Alond Capsules

Neuropathic pain

ALOND is indicated for the treatment of adult patients with neuropathic pain due to Herpes zoster infections and diabetes.

Posology

The recommended starting dose for ALOND is 75 mg twice daily (150 mg/day), with or without food. Based on individual patient response and tolerability, the dose may be increased to 150 mg twice daily after an interval of 3 to 7 days.

In accordance with current clinical practice, if ALOND has to be discontinued, it is recommended this should be done gradually over a minimum of 1 week.

Special populations

Renal impairment

ALOND is eliminated from the systemic circulation primarily by renal excretion as unchanged medicine. As ALOND clearance is directly proportional to creatinine clearance (see section 5.2, Pharmacokinetics in special populations u2013 Renal impairment), dosage reduction in patients with compromised renal function must be individualised according to creatinine clearance (CL cr), as indicated in Table 1 determined using the following formula:

CL cr (mL/min) = (140 u2013 age[years]) x Weight (kg) / (0,82 x Serum creatinine (u03bcmol/l))
*For females multiply the CL cr by 0,85

ALOND is removed effectively from plasma by haemodialysis (50 % of medicine in 4 hours). For patients receiving haemodialysis, the ALOND daily dose should be adjusted based on renal function. In addition to the daily dose, a supplementary dose should be given immediately following every 4-hour haemodialysis treatment (see Table 1).

Table 1. ALOND dosage adjustment based on renal function

Creatinine clearance (CL cr) (mL/min) Total ALOND daily dose* Dose regimen

• u2265 60 150 300 BD
• 30 u2013 60 75 150 OD or BD
• 15 u2013 30 25 u2013 50 75 OD or BD
• < 15 25 25 u2013 50 OD

Supplementary dosage following haemodialysis (mg)

• 25
• 50

Single dose + BD = Twice daily
OD = Once daily
*Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose + Supplementary dose is a single additional dose

Hepatic impairment

No dosage adjustment is required for patients with hepatic impairment (see section 5.2, Pharmacokinetics in special populations u2013 Hepatic impairment).

Elderly population (over 65 years of age)

No dosage adjustment is necessary for elderly patients unless their renal function is compromised, see Table 1.

Paediatric population

The safety and effectiveness of ALOND in patients below the age of 18 years with neuropathic pain has not been established.

Method of administration

For oral use.

ALOND is given orally with or without food.

Hypersensitivity to pregabalin or to any of the excipients of ALOND (listed in section 6.1).

Diabetic patients

In accordance with current clinical practice, some diabetic patients who gain weight on ALOND treatment may need to adjust hypoglycaemic medicines.

Hypersensitivity reactions

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

Severe cutaneous adverse reactions (SCARs)

SCARs including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported rarely in association with ALOND treatment. At the time of prescription, patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, ALOND should be withdrawn immediately, and an alternative treatment considered (as appropriate).

Dizziness, somnolence, loss of consciousness, confusion and mental impairment

ALOND treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall) in the elderly population. There have 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 medicine (see section 4.8).

Vision-related effects

In controlled trials, a higher proportion of patients treated with ALOND reported blurred vision than did patients treated with placebo, which resolved in a majority of cases with continued dosing. In the clinical studies where ophthalmologic testing was conducted, the incidence of visual acuity reduction and visual field changes was greater in ALOND-treated patients than in placebo-treated patients; the incidence of fundoscopic changes was greater in placebo-treated patients.

In the post-marketing experience, visual adverse reactions have also been reported, including loss of vision, visual blurring or other changes of visual acuity, many of which were transient. Discontinuation of ALOND may result in resolution or improvement of these visual symptoms.

Respiratory depression

There have been reports of severe respiratory depression in relation to ALOND use. Patients with compromised respiratory function, respiratory or neurological disease, renal impairment, concomitant use of CNS depressants and the elderly may be at higher risk of experiencing this severe adverse reaction. Dose adjustments may be necessary in these patients (see section 4.2).

Suicidal ideation and behaviour

Suicidal ideation and behaviour have been reported in patients treated with ALOND in several indications. Cases of suicidal ideation and behaviour have been observed in patients treated with ALOND in the post-marketing experience (see section 4.8). An epidemiological study using a self-controlled study design (comparing treatment periods with non-treatment periods within an individual) showed evidence of an increased risk of new onset of suicidal behaviour and death by suicide in patients treated with ALOND. A meta-analysis of randomised placebo-controlled studies of anti-epileptic medicines 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 ALOND.

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

Concomitant use with opioids

Caution is advised when prescribing ALOND concomitantly with opioids due to risk of CNS depression. In an observational study of opioid users, those patients who took ALOND concomitantly with an opioid had an increased risk for opioid-related death compared to opioid use alone (adjusted odds ratio [aOR], 1.68 [95% CI, 1.19 to 2.36]).

Misuse, abuse potential or dependence

ALOND can cause drug dependence, which may occur at therapeutic doses. Cases of abuse, misuse and dependence have been reported. Patients with a history of substance abuse and/or psychiatric disorders may be at higher risk for ALOND misuse, abuse and dependence and ALOND should be used with caution in such patients. Before prescribing ALOND, the patientu2019s risk of misuse, abuse or dependence should be carefully evaluated.

Patients treated with ALOND should be monitored for symptoms of ALOND misuse, abuse or dependence, such as development of tolerance, dose escalation and drug-seeking behaviour.

Withdrawal symptoms

After discontinuation of short-term and long-term treatment with ALOND, withdrawal symptoms have been observed in some patients. The following events have been reported: insomnia, headache, nausea, anxiety and diarrhoea (see section 4.8).

Renal failure

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 ALOND has been reported (see section 4.8). Renal failure has occurred.

Congestive heart failure

There have been post-marketing reports of congestive heart failure or deterioration of heart failure in some patients receiving ALOND. 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. ALOND should be used with caution in patients with congestive heart failure (see section 4.8).

Women of childbearing potential/Contraception

ALOND use in the first trimester of pregnancy may cause major birth defects in the unborn child. ALOND should not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus. Women of childbearing potential must use effective contraception during treatment (see section 4.6).

Lactose intolerance

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

In vivo studies and population pharmacokinetic analysis

Accordingly, in in vivo studies no clinically relevant pharmacokinetic interactions were observed between ALOND and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone or ethanol. In addition, population pharmacokinetic analysis indicated that the 3 commonly used medicine classes, oral antidiabetics, diuretics and insulin, and the commonly used anti-epileptic medicines, phenytoin, carbamazepine, valproic acid, lamotrigine, phenobarbital, tiagabine, and topiramate, had no clinically significant effect on pregabalin clearance. Similarly, these analyses indicated that ALOND had no clinically significant effect on the clearance of phenytoin, carbamazepine, valproic acid, lamotrigine, topiramate and phenobarbital.

Oral contraceptives, norethisterone and/or ethinyl oestradiol

Co-administration of ALOND with the oral contraceptives norethisterone and/or ethinyl estradiol does not influence the steady-state pharmacokinetics of either medicine.

Central nervous system influencing medicines

Multiple oral doses of ALOND co-administered with oxycodone, lorazepam, or ethanol did not result in clinically important effects on respiration. ALOND appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone. ALOND may potentiate the effects of ethanol and lorazepam.

In post-marketing experience, there are reports of respiratory failure, coma and deaths in patients taking ALOND and other CNS depressant medicines, 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 ALOND was co-administered with medicines that have the potential to produce constipation, such as opioid analgesics.

Women of childbearing potential/ Contraception in males and females

Women of childbearing potential have to use effective contraception during treatment (see section 4.4).

Pregnancy

There is a limited amount of data on the use of ALOND in pregnant women. Data from a Nordic observational study, which included more than 2 700 pregnancies exposed to ALOND based on routinely collected data from administrative and medical registers, do not suggest substantially increased risks of major congenital malformations, adverse birth outcomes, or abnormal postnatal neurodevelopmental outcomes in ALOND-exposed pregnancies.

Major congenital malformations

The adjusted prevalence ratios (aPRs) and 95 % confidence intervals (CI) in the standard meta-analysis for first-trimester ALOND monotherapy-exposed vs. unexposed to anti-epileptic drugs was 1,13 (0,96 u2013 1,33).

Birth and postnatal neurodevelopmental outcomes

There were no statistically significant findings for stillbirth, low birth weight, preterm birth, small for gestational age, low Apgar score, and microcephaly. In paediatric population exposed in utero, the study did not provide evidence of an increased risk for attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD) and intellectual disabilities.

Studies in animals have shown reproductive toxicity. Therefore, ALOND should not be used during pregnancy.

Breastfeeding

ALOND is excreted into human milk (see section 5.2). The effect of ALOND on newborns/infants is unknown. Because the safety of ALOND in infants is not known, breastfeeding is not recommended during treatment with ALOND.

ALOND frequently causes dizziness and somnolence. Head and body injuries and road traffic incidents have also been reported in patients treated with ALOND. Therefore, patients are advised not to drive, operate complex machinery or engage in other potentially hazardous activities until it is known whether ALOND affects their ability to perform these activities.

Summary of the safety profile

The ALOND clinical programme involved over 8 900 patients who were exposed to ALOND, of whom over 5 600 were in double-blind placebo-controlled trials. The most commonly reported adverse reactions were dizziness and somnolence which were dose related. Adverse reactions were usually mild to moderate in intensity. In all controlled studies, the discontinuation rate due to adverse events was 12 % for patients receiving ALOND and 5 % for patients receiving placebo. The adverse reactions resulting in discontinuation from ALOND treatment groups were dizziness and somnolence.

Tabulated list of adverse reactions

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 (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1 000 to < 1/100); rare (u2265 1/10 000 to < 1/1 000); very rare (< 1/10 000), and Frequency not known as the frequency cannot be estimated from the available data. The adverse reactions listed may also be associated with the underlying disease and concomitant medicines.

Adverse reactions from clinical trials

MedDRA System Organ Class Frequency Adverse reactions

Infections and infestations Common Nasopharyngitis

Blood and lymphatic system disorders Uncommon Neutropenia

Metabolism and nutrition disorders Common Increased appetite

Uncommon Anorexia, hypoglycaemia

Psychiatric disorders Common Euphoric mood, confusion, libido decreased, irritability, depression, disorientation, insomnia

Uncommon Depersonalisation, anorgasmia, restlessness, agitation, mood swings, depressed mood, elevated mood, word finding difficulty, hallucination, abnormal dreams, increased libido

Rare Panic attack, disinhibition, apathy, suicidal behaviour, suicidal ideation

Nervous system disorders Very common Dizziness, somnolence

Common Ataxia, disturbance in attention, abnormal coordination, amnesia, memory impairment, tremor, dysarthria, paraesthesia, hypoaesthesia, sedation, balance disorder, lethargy

Uncommon Cognitive disorder, nystagmus, speech disorder, myoclonus, hyporeflexia, dyskinesia, psychomotor hyperactivity, postural dizziness, hyperaesthesia, burning sensation, intention tremor, syncope

Rare Stupor, hypokinesia, parosmia, ageusia, dysgraphia

Eye disorders Common Blurred vision blurred, diplopia

Uncommon Peripheral vision loss, visual disturbance, dry eye, eye swelling, visual field defect, reduced visual acuity, eye pain, asthenopia, photopsia, increased lacrimation, eye irritation

Rare Mydriasis, oscillopsia, altered visual depth perception, strabismus, visual brightness

Ear and labyrinth disorders Common Vertigo

Uncommon Hyperacusis

Cardiac disorders Uncommon Tachycardia, atrioventricular block first degree, sinus bradycardia

Rare Sinus tachycardia, sinus dysrhythmia

Vascular disorders Uncommon Hypotension, hypertension, flushing, hot flushes, peripheral coldness

Respiratory, thoracic and mediastinal disorders Uncommon Dyspnoea, epistaxis, cough, nasal congestion, rhinitis, snoring

Rare Throat tightness, nasal dryness

Not known Respiratory depression

Gastrointestinal disorders Common Dry mouth, constipation, vomiting, flatulence, abdominal distension

Uncommon Salivary hypersecretion, gastroesophageal reflux disease, oral hypoaesthesia

Rare Ascites, dysphagia, pancreatitis

Skin and subcutaneous tissue disorders Uncommon Sweating, rash papular, urticaria

Rare Cold sweat

Musculoskeletal and connective tissue disorders Common Muscle cramp, arthralgia, back pain, pain in limb, cervical spasm

Uncommon Muscle twitching, joint swelling, myalgia, neck pain, muscle stiffness

Rare Rhabdomyolysis

Renal and urinary disorders Uncommon Dysuria, urinary incontinence

Rare Oliguria, renal failure

Reproductive system and breast disorders Uncommon Erectile dysfunction, delayed ejaculation, sexual dysfunction, dysmenorrhoea

Rare Amenorrhoea, breast pain, breast discharge, breast enlargement

General disorders and administration site conditions Common Fatigue, oedema peripheral, fall, feeling drunk, feeling abnormal, oedema, abnormal gait

Uncommon Generalised oedema, asthenia, thirst, chest tightness, pain, pyrexia, chills

Investigations Common Increased weight

Uncommon Increased alanine aminotransferase, increased blood creatine phosphokinase, increased aspartate aminotransferase, increased blood glucose, decreased platelet count, decreased blood potassium, decreased weight

Rare Increased blood creatinine, decreased white blood cell count

Other special populations

Elderly (over 65 years of age)

In a total of 998 elderly patients, no overall differences in safety were observed compared with patients less than 65 years of age.

Post-marketing (see section 4.4)

MedDRA System Organ Class Adverse reactions

Immune system disorders Angioedema, allergic reaction, hypersensitivity

Psychiatric disorders Drug dependence

Nervous system disorders Headache, loss of consciousness, mental impairment, reversible paralysis

Eye disorders Keratitis

Cardiac disorders Congestive heart failure

Respiratory, thoracic and mediastinal disorders Pulmonary oedema

Gastrointestinal disorders Swollen tongue, diarrhoea, nausea

Skin and subcutaneous tissue disorders Face swelling, pruritus, toxic epidermal necrolysis, Stevens-Johnson syndrome

Renal and urinary disorders Urinary retention

Reproductive system and breast disorders Gynaecomastia

General disorders and administration site conditions Malaise

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

In overdoses up to 15 g, no unexpected adverse reactions were reported. In post-marketing experience, the most commonly reported adverse events observed when ALOND was taken in overdose included affective disorder, somnolence, confusional state, depression, agitation and restlessness. Seizures were also reported. In rare occasions, cases of coma have been reported.

Treatment of ALOND overdose should include general supportive measures and may include haemodialysis if necessary (see section 4.2 u2013 Patients with renal impairment).