Myalica 25 mg, 75 mg or 150 mg Capsules, hard.

MYALICA capsules are indicated for the treatment of adult patients with neuropathic pain due to Herpes zoster infections and diabetes.

Posology
The recommended starting dose for MYALICA 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 - 7 days. In accordance with current clinical practice, if MYALICA must be discontinued, it is recommended this should be done gradually over a minimum of 1 week.

Special populations
MYALICA is eliminated from the systemic circulation primarily by renal excretion as unchanged pregabalin. As MYALICA clearance is directly proportional to creatinine clearance (see section 5.2), dosage reduction in patients with compromised renal function must be individualised according to creatinine clearance (CLcr), as indicated in Table 1 determined using the following formula:
CLcr (ml/min) = (x 0,85 for female patients)

Table 1: MYALICA dosage adjustment based on renal function

Supplementary dose following haemodialysis (mg)
25
50**
Single dose
u2018
BD = Two divided doses
OD = Once daily
* Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose
** 50 mg dose can be achieved by taking 2 x 25 mg capsules
u2018 Supplementary dose is a single additional dose
MYALICA is removed effectively from plasma by haemodialysis (50 % of medicine in 4 hours). For patients receiving haemodialysis, the MYALICA 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).

Use in patients with hepatic impairment
No dosage adjustment is required for patients with hepatic impairment (see section 5.2).

Use in the elderly (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 MYALICA in patients below the age of 18 years with neuropathic pain has not been established.

Method of administration
MYALICA is given orally with or without food.

• Hypersensitivity to pregabalin or to any of the ingredients of MYALICA (see section 6.1).

Diabetic patients
Diabetic patients who gain weight on MYALICA 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. MYALICA 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 pregabalin 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, MYALICA should be withdrawn immediately and an alternative treatment considered (as appropriate).

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

Vision-related effects
Visual adverse reactions have been reported, including loss of vision, visual blurring or other changes of visual acuity, many of which were transient. Discontinuation of MYALICA may result in resolution or improvement of these visual symptoms.

Renal failure
Renal failure has been reported and discontinuation of pregabalin, as in MYALICA, did show reversibility of this adverse reaction.

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

Convulsions, including status epilepticus and grand mal convulsions, may occur during MYALICA use or shortly after discontinuing.

Discontinuation of long-term treatment of pregabalin, as in MYALICA, data suggest that the incidence and severity of withdrawal symptoms may be dose related.

Congestive heart failure
Congestive heart failure has been reported. These reactions are mostly seen in elderly cardiovascular compromised patients during pregabalin treatment for a neuropathic indication. MYALICA should be used with caution in these patients. Discontinuation of MYALICA may resolve the reaction.

Suicidal ideation and behaviour
Suicidal ideation and behaviour have been reported in patients treated with gabapentinoids such as pregabalin, as in MYALICA, in several indications. 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.

Cases of suicidal ideation and behaviour have been observed in patients treated with pregabalin 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 pregabalin u2013 as in MYALICA.

Withdrawal of concomitant anti-epileptic medicines
There are insufficient data for the withdrawal of concomitant anti-epileptic medicines, once seizure control with pregabalin in the add-on situation has been reached, in order to reach monotherapy on MYALICA.

Treatment of central neuropathic pain due to spinal cord injury
In the treatment of central neuropathic pain due to spinal cord injury, the incidence of adverse reactions in general, central nervous system adverse reactions and especially somnolence was increased. This may be attributed to an additive effect due to concomitant medicines (e.g. anti-spasticity agents) needed for this condition. This should be considered when prescribing MYALICA in this condition.

Reduced lower gastrointestinal tract function
Reduced lower gastrointestinal tract function (e.g. intestinal obstruction, paralytic ileus, constipation) has been reported when pregabalin was co-administered with medicines that have the potential to produce constipation, such as opioid analgesics. When MYALICA and opioids will be used in combination, measures to prevent constipation may be considered (especially in female patients and the elderly).

Risk of respiratory depression and dyspnoea
There have been reports of respiratory depression and dyspnoea associated with the use of gabapentinoids (gabapentin, or pregabalin as in MYALICA). Serious breathing difficulties may occur in patients using pregabalin (as in MYALICA), who have respiratory risk factors such as compromised respiratory function, respiratory disease (such as chronic obstructive pulmonary disease), or neurological disease, and renal impairment. These include the use of opioid pain medicines and other medicines that depress the central nervous system (a gabapentinoid, benzodiazepine, sedating antidepressant, sedating antipsychotic, antihistamine, or other product). Elderly patients (over 65 years of age) are also at increased risk. These patients should be carefully observed for signs of CNS depression such as somnolence, sedation, and respiratory depression. The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants, including the gabapentinoid. Gabapentinoids used for analgesia (such as MYALICA) or seizure control should be tapered prior to discontinuation. Adjustments in dose or dosing regimen may be necessary. Healthcare professionals should start gabapentinoids at the lowest dose and monitor patients for symptoms of respiratory depression and sedation when co-prescribing gabapentinoids with an opioid or other CNS depressants.

Caution is advised when prescribing pregabalin concomitantly with opioids due to risk of CNS depression (see section 4.5). In a case control study of opioid users, those patients who took pregabalin concomitantly with an opioid had an increased risk for opioid-related death compared to opioid use alone. This increased risk was observed at low doses of pregabalin (u2264 300 mg) and there was a trend for a greater risk at high doses of pregabalin (> 300 mg).

Misuse, abuse potential or dependence
Cases of misuse, abuse and dependence have been reported. Before prescribing MYALICA, the patient's risk of misuse, abuse or dependence should be carefully evaluated. Caution should be exercised in patients with a history of substance abuse and the patient should be monitored for symptoms of MYALICA misuse, abuse or dependence (development of tolerance, dose escalation, intentional overdose and drug-seeking behaviour).

Encephalopathy
Encephalopathy has been reported, mostly in patients with underlying conditions that may precipitate encephalopathy.

Women of childbearing potential/Contraception
Pregabalin use in the first trimester of pregnancy may cause major birth defects in the unborn child. Women of childbearing potential must use effective contraception during treatment (see section 4.6).

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 medicine metabolism in vitro, and is not bound to plasma proteins, MYALICA 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 MYALICA 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, phenobarbitone, tiagabine and topiramate had no clinically significant effect on pregabalin clearance. Similarly, these analyses indicated that MYALICA had no clinically significant effect on the clearance of phenytoin, carbamazepine, valproic acid, lamotrigine, topiramate and phenobarbitone.

Oral contraceptives, norethisterone and/or ethinyl oestradiol
Co-administration of MYALICA with the oral contraceptives norethisterone and/or ethinyl oestradiol does not influence the steady-state pharmacokinetics of either medicine.

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

In the post marketing experience, there are reports of respiratory failure and coma in patients taking MYALICA and opioids and/or other CNS depressant medications.

Interactions and the elderly
No specific pharmacodynamic interaction studies were conducted in elderly volunteers. Interaction studies have only been performed in adults.

Women of childbearing potential / Contraception in males and females
As potential risk for humans is unknown, effective contraception must be used in women of child-bearing potential.

Pregnancy
There are no adequate data on the use of MYALICA in pregnant women. Studies in animals have shown reproductive toxicity. Pregabalin has been shown to cross the placenta in rats. Pregabalin may cross the human placenta. The potential risk to humans is unknown. Therefore, MYALICA should not be used during pregnancy.

Major congenital malformations
Data from a Nordic observational study of more than 2700 pregnancies exposed to pregabalin in the first trimester showed a higher prevalence of major congenital malformations (MCM) among the paediatric population (live or stillborn) exposed to pregabalin compared to the unexposed population (5,9 % vs. 4,1 %). The risk of MCM among the paediatric population exposed to pregabalin in the first trimester was slightly higher compared to unexposed population (adjusted prevalence ratio and 95 % confidence interval: 1,14 (0,96-1,35)), and compared to population exposed to lamotrigine (1,29 (1,01u2013 1,65)) or to duloxetine (1,39 (1,07u2013 1,82)). The analyses on specific malformations showed higher risks for malformations of the nervous system, the eye, orofacial clefts, urinary malformations and genital malformations, but numbers were small and estimates imprecise.

Breastfeeding
Pregabalin is excreted into human milk (see section 5.2). The effect of pregabalin on new-borns/infants is unknown. Therefore, breastfeeding is not recommended during treatment with MYALICA.

Fertility
There is no clinical data on the effects of pregabalin on female fertility. A fertility study in female rats has shown adverse reproductive effects. Fertility studies in male rats have shown adverse reproductive and development effects.

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

Summary of the safety profile
The most frequently reported adverse reactions were dizziness and somnolence. The most frequent adverse reactions resulting in discontinuation from pregabalin treatment are dizziness and somnolence. In the table below the adverse reactions are listed by system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Additional reactions reported from post marketing experience are also included and listed according to frequency. In the treatment of central neuropathic pain due to spinal cord injury the incidence of adverse reactions in general, CNS adverse reactions and especially somnolence was increased (see section 4.4).

Tabulated list of adverse effects

* Alanine aminotransferase increased (ALT) and aspartate aminotransferase increased (AST).

a. Description of selected adverse reactions
After discontinuation of short-term and long-term treatment with pregabalin withdrawal symptoms have been observed in some patients. The following reactions have been mentioned: insomnia, headache, nausea, anxiety, diarrhoea, flu syndrome, convulsions, nervousness, depression, pain, hyperhidrosis and dizziness, suggestive of physical dependence. The patient should be informed about this at the start of the treatment. Concerning discontinuation of long-term treatment of pregabalin, data suggest that the incidence and severity of withdrawal symptoms may be dose related.

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. Healthcare professionals 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. An email can be sent directly to the company, [email protected], to ensure safety of the product.

Signs and symptoms
In the post marketing experience, the most commonly reported adverse reactions observed when pregabalin was taken in overdose included affective disorder, somnolence, confusional state, agitation, depression and restlessness. Seizures were also reported. In rare occasions, cases of coma have been reported.

Management of overdose
Treatment of pregabalin overdose should include general supportive measures and may include haemodialysis if necessary (see section 4.2 Table 1).