabalin in pregnant women. Studies in animals have shown reproductive toxicity (see Section 5.3 Preclinical safety data). The potential risk to humans is unknown. Therefore, pregabalin should not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus. Effective contraception must be used in women of child-bearing potential.

Lactation

Pregabalin is excreted in the milk of lactating women (see Section 5.2 Pharmacokinetic properties). As the safety of pregabalin in infants is not known, breast-feeding is not recommended during treatment with pregabalin. A decision must be made whether to discontinue breast-feeding or to discontinue from pregabalin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Pregabalin may cause dizziness and somnolence and therefore may influence the ability to drive or use machines. Patients are advised not to drive, operate complex machinery or engage in other potentially hazardous activities until it is known whether this medication affects their ability to perform these activities.

The pregabalin clinical program involved over 12,000 patients who were exposed to pregabalin, of whom over 7,000 were in double-blind placebo controlled trials. The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were usually mild to moderate in intensity. In all controlled studies, the discontinuation rate due to adverse reactions was 14% for patients receiving pregabalin and 5% for patients receiving placebo. The most common adverse reactions resulting in discontinuation from pregabalin treatment groups were dizziness and somnolence.

Selected adverse drug reactions that were treatment related in the pooled analysis of clinical trials, are listed in the table below by System Organ Class (SOC). The frequency of these terms has been based on all-causality adverse drug reactions in the clinical trial data set (very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100) and rare (<1/1000)).

The adverse reactions listed may also be associated with the underlying disease and/or concomitant medications.

Table 2. Adverse Drug Reactions from Clinical Trial Experience:

The following adverse drug reactions were reported during POST-MARKETING SURVEILLANCE:

Immune system disorder

Uncommon: Hypersensitivity

Rare: Angioedema, allergic reaction

Nervous system disorders

Very Common: Headache

Uncommon: Loss of consciousness, mental impairment

Eye disorders

Rare: Keratitis^§

Cardiac disorders

Rare: Congestive heart failure

Respiratory, thoracic and mediastinal disorders

Rare: Pulmonary oedema^§

Gastrointestinal disorders

Common: Nausea, diarrhoea

Rare: Swollen tongue

Skin and subcutaneous tissue disorders

Uncommon: Face swelling, pruritus

Renal and urinary disorders

Rare: Urinary retention

Reproductive system and breast disorders

Rare: Gynaecomastia^§

General disorders and administration site conditions

Uncommon: Malaise^§

^§ Adverse drug reaction frequency estimated using “The Rule of 3”.

Not applicable.