Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Aventis Pharma Limited, One Onslow StreetGuildford, Surrey, GU1 4YS, UK or trading as: Sanofi-aventis or Sanofi, One Onslow Street, Guildford, Surrey, GU1 4YS, UK
Epilim is contraindicated in the following situations:
Although there is no specific evidence of sudden recurrence of underlying symptoms following withdrawal of valproate, discontinuation should normally only be done under the supervision of a specialist in a gradual manner. This is due to the possibility of sudden alterations in plasma concentrations giving rise to a recurrence of symptoms. NICE has advised that generic switching of valproate preparations is not normally recommended due to the clinical implications of possible variations in plasma concentrations.
Severe liver damage, including hepatic failure sometimes resulting in fatalities, has been very rarely reported. Experience in epilepsy has indicated that patients most at risk, especially in cases of multiple anti-convulsant therapy, are infants and in particular young children under the age of 3 years and those with severe seizure disorders, organic brain disease, and (or) congenital metabolic or degenerative disease associated with mental retardation. After the age of 3 years, the incidence of occurrence is significantly reduced and progressively decreases with age.
The concomitant use of salicylates should be avoided in children under 3 years due to the risk of liver toxicity. Additionally, salicylates should not be used in children under 16 years (see aspirin/salicylate product information on Reye’s syndrome).
Monotherapy is recommended in children under the age of 3 years when prescribing Epilim, but the potential benefit of Epilim should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy
In most cases, such liver damage occurred during the first 6 months of therapy, the period of maximum risk being 2–12 weeks.
Clinical symptoms are essential for early diagnosis. In particular the following conditions, which may precede jaundice, should be taken into consideration, especially in patients at risk (see above: ‘Conditions of occurrence’):
These are an indication for immediate withdrawal of the drug.
Patients (or their family for children) should be instructed to report immediately any such signs to a physician should they occur. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately.
Liver function should be measured before therapy and then periodically monitored during the first 6 months of therapy, especially in those who seem most at risk, and those with a prior history of liver disease.
Amongst usual investigations, tests which reflect protein synthesis, particularly prothrombin rate, are most relevant.
Confirmation of an abnormally low prothrombin rate, particularly in association with other biological abnormalities (significant decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) requires cessation of Epilim therapy.
As a matter of precaution and in case they are taken concomitantly salicylates should also be discontinued since they employ the same metabolic pathway.
As with most anti-epileptic drugs, increased liver enzymes are common, particularly at the beginning of therapy; they are also transient.
More extensive biological investigations (including prothrombin rate) are recommended in these patients; a reduction in dosage may be considered when appropriate and tests should be repeated as necessary.
Pancreatitis, which may be severe and result in fatalities, has been very rarely reported. Patients experiencing nausea, vomiting or acute abdominal pain should have a prompt medical evaluation (including measurement of serum amylase).Young children are at particular risk; this risk decreases with increasing age. Severe seizures and severeneurological impairment with combination anti-convulsant therapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome. In case of pancreatitis, Epilim should be discontinued.
Valproate has a high teratogenic potential and children exposed in utero to valproate have a high risk for congenital malformations and neurodevelopmental disorders (see section 4.6).
Epilim is contraindicated in the following situations:
Conditions of Pregnancy Prevention Programme:
The prescriber must ensure that:
The prescriber must ensure that:
The parents/caregivers of female children understand the need to contact the specialist once the female child using valproate experiences menarche.
The parents/caregivers of female children who have experienced menarche are provided with comprehensive information about the risks of congenital malformations and neurodevelopmental disorders including the magnitude of these risks for children exposed to valproate in utero.
In patients who have experienced menarche, the prescribing specialist must annually reassess the need for valproate therapy and consider alternative treatment options. If valproate is the only suitable treatment, the need for using effective contraception and all other conditions of the pregnancy prevention programme should be discussed. Every effort should be made by the specialist to switch female children to alternative treatment before they reach adulthood.
Pregnancy must be excluded before start of treatment with valproate. Treatment with valproate must not be initiated in women of childbearing potential without a negative pregnancy test (plasma pregnancy test) result, confirmed by a healthcare provider, to rule out unintended use in pregnancy.
Women of childbearing potential who are prescribed valproate must use effective contraception without interruption during the entire duration of treatment with valproate. These patients must be provided with comprehensive informationon pregnancy prevention and should be referred for contraceptive advice if they are not using effective contraception. At least one effective method of contraception (preferably a user independent form such as an intra-uterine device or implant) or two complementary forms of contraception including a barrier method should be used. Individual circumstances should be evaluated in each case when choosing the contraception method, involving the patient in the discussion to guarantee her engagement and compliance with the chosen measures. Even if she has amenorrhea she must follow all the advice on effective contraception.
Oestrogen-containing products:
Concomitant use with oestrogen-containing products, including oestrogen-containing hormonal contraceptives, may potentially result in decreased valproate efficacy (see section 4.5). Prescribers should monitor clinical response (seizure control) when initiating, or discontinuing oestrogen-containing products.
On the opposite, valproate does not reduce efficacy of hormonal contraceptives.
The specialist should review at least annually whether valproate is the most suitable treatment for the patient. The specialist should discuss the Annual Risk Acknowledgement Form at initiation and during each annual review, and ensure that the patient has understood its content.
If a woman is planning to become pregnant, a specialist experienced in the management of epilepsy must reassess valproate therapy and consider alternative treatment options. Every effort should be made to switch to appropriate alternative treatment prior to conception and before contraception is discontinued (see section 4.6). If switching is not possible, the woman should receive further counselling regarding the risks of valproate for the unborn child to support her informed decision-making regarding family planning.
If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to re-evaluate treatment with valproate and consider alternative treatment options. The patients with valproate-exposed pregnancy and their partners should be referred to a specialist experienced in prenatal medicine for evaluation and counselling regarding the exposed pregnancy (see section 4.6).
Pharmacists must ensure that:
In order to assist healthcare professionals and patients in avoiding exposure to valproate during pregnancy, the Marketing Authorisation Holder has provided educational materials to reinforce the warnings, provide guidance regarding use of valproate in women of childbearing potential and provide details of the Pregnancy Prevention Programme. A Patient Guide and Patient Card should be provided to all women of childbearing potential using valproate.
An Annual Risk Acknowledgement Form needs to be used at time of treatment initiation and during each annual review of valproate treatment by the specialist.
Valproate therapy should only be continued after a reassessment of the benefits and risks of the treatment with valproate for the patient by a specialist experienced in the management of epilepsy.
As with other anti-epileptic drugs, some patients may experience, instead of an improvement, a reversible worsening of convulsion frequency and severity (including status epilepticus), or the onset of new types of convulsions with valproate. In case of aggravated convulsions, the patients should be advised to consult their physician immediately (see section 4.8).
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 does not exclude the possibility of an increased risk for sodium valproate.
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.
The concomitant use of valproate and carbapenem agents is not recommended.
Valproate may trigger or worsen clinical signs of underlying mitochondrial diseases caused by mutations of mitochondrial DNA as well as the nuclear encoded POLG gene. In particular, valproate-induced acute liver failure and liver-related deaths have been reported at a higher rate in patients with hereditary neurometabolic syndromes caused by mutations in the gene for the mitochondrial enzyme polymerase γ (POLG), e.g. Alpers-Huttenlocher Syndrome.
POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG- related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders (see section 4.3).
Blood tests (blood cell count, including platelet count, bleeding time and coagulation tests) are recommended prior to initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding (see section 4.8).
In patients with renal insufficiency, it may be necessary to decrease dosage. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring (see sections 4.2 and 5.2).
Although immune disorders have only rarely been noted during the use of Epilim, the potential benefit of Epilim should be weighed against its potential risk in patients with systemic lupus erythematosus (see section 4.8).
When a urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of the risk of hyperammonaemia with Epilim (see section 4.3).
Epilim very commonly causes weight gain, which may be marked and progressive. Patients should be warned of the risk at the initiation of therapy and appropriate strategies should be adopted to minimise it (see section 4.8).
Epilim is eliminated mainly through the kidneys, partly in the form of ketone bodies; this may give false positives in the urine testing of possible diabetics.
Patients with an underlying carnitine palmitoyltransferase (CPT) type II deficiency should be warned of the greater risk of rhabdomyolysis when taking Epilim.
Alcohol intake is not recommended during treatment with valproate.
Epilim may potentiate the effect of other psychotropics such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; therefore, clinical monitoring is advised and the dosage of the other psychotropics should be adjusted when appropriate.
In particular, a clinical study has suggested that adding olanzapine to valproate or lithium therapy may significantly increase the risk of certain adverse events associated with olanzapine e.g. neutropenia, tremor, dry mouth, increased appetite and weight gain, speech disorder and somnolence.
Epilim has no effect on serum lithium levels.
Valproic acid may decrease the olanzapine plasma concentration.
Epilim increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur, particularly in children. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate.
Epilim increases primidone plasma levels with exacerbation of its adverse effects (such as sedation); these signs cease with long term treatment. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
Epilim decreases phenytoin total plasma concentration. Moreover Epilim increases phenytoin free form with possible overdose symptoms (valproic acid displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism). Therefore clinical monitoring is recommended; when phenytoin plasma levels are determined, the free form should be evaluated.
Clinical toxicity has been reported when Epilim was administered with carbamazepine as Epilim may potentiate toxic effects of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.
Epilim reduces the metabolism of lamotrigine and increases the lamotrigine mean half-life by nearly two fold. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes. Therefore clinical monitoring is recommended and dosages should be adjusted (lamotrigine dosage decreased) when appropriate.
Valproic acid may decrease the felbamate mean clearance by up to 16%.
Valproic acid may lead to an increase in plasma levels of rufinamide. This increase is dependent on concentration of valproic acid. Caution should be exercised, in particular in children, as this effect is larger in this population.
Valproic acid may lead to an increased blood level of propofol. When co-administered with valproate, a reduction of the dose of propofol should be considered.
Epilim may raise zidovudine plasma concentration leading to increased zidovudine toxicity.
In patients concomitantly treated with sodium valproate and nimodipine the exposure to nimodipine can be increased by 50%. The nimodipine dose should therefore be decreased in case of hypotension.
Co-administration of temozolomide and Epilim may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.
Anti-epileptics with enzyme inducing effect (including phenytoin, phenobarbital, carbamazepine) decrease valproic acid plasma concentrations. Dosages should be adjusted according to clinical response and blood levels in case of combined therapy.
Valproic acid metabolite levels may be increased in the case of concomitant use with phenytoin or phenobarbital. Therefore patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonaemia.
On the other hand, combination of felbamate and Epilim decreases valproic acid clearance by 22% – 50% and consequently increase the valproic acid plasma concentrations. Epilim dosage should be monitored.
Mefloquine and chloroquine increase valproic acid metabolism and may lower the seizure threshold; therefore epileptic seizures may occur in cases of combined therapy. Accordingly, the dosage of Epilim may need adjustment.
In case of concomitant use of Epilim and highly protein bound agents (e.g. aspirin), free valproic acid plasma levels may be increased.
The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased following displacement from plasma protein binding sites by valproic acid. The prothrombin time should be closely monitored.
Valproic acid plasma levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or erythromycin.
Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60% – 100% decrease in valproic acid levels within two days, sometimes associated with convulsions. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stabilised on valproic acid should be avoided (see section 4.4). If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood levels should be performed.
Rifampicin may decrease the valproic acid blood levels resulting in a lack of therapeutic effect. Therefore, valproate dosage adjustment may be necessary when it is co-administered with rifampicin.
Protease inhibitors such as lopinavir and ritonavir decrease valproate plasma level when co-administered.
Cholestyramine may lead to a decrease in plasma level of valproate when co-administered.
Oestrogens are inducers of the UDP-glucuronosyl transferase (UGT) isoforms involved in valproate glucuronidation and may increase the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy (see section 4.4). Consider monitoring of valproate serum levels.
On the opposite, valproate has no enzyme inducing effect; as a consequence, valproate does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception.
Caution is advised when using Epilim in combination with newer anti-epileptics whose pharmacodynamics may not be well established.
Concomitant administration of valproate and topiramate or acetazolamide has been associated with encephalopathy and/or hyperammonaemia. In patients taking these two drugs, careful monitoring for signs and symptoms is advised in particularly at-risk patients such as those with pre-existing encephalopathy.
Co-administration of Epilim and quetiapine may increase the risk of neutropenia/leucopenia.
Concomitant food intake does not significantly influence the bioavailability of sodium valproate when administered as the Chronosphere formulation.
Valproate is contraindicated as treatment for epilepsy during pregnancy unless there is no suitable alternative to treat epilepsy.
Valproate is contraindicated for use in women of childbearing potential unless the conditions of the Pregnancy Prevention Programme are fulfilled (see sections 4.3 and 4.4).
Both valproate monotherapy and valproate polytherapy are associated with abnormal pregnancy outcomes. Available data suggest that anti-epileptic polytherapy including valproate is associated with a greater risk of congenital malformations than valproate monotherapy.
Data derived from a meta-analysis (including registries and cohort studies) has shown that 10.73% of children of epileptic women exposed to valproate monotherapy during pregnancy suffer from congenital malformations (95% CI: 8.16–13.29). This is a greater risk of major malformations than for the general population, for whom the risk is about 2–3%. The risk is dose dependent but a threshold dose below which no risk exists cannot be established.
Available data show an increased incidence of minor and major malformations. The most common types of malformations include neural tube defects, facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal andurogenital defects, limb defects (including bilateral aplasia of the radius), and multiple anomalies involving various body systems.
Data have shown that exposure to valproate in utero can have adverse effects on mental and physical development of the exposed children. The risk seems to be dose-dependent but a threshold dose below which no risk exists, cannot be established based on available data. The exact gestational period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded.
Studies in preschool children exposed in utero to valproate show that up to 30–40% experience delays in their early development such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding) and memory problems.
Intelligence quotient (IQ) measured in school aged children (age 6) with a history of valproate exposure in utero was on average 7–10 points lower than those children exposed to other anti-epileptics. Although the role of confounding factors cannot be excluded, there is evidence in children exposed to valproate that the risk of intellectual impairment may be independent from maternal IQ.
There are limited data on the long term outcomes.
Available data show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately three-fold) and childhood autism (approximately five-fold) compared with the general study population.
Limited data suggests that children exposed to valproate in utero may be more likely to develop symptoms of attention deficit/hyperactivity disorder (ADHD).
(see above and section 4.4)
Oestrogen-containing products, including oestrogen-containing hormonal contraceptives, may increase the clearance of valproate, which would result in decreased serum concentration of valproate and potentially decreased valproate efficacy (see sections 4.4 and 4.5).
If a woman is planning to become pregnant, a specialist experienced in the management of epilepsy must reassess valproate therapy and consider alternative treatment options. Every effort should be made to switch to appropriate alternative treatment prior to conception and before contraception is discontinued (see section 4.4). If switching is not possible, the woman should receive further counselling regarding the risks of valproate for the unborn child to support her informed decision-making regarding family planning.
Valproate as treatment for epilepsy is contraindicated in pregnancy unless there is no suitable alternative treatment (see sections 4.3 and 4.4). If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to consider alternative treatment options.
During pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia may carry a particular risk of death for the mother and the unborn child. If in exceptional circumstances, despite the known risks of valproate in pregnancy and after careful consideration of alternative treatment, a pregnant woman must receive valproate for epilepsy, it is recommended to:
All patients with valproate-exposed pregnancy and their partners should be referred to a specialist experienced in prenatal medicine for evaluation and counselling regarding the exposed pregnancy. Specialised prenatal monitoring should take place to detect the possible occurrence of neural tube defects or other malformations. Folate supplementation before the pregnancy may decrease the risk of neural tube defects which may occur in all pregnancies. However the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure.
Cases of haemorrhagic syndrome have been reported very rarely in neonates whose mothers have taken valproate during pregnancy. This haemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenemia and/or to a decrease in other coagulation factors. Afibrinogenemia has also been reported and may be fatal. However, this syndrome must be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and enzymatic inducers. Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.
Cases of hypoglycaemia have been reported in neonates whose mothers have taken valproate during the third trimester of their pregnancy.
Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy.
Withdrawal syndrome (such as, in particular, agitation, irritability, hyper-excitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions and feeding disorders) may occur in neonates whose mothers have taken valproate during the last trimester of their pregnancy.
Valproate is excreted in human milk with a concentration ranging from 1%–10% of maternal serum levels. Haematological disorders have been shown in breastfed newborns/infants of treated women (see section 4.8).
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Epilim therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
Amenorrhoea, polycystic ovaries and increased testosterone levels have been reported in women using valproate (see section 4.8). Valproate administration may also impair fertility in men (see section 4.8). Case reports indicate that fertility dysfunctions are reversible after treatment discontinuation.
Use of Epilim may provide seizure control such that the patient may be eligible to hold a driving licence.
However, patients should be warned of the risk of transient drowsiness, especially in cases of anti-convulsant polytherapy or association with benzodiazepines (see section 4.5 Interactions with Other Medicaments and Other Forms of Interaction).
The following CIOMS frequency rating is used, when applicable: very common (≥1/10); common (≥1/100 to ≤1/10); uncommon (≥1/1,000 to ≤1/100); rare (≥1/10,000 to ≤1/1,000); very rare (≤1/10,000); not k nown (cannot be estimated from the available data).
(see sections 4.4 and 4.6).
Common: liver injury (see section 4.4.1)
Severe liver damage, including hepatic failure sometimes resulting in death, has been reported (see sections 4.2, 4.3 and 4.4.1). Increased liver enzymes are common, particularly early in treatment, and may be transient (see section 4.4.1).
Very common: nausea
Common: vomiting, gingival disorder (mainly gingival hyperplasia), stomatitis, gastralgia, diarrhoea
The above adverse events frequently occur at the start of treatment, but they usually disappear after a few days without discontinuing treatment. These problems can usually be overcome by taking Epilim with or after food.
Uncommon: pancreatitis, sometimes lethal (see section 4.4)
Very common: tremor
Common: extrapyramidal disorder, stupor*, somnolence, convulsion*, memory impairment, headache, nystagmus
Uncommon: coma*, encephalopathy, lethargy* (see below), reversible parkinsonism, ataxia, paraesthesia, aggravated convulsions (see section 4.4)
Rare: reversible dementia associated with reversible cerebral atrophy, cognitive disorder
Sedation has been reported occasionally, usually when in combination with other anti-convulsants. In monotherapy it occurred early in treatment on rare occasions, and is usually transient.
* Rare cases of lethargy, occasionally progressing to stupor, sometimes with associated hallucinations or convulsions, have been reported. Encephalopathy and coma have very rarely been observed. These cases have often been associated with too high a starting dose or too rapid a dose escalation, or concomitant use of other anti-convulsants, notably phenobarbital or topiramate. They have usually been reversible on withdrawal of treatment or reduction of dosage.
An increase in alertness may occur; this is generally beneficial, but occasionally aggression, hyperactivity and behavioural deterioration have been reported.
Common: confusional state, hallucinations, aggression*, agitation*, disturbance in attention*
Rare: abnormal behaviour*, psychomotor hyperactivity*, learning disorder*
* These ADRs are principally observed in the paediatric population.
Common: hyponatraemia, weight increased*
* Weight increase should be carefully monitored since it is a factor for polycystic ovary syndrome (see section 4.4).
Rare: hyperammonaemia* (see section 4.4.2), obesity
* Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur, are usually transient and should not cause treatment discontinuation. However, they may present clinically as vomiting, ataxia, and increasing clouding of consciousness. Should these symptoms occur Epilim should be discontinued.
Hyperammonaemia associated with neurological symptoms has also been reported (see section 4.4.2). In such cases further investigations should be considered.
Uncommon: Syndrome of Inappropriate Secretion of ADH (SIADH), hyperandrogenism (hirsutism, virilism, acne, male pattern alopecia, and/or androgen increase)
Rare: hypothyroidism (see section 4.6)
Common: anaemia, thrombocytopenia (see section 4.4.2)
Uncommon: pancytopenia, leucopenia
Rare: bone marrow failure, including pure red cell aplasia, agranulocytosis, anaemia macrocytic, macrocytosis
The blood picture returned to normal when the drug was discontinued.
Isolated findings of a reduction in blood fibrinogen and/or an increase in prothrombin time have been reported, usually without associated clinical signs and particularly with high doses (Epilim has an inhibitory effect on the second phase of platelet aggregation). Spontaneous bruising or bleeding is an indication for withdrawal of medication pending investigations (see section 4.6).
Common: hypersensitivity, transient and/or dose related alopecia (hair loss), nail and nail bed disorders. Regrowth normally begins within six months, although the hair may become more curly than previously.
Uncommon: angioedema, rash, hair disorder (such as abnormal hair texture, hair colour changes, abnormal hair growth)
Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome
Common: dysmenorrhea
Uncommon: amenorrhea
Rare: male infertility, polycystic ovaries
Very rarely gynaecomastia has occurred.
Common: haemorrhage (see sections 4.4.2 and 4.6)
Uncommon: vasculitis
Rare: diplopia
Common: deafness, a cause and effect relationship has not been established.
Common: urinary incontinence
Uncommon: renal failure
Rare: enuresis, tubulointerstitial nephritis, reversible Fanconi syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with Epilim therapy, but the mode of action is as yet unclear.
Uncommon: hypothermia, non-severe peripheral oedema
Uncommon: bone mineral density decreased, osteopenia, osteoporosis and fractures in patients on long-term therapy with Epilim. The mechanism by which Epilim affects bone metabolism has not been identified.
Rare: systemic lupus erythematosus, rhabdomyolysis (see section 4.4.2)
Uncommon: pleural effusion
Rare: coagulation factors decreased (at least one), abnormal coagulation tests (such as prothrombin time prolonged, activated partial thromboplastin time prolonged, thrombin time prolonged, INR prolonged) (see sections 4.4 and 4.6)
Rare: myelodysplastic syndrome
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
This medicinal product must not be administered with hot meals or drinks.
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