Xyrem · 4.4 Special warnings and precautions for use · 1

HOS-093960 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile Clinical Studies 8 The safety profile was qualitatively the same in adult and paediatric studies. In adults the most commonly reported adverse reactions were dizziness, nausea, and headache, all occurring in 10% to 20% of patients. The most serious adverse reactions are suicidal attempt, psychosis, respiratory depression and convulsion. In adults the efficacy and safety of sodium oxybate for the treatment of narcolepsy symptoms was established in four multicentre, randomised, double-blind, placebo-controlled, parallel-group trials in patients with narcolepsy with cataplexy except for one trial where cataplexy was not required for enrolment. Two Phase 3 and one Phase 2 double-blind, parallel-group, placebo-controlled studies were performed to assess the indication of sodium oxybate for fibromyalgia in adults. Additionally, randomised, double-blind, placebo-controlled, crossover drug-drug interaction studies with ibuprofen, diclofenac and valproate were performed in healthy adult subjects and are summarised in section 4.5. Post-marketing experience In addition to the adverse reactions reported during clinical studies, adverse reactions have been reported in post-marketing experience. It is not always possible to reliably estimate the frequency of their incidence in the population to be treated. Tabulated summary of adverse reactions Undesirable effects are listed according to MedDRA System Organ Class. Frequency estimate: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Infections and infestations Common: nasopharyngitis, sinusitis Immune system disorders Uncommon: hypersensitivity Metabolism and nutrition disorders Common: anorexia, decreased appetite Not known: Dehydration, increased appetite Psychiatric disorders Common: depression, cataplexy, anxiety, abnormal dreams, confusional state, disorientation, nightmares, sleepwalking, sleep disorder, insomnia, middle insomnia, nervousness Uncommon: suicide attempt, psychosis, paranoia, hallucination, abnormal thinking, agitation, initial insomnia Not known: suicidal ideation, homicidal ideation, aggression, euphoric mood, sleep-related eating disorder, panic attack, mania / bip

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HOS-093956 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Patients with major depression. Patients with succinic semialdehyde dehydrogenase deficiency. Patients being treated with opioids or barbiturates.

HOS-093955 · has-indication-information · PDF-Seite 2

Treatment of narcolepsy with cataplexy in adult patients, adolescents and children from the age of 7 years.

HOS-093958 · has-interaction-information · PDF-Seite 6

The combined use of alcohol with sodium oxybate may result in potentiation of the central nervous system-depressant effects of sodium oxybate. Patients should be warned against the use of any alcoholic beverages in conjunction with sodium oxybate. 6 Sodium oxybate should not be used in combination with sedative hypnotics or other CNS depressants. Sedative hypnotics Drug interaction studies in healthy adults with sodium oxybate (single dose of 2.25 g) and lorazepam (single dose of 2 mg) and zolpidem tartrate (single dose of 5 mg) demonstrated no pharmacokinetic interactions. Increased sleepiness was observed after concomitant administration of sodium oxybate (2.25 g) and lorazepam (2 mg). The pharmacodynamic interaction with zolpidem has not been assessed. When higher doses up to 9 g/d of sodium oxybate are combined with higher doses of hypnotics (within the recommended dose range) pharmacodynamic interactions associated with symptoms of CNS depression and/or respiratory depression cannot be excluded (see section 4.3). Tramadol A drug interaction study in healthy adults with sodium oxybate (single dose of 2.25 g) and tramadol (single dose of 100 mg) demonstrated no pharmacokinetic/pharmacodynamic interaction. When higher doses up to 9 g/day of sodium oxybate are combined with higher doses of opioids (within the recommended dose range) pharmacodynamic interactions associated with symptoms of CNS depression and/or respiratory depression cannot be excluded (see sections 4.3). Antidepressants Drug interaction studies in healthy adults demonstrated no pharmacokinetic interactions between sodium oxybate (single dose of 2.25 g) and the antidepressants protriptyline hydrochloride (single dose of 10 mg) and duloxetine (60 mg at steady state). No additional effect on sleepiness was observed when comparing single doses of sodium oxybate alone (2.25 g) and sodium oxybate (2.25 g) in combination with duloxetine (60 mg at steady state). Antidepressants have been used in the treatment of cataplexy. A possible additive effect of antidepressants and sodium oxybate cannot be excluded. The rate of adverse reactions has increased when sodium oxybate is co-administered with tricyclic antidepressants. Modafinil A drug interaction study in healthy adults demonstrated no pharmacokinetic interactions between sodium oxybate (single dose of 4.5 g) and modafinil (single dose of 200 mg). Sodium oxybate has been administered con

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HOS-093959 · has-pregnancy-information · PDF-Seite 8

Pregnancy Animal studies have shown no evidence of teratogenicity but embryo lethality was seen in both rat and rabbit studies (see section 5.3). Data from a limited number of pregnant women exposed in the first trimester indicate a possible increased risk of spontaneous abortions. To date no other relevant epidemiological data are available. Limited data from pregnant patients during second and third trimester indicate no malformative or foeto/neonatal toxicity of sodium oxybate. Sodium oxybate is not recommended during pregnancy. Breast-feeding Sodium oxybate and/or its metabolites are excreted into breast milk. Changes in sleep patterns have been observed in breastfed infants from exposed mothers, which may be consistent with the effects of sodium oxybate on the nervous system. Sodium Oxybate should not be used during breastfeeding. Fertility There is no clinical data available on the effect of sodium oxybate on fertility. Studies in male and female rats at doses up to 1,000 mg/kg/day GHB have shown no evidence of an adverse effect on fertility.

HOS-093957 · has-warning-information · PDF-Seite 4

Xyrem has the potential to induce respiratory depression Respiratory and CNS depression Sodium oxybate also has the potential to induce respiratory depression. Patients should be assessed before treatment for sleep apnoea and caution should be exercised when considering treatment. Apnoea and respiratory depression have been observed in a fasting healthy subject after a single intake of 4.5g (twice the recommended starting dose). During post-marketing surveillance, it has been observed that the use of sodium oxybate may predispose the patients to choking sensation during sleep. Patients should be questioned regarding signs of Central Nervous System (CNS) or respiratory depression. Special caution should be observed in patients with an underlying respiratory disorder. Patients should be monitored for signs of respiratory depression during treatment. Because of the higher risk of sleep apnoea, patients with a BMI ≥40 kg/m2 should be monitored closely when taking sodium oxybate. Approximately 80% of patients who received sodium oxybate during clinical trials maintained CNS stimulant use. Whether this affected respiration during the night is unknown. Before increasing the sodium oxybate dose (see section 4.2), prescribers should be aware that sleep apnoea occurs in up to 50% of patients with narcolepsy. • Benzodiazepines Given the possibility of increasing the risk of respiratory depression, the concomitant use of benzodiazepines and sodium oxybate should be avoided. • Alcohol and CNS depressants The combined use of alcohol, or any CNS -depressant medicinal product, with sodium oxybate may result in potentiation of the CNS-depressant effects of sodium oxybate as well as increased risk of respiratory depression. Therefore, patients should be warned against the use of alcohol in conjunction with sodium oxybate. • Gamma hydroxybutyrate (GHB) dehydrogenase inhibitors Caution is required in patients who are treated concomitantly with valproate or other GHB dehydrogenase inhibitors as pharmacokinetic and pharmacodynamic interactions have been observed when sodium oxybate is co-administered with valproate (see section 4.5). If concomitant use is warranted, dose adjustment is to be considered (see section 4.2). Additionally, patient response and tolerability should be carefully monitored and dose should be a

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