Here you can find answers to some of the most common questions concerning Circadin®.
For more specific questions, we invite you to contact us – our Medical Advisers and Experts are always happy to help.
Circadin® 2 mg is a prolonged-release melatonin formulation, approved as monotherapy for the short-term treatment of primary insomnia characterised by poor Quality of Sleep in patients who are aged 55 or over1. Treatment can be continued for up to 3 months without interruption1.
The melatonin in Circadin is a synthetic molecule and 100% equal to the human melatonin molecule (N-acetyl-5-methoxytryptamine).
Melatonin is a naturally occurring neuro-hormone mainly released from the pineal gland in the head in the evening and during the night1 2 3. Melatonin signals 'darkness', is associated with feeling sleepy, and regulates the sleep-wake cycle1 2 3 4. Individual levels of melatonin vary, but it has been found that otherwise healthy people suffering from insomnia often have lower levels of melatonin than people without insomnia, and that melatonin therapy ameliorates the symptoms of insomnia5. Circadin® is prolonged-release melatonin, which adds exogenous melatonin to the endogenous melatonin throughout the night, thereby facilitating the feeling of sleepiness, the ability to fall asleep, and improving sleep quality and daytime functioning1.
Untreated poor sleep carries a risk to the patient's health. Sleep difficulties are linked to, e.g., increased risk of fatigue, depression, anxiety, and physical morbidity6 7. It is therefore important to treat insomnia. However, treatment is difficult due to the drawbacks with current hypnotics. Firstly, due to the fact that all available hypnotics have been developed and approved with the focus on their ability to improve poor sleep quantity, they rarely improve sleep quality and daytime functioning. Secondly, current hypnotics often cause serious side effects related to daytime functioning - memory impairment, cognitive deficits, risk of falls and accidents8. On top of this, they carry a high risk of dependence and even abuse. This means that the risk-benefit ratio of current therapies is low, especially in the already vulnerable elderly population who are at increased risk of suffering from sleep problems8. Physicians are often reluctant to prescribe a hypnotic, and patients are equally reluctant to take it. By prescribing Circadin®, the physician will be able to offer the patient a safe and effective medication which improves the patient's Quality of Sleep, daytime functioning, time to fall asleep and Quality of Life - without the risk of withdrawal effects, rebound insomnia and amnesic effects, or the risk of dependence.
Untreated insomnia may lead to various health problems6 7. Market research has shown that many people suffering from insomnia are reluctant to take sleep medications due to fear of dependency and side effects. Therefore, many patients, although suffering with the consequences of insomnia, e.g., fatigue, low daytime performance and even anxiety and depression, do not seek medical consultation but use various over-the-counter (OTC) and herbal remedies, and even alcohol, with limited efficacy at best9 10.
Circadin® improves Quality of Sleep and has clinically proven improvement on next-day alertness, a 'placebo like' adverse event profile5, and no drug-related risk of amnesia, cognitive impairments falls or evidence of dependence.
As a post-approval commitment, a study to confirm the lack of dependence, rebound and withdrawal effects was completed and the results will be published shortly12. Further studies are performed in East Asia as part of the registration process in those countries.
Circadin®'s prolonged-release formulation releases melatonin gradually over 8-10 hours, providing a terminal (apparent) half-life of 3.5–4 hours12. The released melatonin is rapidly metabolised by the liver (half-life 40–50 minutes)12 1. The principal metabolite is 6-sulphatoxy-melatonin (6-SMT), which is inactive and accounts for ~80% of the dose excreted in the urine1. Excretion of the metabolites is completed within 12 hours after ingestion12.
Circadin® is a prolonged-release formulation of melatonin, which circumvents the fast clearance of the hormone by releasing the melatonin over an extended period of time12, thereby mimicking physiological patterns of melatonin secretion. Administration of exogenous melatonin does not affect the endogenous secretion of melatonin14. Other melatonin formulations are immediate-release – meaning that they are rapidly absorbed and metabolised with an elimination half-life of ~60 minutes15. Following oral administration of immediate-release melatonin, peak plasma levels that are 5-10 fold higher than those of Circadin®, are reached after ~50 minutes15, rapidly falling off again due to the first-pass hepatic metabolism. Immediate-release melatonin is quickly cleared from the circulation. The differences in the effects of fast vs slow release formulations is best exemplified by their effects on the blood pressure rhythm. Whereas Circadin improves blood pressure control in nocturnal hypertension fast release formulations are not efficacious16. Despite common beliefs, the effect of Circadin® on sleep latency is no less than that of fast release melatonin because the brain is very sensitive to low doses of melatonin in the beginning of the night17 11.
In a study that was performed in the UK in order to assess the efficacy and safety of melatonin in treating patients with REM sleep behaviour disorder it was found out that Circadin® is more effective than standard melatonin preparations (Freeman A, Muza R, Leschziner G, et al. Sustained Release and Standard Preparation Melatonin for the Treatment of REM Sleep Behavioural Disorder. Sleep 2011; 34: A197-A198).
Published literature has shown that administration of exogenous melatonin does not affect the endogenous production of melatonin18 19 14. A long term study of Circadin®, for up to 1 year, showed that melatonin rhythms are preserved in the patients even after 6 months of treatment20.
The age-related decline in melatonin production, that is proposed to contribute to poor sleep quality, is well-documented21. Additionally, it has been demonstrated that elderly insomnia sufferers exhibit lower melatonin levels than elderly people without insomnia5. However, the inter-individual variations in 'normal' levels of melatonin are large. Therefore, measurement of melatonin is not considered relevant in clinical practice. Age is a good surrogate marker of melatonin deficiency in the primary insomnia patient population22.
Dosing and administration
Circadin® dose-ranging studies indicated that a 2 mg dose of Circadin® would provide a beneficial effect in insomnia patients aged 55 years or over12.
In clinical trials over 12 months, Circadin® has been administered at 5 mg daily doses without significantly changing the nature of the adverse reactions reported1. There are reports in the literature of the administration of daily doses of up to 300 mg melatonin without causing clinically significant adverse reactions1. No case of Circadin® overdose has been reported1. If overdose of Circadin® occurs, drowsiness is to be expected1. Clearance of the active substance is expected within 12 hours of ingestion1. No special treatment is required1.
Under normal circumstances, physiological melatonin has a very short half-life, but full-night melatonin levels are ensured via the continued production and release of melatonin throughout the night. With the onset of darkness, melatonin levels increase, even the small increase is sufficient to induce fatigue in healthy individuals. Melatonin levels are then sustained during sleep, and fall off again at the end of the sleeping period, thus melatonin acts as a signal for the entire night. Exogenous (fast / immediate-release) melatonin, unless modified in a prolonged-release formulation such as Circadin®, will not provide continuous melatonin throughout the night23. Immediate-release melatonin reaches maximum levels shortly after being taken at the beginning of the night and, due to the very short half-life15, melatonin levels will diminish within a short period thereafter. Thus, in the later part of the night, immediate-release melatonin will already have been cleared from the body. Further, there has been no thorough clinical development programme to demonstrate the effects of immediate-release formulations of melatonin on Quality of Sleep, morning alertness and Quality of Life or on patients' safety. Circadin®, the prolonged-release formulation of melatonin, circumvents the fast clearance of the hormone and provides a melatonin profile in the blood more closely matched to normal physiological release24. It has been studied extensively in clinical trials to show its efficacy and safety profiles.
The effect of alcohol on Circadin® has not been formally studied. Data from the literature indicate that alcohol directly inhibits pineal gland function (endogenous secretion of melatonin)25. It is recommended that alcohol should not be taken with Circadin® because it reduces the effectiveness of Circadin® on sleep1. As alcohol is cleared from the body at a rate of approximately one unit per hour, one unit of alcohol (e.g., a glass of wine) taken at 6 pm should, theoretically, have been cleared from the body and therefore would not be able to interact with Circadin® taken at 9 pm. However, metabolism differs between individuals and a firm recommendation on time of alcohol intake prior to Circadin® cannot be made. However, although the efficacy of Circadin®, if taken with alcohol, might be diminished, there is no safety concern resulting from the interaction with Circadin® and alcohol. In particular, there is no CNS-depressant effect such as that resulting from the interaction of Circadin® with the BZDs 1.
Circadin® works by increasing the levels of melatonin in the body1. There is a general decline in melatonin production with age26 21 27. Also, insomnia sufferers have shown poorer melatonin production than people without insomnia across all age groups5. Therefore, the impairment in melatonin production as a result of ageing may be a cause of insomnia.
Insomnia sufferers aged 55 years and older were selected to be studied in clinical trials as they would, theoretically, have poorer melatonin production (due to both age and insomnia) and were hypothesised to benefit the most from therapy with Circadin®1. As there are large inter-individual variations in 'normal' physiologic levels of melatonin across (as well as within) age groups, younger adults with insomnia may benefit from Circadin®. Circadin® was given to insomnia patients aged 20-80 years in clinical trials showing its safety for 6 and 12 months11 20.
However, the current indication for Circadin®, as stated in the Summary of Product Characteristics (SPC), is for use in people aged 55 and over1. The physicians would need to make their own clinical judgement, in consultation with the patient, if they were to use Circadin® to treat younger adults suffering from insomnia.
Circadin® shortens sleep latency (time to get to sleep) by approximately 9 minutes compared with placebo, corresponding to a 40% reduction of sleep latency compared with baseline (measured objectively)28. Similar decreased values were seen for the Duration of Wake Prior to Sleep Onset (DWAPSO), and the percentage of Time Spent Asleep (TSA)29. These two parameters were improved by approximately 50%, as compared to placebo values28. Although the effect of Circadin® on sleep latency is comparable to that of the 'z'-drugs29, Circadin® should not be considered a 'hypnotic' in the traditional sense due to the fact that it is not a CNS depressant. In line with this, Circadin® should not be taken on an 'as needed' basis, but as a course of 21 tablets1. Continued use of Circadin® can provide even greater benefit as seen in a long-term (6 months) double blind clinical trial. (Trial results)
Clinical trials of virtually all drugs that act on brain functions, and which are typically assessed using questionnaires, have large effects in the placebo group. Despite this, it was possible to show a statistically significant and clinically relevant effect of Circadin® on sleep quality and morning alertness in people over 55 years with primary insomnia30 31. It is important to realise that Circadin® represents a new paradigm in the treatment of sleep disorders, in which Quality of Sleep and daytime functioning are the primary efficacy parameters for treatment. This approach is in line with recommendations from, e.g., The German Society of Sleep Medicine, which has published a formal consensus that defined non-restorative sleep - a reflection of impaired sleep quality, according to DSM-IV and ICD-10 criteria - to be the key syndrome in the clinical algorithm to diagnose and treat insomnia31 (EMA Guidelines). Therefore, the regulatory authorities requested that the clinical study efficacy parameters be demonstrated in a rather stringent way. Thus, efficacy of Circadin® needed to be demonstrated in not just one parameter (Quality of Sleep, or morning alertness), but two parameters combined (Quality of Sleep and morning alertness). The effect size on each individual parameter is, of course, higher than the effect size on combined parameters. This differs from the currently available sleep drugs, which have been approved based on their effect on quantity of sleep (sleep latency and sleep maintenance). However, very few of the trials of existing drugs have measured Quality of Sleep, and none have measured daytime functioning. Circadin® also has a safety profile comparable to that of placebo1. The current hypnotic drugs carry a high risk of adverse effects8. Indeed the value of current hypnotics in the vulnerable elderly population has been questioned in a recent meta-analysis (Glass et al., 2005)8. The authors concluded, “Improvements in sleep with sedative use are statistically significant, but the magnitude of effect is small. The increased risk of adverse events is statistically significant and potentially clinically relevant in older people at risk of falls and cognitive impairment. In people over 60, the benefits of these drugs may not justify the increased risk, particularly if the patient has additional risk factors for cognitive or psychomotor adverse events”8. Circadin® has demonstrated significant improvement in Quality of Sleep and morning alertness30 31. Combined with its safety profile, the use of Circadin® in older patients , has a good risk / benefit ratio.
Apart from the risk of dependence, 'z'-drugs such as zolpidem and zopiclone have been associated with residual sedative effects, marked rebound insomnia, strange behaviour at night, anterograde memory disturbances and an increased risk of falls8 32 33. In contrast, Circadin® does not cause impairment of cognitive skills or a negative effect on next-morning vigilance34 35. In fact, in clinical trials, Circadin® improved morning alertness and functioning30 31 12. Circadin® does not alter sleep architecture, and there is no evidence of increased risk of falls, dependence, rebound or withdrawal effects34 31 30. Furthermore, Circadin® shortens sleep latency to the same extent as the 'z'-drugs34 30 29. Unlike zolpidem and the other hypnotics, Circadin® improves quality of sleep, daytime functioning, and quality of life30 31 34 12.
BZDs have been associated with rebound insomnia, dependence, and neuropsychiatric reactions such as hostility and depression. Also, although effective in getting patients to sleep, these hypnotics further disrupt sleep architecture and structure - primarily by reducing 'deep sleep' (NREM stages 3 and 4) as well as REM stages of sleep36 37. As one of the many theories surrounding the function of sleep is memory consolidation which involves NREM/deep sleep, the reduction in the amount of this deep sleep observed with the use of hypnotics may impair the consolidation of memories. In addition, the use of sedative hypnotics has been associated with road traffic accidents and a higher risk of falls8 38, especially in the elderly population. Circadin® is safe and is not associated with any of these adverse effects. Furthermore, Circadin® shortens sleep latency to the same extent as most of the 'z'-drugs but, in addition and unlike BZDs and 'z'-drugs, Circadin® improves the restorative value of sleep which translates into improved quality of sleep, daytime functioning, and quality of life34 29 31 30.
It is important to understand that adverse events (AEs) are reported regardless of any perceived relationship to drug treatment. In the overall clinical development programme, which included long term open-label studies, patients were treated for longer periods with Circadin® than with placebo. Due to this fact, the AE rates have been measured in patient weeks to allow for a direct comparison between Circadin® and placebo. As measured by the rate of patients with AEs per 100 patient weeks in clinical trials, the AE rate was lower in patients treated with Circadin® than those receiving placebo (3.17 for Circadin® versus 8.21 for placebo)1. The most commonly observed AEs were headache, pharyngitis, back pain, and asthenia, listed as common by MedDRA definition (i.e., with a frequency of =1/100 to < 1/10)1, In both the Circadin® and placebo-treated groups12. It is very rare that active treatment demonstrates a lower rate of AEs than placebo, but may be explained by the fact that untreated insomnia (placebo group) is associated with many 'adverse events'.
There is no experience of the use of Circadin® in patients with liver impairment1. The metabolism of melatonin is reduced in people with hepatic impairment and these individuals demonstrate markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance1. Therefore, Circadin® is not recommended for use in patients with hepatic impairment1.
The effect of any stage of renal insufficiency on melatonin pharmacokinetics has not been studied1. Caution should be used when melatonin is administered to such patients1.
Circadin® is mainly metabolised by hepatic enzymes CYP1A1, CYP1A2, and possibly CYP2C19, which is thought to be less important1 12. Other drugs that are metabolised by these enzymes may interfere with the metabolism of Circadin®, and vice versa. The SSRI fluvoxamine inhibits CYP1A2, thereby inhibiting Circadin® metabolism and raising melatonin levels1. Therefore, this combination should be avoided1. Escitalopram and citalopram are metabolised by CYP2C1939 40. An interaction with Circadin®, in which either drug level may be raised, is hypothetical but cannot be ruled out. In one study patients were administered 20 mg of fluoxetine and 5 mg Circadin® and "No particular side effects were noted from the combination of fluoxetine and slow release melatonin" (Dolberg et al, Am J Psychiatry 1998).
Two long-term studies of 5 months and 6 months were conducted in diabetic type II patients suffering from insomnia (NEU 951005; NEU 951005a). No safety concerns were found with Circadin® upon long-term treatment (6-months) in diabetes type II patients. Moreover, a decrease in HbA1C level vs. baseline was found12.
All clinical trials with Circadin included patients with hypertension and/or cardiovascular diseases as the insomnia patient population is quite enriched with such comorbidities41.
Circadin® was found safe and effective in such patients (data on file). In a study in patients with nocturnal hypertension Circadin® significantly improved nocturnal blood pressure42 in a meta analysis of published studies it was found that only controlled release melatonin preparations are beneficial in alleviating nocturnal hypertension whereas fast release formulations are not efficacious16. Reduction innocturnal hypertension is of major importance in the prevention of cardiovascular and cerebrovascular morbidity.
Long term, open label studies have shown that there are no particular safety concerns associated with 12 months treatment20. Long term placebo controlled study in patients 18-80 has demonstrated good safety profile in all ages49 56. It is however recommended to continuously monitor the efficacy and safety of Circadin® treatment irrespective of how long the patient is treated with Circadin®. The company received reports regarding patients that are treated with Circadin® for longer periods with good effect and no safety problems.
Circadin® is the first fully developed melatonin product authorised by the regulatory authorities, but it is not indicated for use in children1. No other melatonin formulations have been approved for use in children in the EU or elsewhere in the world.
In spite of this, melatonin products – both immediate-release and Circadin® – have been used in the clinical setting to treat sleep–wake cycle disorders in children with underlying neuro-developmental difficulties22 43 44 45 46.
Several published studies have investigated the use of Circadin® and immediate-release melatonin in children45 46 47. Despite the various underlying disorders of the children, and the concomitant use of several other drugs, most studies are positive, with parents reporting improved sleep and health of the children, and very few AEs45 46 47. Sleep maintenance problems in children are better addressed with prolonged release formulations. Therefore Circadin® is recommended as first line treatment for children with neurodevelopmental disorders in Norway, Iceland and Finland.
In summary, no melatonin product is indicated in children, but melatonin products are still widely used clinically in the treatment of neuro-developmental sleep–wake cycle disorders. As the only pharmaceutical grade melatonin product, Circadin® is a well studied and safe source of melatonin, compared to other, uncontrolled melatonin products.
In some countries, the red triangle is a regulatory requirement to be put on the labelling of all sleep medicines as a warning that the drug should not be used while the patient is driving a car, or using other machinery, because of its sedative effects48.
The release of melatonin from Circadin® is more rapid if the tablet is taken on an empty stomach48.
If taken in the morning, Circadin® will likely make the individual feel sleepy or drowsy. Also, if taken regularly in the morning, Circadin® may shift the circadian rhythm. Apart from its soporific action effect, exogenous melatonin may affect sleep through its phase-resetting action on the biological clock. Melatonin administration advanced sleep in delayed-sleep phase syndrome patients and synchronised sleep to the day-night cycles in blind subjects46. Such activities are usually desired in shift workers and travelers suffering from jet lag.
For the treatment of insomnia, patients should take Circadin® at night only1.
In the study Neu112006 patients were randomized to Circadin® and placebo for 3 weeks. Circadin® patients continued treatment for 6 months and the placebo treated group was re-randomized to Circadin® and placebo for 6 more months49 11.
In the clinical study Neurim V, patients were treated open-label up to 12 months12. In the clinical study NEU 951003, patients were randomised to Circadin® or placebo for 6 months, and then continued on open-label Circadin® for up to 12 months12. For some patients, the total duration of treatment was therefore 18 months.
Circadin® has been developed for insomnia, and has not been studied for jet lag. However, a Cochrane review (Herxheimer & Petrie, 2002) demonstrated a good effect of melatonin in treating the symptoms of jet lag50. One study (Suhner et al., 1998) found that a slow-release formulation of melatonin was somewhat less effective than immediate-release melatonin51 but recent studies showed that fast and controlled release formulation are equally potent in phase shifting 52.
In conclusion, Circadin®, like natural melatonin, affects the endogenous clock53. However, the effect of Circadin® on jet-lag has not been studied in a clinical trial.
Onset of sleepiness occurs about 1–2 hours after taking Circadin®1, due to the sleep-promoting effect of melatonin. As Circadin® efficacy is measured as improvement in quality, rahter than quantity of sleep, this improvement has not been measured on a day-to-day basis, but a baseline, and again after 3 weeks and then up to 6 months. This is similar to other disease areas, e.g., depression and hypertension, where full treatment effect is expected after days or weeks, as the body adjusts to the treatment. It is, therefore, recommended to take Circadin® at the same time every night, continuously for 21 days50. Benefit may be greater with continuous use of up to 3 months.
It is important to realise that, while historically, the treatment of insomnia has involved achieving a rapid CNS suppressant effect by using CNS depressants such as BZDs or 'z'-drugs, Circadin® represents a new paradigm in the treatment of insomnia, in which treatment of insomnia with poor Quality of Sleep must be approached with the same expectations of gradual improvement as many other diseases, and not a quick 'knock out' effect.
Circadin® increases the level of melatonin, facilitating both sleep onset and good quality sleep31 30. However, contrary to CNS-suppressant drugs (BZDs and 'z'-drugs), and similar to treatment in other disease areas (e.g., depression), the effect on Quality of Sleep is expected to be higher after some days. Therefore, Circadin® efficacy was measured at baseline, and again after 21 days. It is therefore recommended to take the 21 Circadin® tablets as a course, and not on an 'as needed' basis1. Treatment may continue with added benefits up to 13 weeks without interruption. The prescribing information and the clinical data do not, at present, support treatment for longer use due to the fact the placebo-controlled phases of the Circadin® clinical studies have all been of 3 weeks up to 6 months duration31 30 1. Similarly, BZD and 'z'-drugs are indicated for 2–4 weeks. Long term, open-label studies with Circadin® have shown that there are no particular safety concerns associated with 6 and even 12 months of treatment12 49 11 20. After the 21-day course, the patient must be evaluated with regard to benefit of treatment and a continued need for medication. Treatment for more than 13 weeks – either continued or as repeated 13-week courses – is ultimately a decision to be made by the treating physician in consultation with the patient, taking into account the benefit of treatment and potential risk.
Treatment with Circadin® for 21 days and up to 13 weeks, ensures a continued effect of Circadin® in this period. Circadin® is, however, a symptomatic treatment. After discontinuation of Circadin®, the beneficial effect remains for some time before sleep variables (time to sleep, Quality of Sleep, etc.) gradually return to pre-treatment levels1. Stopping Circadin® treatment does not cause rebound insomnia8 1.
It is the decision of the treating physician whether to start a new course of Circadin® if the insomnia is back.
No, Circadin® is gluten free.
Circadin® is the first fully developed melatonin-containing product to be licensed by the regulatory authorities. Circadin® has undergone preclinical toxicology evaluations, has a well defined pharmaceutical characterisation, and has been extensively studied with regard to clinical efficacy, safety and drug interactions12. Other melatonin products may be purchased on the Internet. However, as there is inadequate international legislation with respect to production and manufacturing of those products, they have not been adequately tested, their safety is not monitored, and the consumer has no guarantee of their contents. Therefore, as a new and approved medicinal product, Circadin® is a prescription-only medicine (POM) due to regulatory requirements.
It is common to assume that insomnia is a symptom of, or secondary to, other causes. Often this is the case, and proper treatment is then based on identifying the underlying cause. Primary insomnia does indeed exist, however, and is defined in ICD-10 and DSM-IV as sleeplessness that is not attributable to a medical, psychiatric or environmental cause54 55. It could be argued that a psychological conditioning process, due to a medical or psychosocial stressor, precedes the development of insomnia. However, due to conditioning, the insomnia may persist even if the original stressor has been resolved. For example, a person losing their job could become anxious and develop insomnia; the person spends more time in bed; the bed becomes associated with the stress of trying to and failing to sleep; this conditioning remains even after resolving the job situation. When other causes of insomnia are ruled out, primary insomnia is characterised by either trouble falling or staying asleep or non-refreshing sleep. Insomnia can exists with various comorbidities, hypertension, diabetes, etc., which are not considered to impair sleep41.
It is important to differentiate between these characteristics, as the appropriate treatment might differ. It is often overlooked that non-refreshing (poor quality) sleep is independent of the number of hours spent asleep. A person may spend the 'normal' 7–8 hours in bed asleep, but still wake up feeling unrefreshed. This insomnia is important to treat, as it is linked to fatigue, low daytime performance, depression and anxiety. Circadin® is approved for the treatment of insomnia characterised by poor Quality of Sleep1. Circadin® also improves sleep latency1 30 34. These features, together with its favorable safety profile, relative to BZDs and 'z'-drugs, should place Circadin® as a first-choice treatment of primary insomnia.
In patients who can't fall asleep due to agitation or distress, it is important to evaluate whether this is a transient or chronic condition, and whether or not the patient also suffers from poor Quality of Sleep. Although Circadin® shortens sleep latency to the same extent as 'z'-drugs34 29, Circadin® is not indicated for treatment of transient insomnia1, and does not have an immediate sedative ('knock-out') effect. Further, Circadin® should be taken as a course for 21 days of treatment, and not on an 'as needed' basis because it needs time to stabilize the clock system.
Circadin® has a distinctive smell which is due to the natural excipient smell of resins used in the sustained-release formulation.