In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolve without apparent residual effects.
ABSORICA causes serious birth defects at any dosage (see BOXED
The oral LD50 of isotretinoin is greater than 4000 mg/kg in rats and mice ( > 600 times the recommended clinical dose of 1.0 mg/kg/day after normalization of the rat dose for total body surface area and > 300 times the recommended clinical dose of 1.0 mg/kg/day after normalization of the mouse dose for total body surface area) and is approximately 1960 mg/kg in rabbits (653 times the recommended clinical dose of 1.0 mg/kg/day after normalization for total body surface area). In humans, overdosage has been associated with vomiting, facial flushing, cheilosis, abdominal pain, headache, dizziness, and ataxia. These symptoms quickly resolve without apparent residual effects.
Actaven (isotretinoin) causes serious birth defects at any dosage (see Boxed
Isotretinoin is a derivative of vitamin A. Although the acute toxicity of isotretinoin is low, signs of hypervitaminosis A could appear in cases of accidental overdose. Manifestations of acute vitamin A toxicity include severe headache, nausea or vomiting, drowsiness, irritability and pruritus. Signs and symptoms of accidental or deliberate overdosage with isotretinoin would probably be similar. These symptoms would be expected to be reversible and to subside without the need for treatment.
Actaven is a derivative of vitamin A. Although the acute toxicity of Actaven is low, signs of hypervitaminosis A could appear in cases of accidental overdose. Manifestations of acute vitamin A toxicity include severe headache, nausea or vomiting, drowsiness, irritability and pruritus. Signs and symptoms of accidental or deliberate overdosage with Actaven would probably be similar. These symptoms would be expected to be reversible and to subside without the need for treatment.
Symptoms and signs
Oral ingestion of a 30g tube of topical isotretinoin would result in less exposure than achieved with the recommended dosage of oral isotretinoin. Consequently, the theoretical occurrence of symptoms of overdosage (e.g. hypervitaminosis A) is highly unlikely.
The gel formulation contains more than 95% ethanol. Systemic absorption of this should be considered in the event of oral ingestion.
Treatment
Further management should be as clinically indicated or as recommended by the national poisons centre, where available.
Not applicable.
Acute toxicity
The acute oral toxicity of isotretinoin was determined in various animal species. LD50 is approximately 2000 mg/kg in rabbits, approximately 3000 mg/kg in mice, and over 4000 mg/kg in rats.
Chronic toxicity
A long-term study in rats over 2 years (isotretinoin dosage 2, 8 and 32 mg/kg/d) produced evidence of partial hair loss and elevated plasma triglycerides in the higher dose groups. The side effect spectrum of isotretinoin in the rodent thus closely resembles that of vitamin A, but does not include the massive tissue and organ calcifications observed with vitamin A in the rat. The liver cell changes observed with vitamin A did not occur with isotretinoin.
All observed side effects of hypervitaminosis A syndrome were spontaneously reversible after withdrawal of isotretinoin. Even experimental animals in a poor general state had largely recovered within 1-2 weeks.
Teratogenicity
Like other vitamin A derivatives, isotretinoin has been shown in animal experiments to be teratogenic and embryotoxic.
4, ).Mutagenicity
Isotretinoin has not been shown to be mutagenic in in vitro or in vivo animal tests.
Acute toxicity
The acute oral toxicity of Actaven was determined in various animal species. LD50 is approximately 2000 mg/kg in rabbits, approximately 3000 mg/kg in mice, and over 4000 mg/kg in rats.
Chronic toxicity
A long-term study in rats over 2 years (Actaven dosage 2, 8 and 32 mg/kg/d) produced evidence of partial hair loss and elevated plasma triglycerides in the higher dose groups. The side effect spectrum of Actaven in the rodent thus closely resembles that of vitamin A, but does not include the massive tissue and organ calcifications observed with vitamin A in the rat. The liver cell changes observed with vitamin A did not occur with Actaven.
All observed side effects of hypervitaminosis A syndrome were spontaneously reversible after withdrawal of Actaven. Even experimental animals in a poor general state had largely recovered within 1-2 weeks.
Teratogenicity
Like other vitamin A derivatives, Actaven has been shown in animal experiments to be teratogenic and embryotoxic.
4 ).Mutagenicity
Actaven has not been shown to be mutagenic nor carcinogenic in in vitro or in vivo animal tests respectively.
Carcinogenesis/Mutagenesis
In a carcinogenicity study in Fischer 344 rats given oral isotretinoin up to 32 mg/kg/day, there was an increased incidence of phaeochromocytomas relative to controls in both sexes at 32 mg/kg/day and in males at 8 mg/kg/day. Given the high rate of spontaneous rate of occurrence of phaeochromoyctoma in Fischer 344 rats, the relevance of this tumour to humans is uncertain.
Studies in hairless mice suggest that concurrent dermal exposure to isotretinoin at dose levels up to 500 mg/kg may enhance the tumorigenic potential of UV irradiation. The significance of these studies to humans is not clear.
The mutagenic potential of isotretinoin was evaluated in the Ames assay with and without S9 metabolic activation and in the Chinese hamster lung cell for chromosome aberrations, both of which were negative.
Reproductive Toxicology
Fertility
In rats, no adverse effects on gonadal function, fertility, conception rate, gestation or parturition were observed at oral dose levels of isotretinoin up to 32 mg/kg/day.
In dogs, testicular atrophy was noted after approximately 30 weeks at isotretinoin dose levels of 20 or 60 mg/kg/day. However, in studies of men receiving oral isotretinoin, no significant effects have been seen on semen parameters.
Pregnancy
Reproduction studies conducted in rabbits using isotretinoin gel applied topically at up to 60 times the human dose have revealed no harm to the foetus.
Topical application of high doses of tretinoin (an isomer of isotretinoin) induces maternal toxicity, which limits the maximum dose to a level potentially below that associated with embryofoetal alterations by other routes of administration.
In one study, topical doses of a 0.1% ethanol solution, given to Wistar rats through gestational days (GDs) 6 to 16, were not tolerated at 10 mg/kg/day, causing severe local and systemic maternal toxicity. Offspring of dams receiving 5 mg/kg weighed significantly less than those of controls. Maternal toxicity (reduced weight gain and food consumption) was also evident at doses of 2.5 mg/kg/day or more. A significant increase in the occurrence of supernumerary ribs was observed at this dose, a result thought to be nonspecific or maternally mediated.
Topical administration of tretinoin at a dose of 10.5 mg/kg/day for 3 days to intact skin of hamsters on GDs 7, 8, and 9 resulted in erythema and/or epidermal hyperplasia at the site of application, but did not cause a significant teratogenic response.
Topical administration of 5 g 0.05% tretinoin ointment (corresponding to a dose of ~ 10 mg/kg) to the shaved backs of pregnant rats on GD 12 resulted in some retinoid-specific patterns of anomalies (humerus short 9%, radius bent 6%, ribs wavy 80%). This dose was ~100 fold that expected in humans.
The pharmacodynamics of ABSORICA are unknown.
Pharmacotherapeutic group: Retinoid for treatment of acne.
ATC code: D10B A01
Mechanism of action
Isotretinoin is a stereoisomer of all-trans retinoic acid (tretinoin). The exact mechanism of action of isotretinoin has not yet been elucidated in detail, but it has been established that the improvement observed in the clinical picture of severe acne is associated with suppression of sebaceous gland activity and a histologically demonstrated reduction in the size of the sebaceous glands. Furthermore, a dermal anti-inflammatory effect of isotretinoin has been established.
Clinical efficacy and safety
Hypercornification of the epithelial lining of the pilosebaceous unit leads to shedding of corneocytes into the duct and blockage by keratin and excess sebum. This is followed by formation of a comedone and, eventually, inflammatory lesions. Isotretinoin inhibits proliferation of sebocytes and appears to act in acne by re-setting the orderly program of differentiation. Sebum is a major substrate for the growth of Propionibacterium acnes so that reduced sebum production inhibits bacterial colonisation of the duct.
Pharmacotherapeutic group: Retinoid for the treatment of acne, ATC code: D10BA01
Mechanism of action
Actaven is a stereoisomer of all-trans retinoic acid (tretinoin). The exact mechanism of action of Actaven has not yet been elucidated in detail, but it has been established that the improvement observed in the clinical picture of severe acne is associated with suppression of sebaceous gland activity and a histologically demonstrated reduction in the size of the sebaceous glands. Furthermore, a dermal anti-inflammatory effect of Actaven has been established.
Clinical efficacy and safety
Hypercornification of the epithelial lining of the pilosebaceous unit leads to shedding of corneocytes into the duct and blockage by keratin and excess sebum. This is followed by formation of a comedone and, eventually, inflammatory lesions. Actaven inhibits proliferation of sebocytes and appears to act in acne by re-setting the orderly programme of differentiation. Sebum is a major substrate for the growth of Propionibacterium acnes so that reduced sebum production inhibits bacterial colonisation of the duct.
Pharmacotherapeutic group: retinoids for topical use in acne, isotretinoin.
ATC Code: D10A D04
Mechanism of action
Isotretinoin is structurally and pharmacologically related to vitamin A which regulates epithelial cell growth and differentiation. It is thought that topically applied isotretinoin acts in a comparable way to its stereoisomer, tretinoin, and:
- stimulates mitosis in the epidermis
- reduces intercelluar cohesion in the stratum corneum
- contests the hyperkeratosis characteristic of acne vulgaris
- aids desquamation, preventing the formation of lesions
- mediates an increased production of less cohesive epidermal sebaceous cells, which appears to promote the initial expulsion of comedones and their subsequent prevention.
Isotretinoin has topical anti-inflammatory actions. Topically applied isotretinoin inhibits leukotriene-B4-induced migration of polymorphonuclear leukocytes, which accounts for topical isotretinoin's anti-inflammatory action. A significant inhibition was produced by topically applied isotretinoin but only a weak inhibition by topical tretinoin. This may account for the reduced rebound effect seen with topical isotretinoin when compared with topical tretinoin.
Pharmacodynamic effects
The pharmacological action of isotretinoin remains to be fully elucidated.
Isotretinoin binds to the 3 retinoic acid receptors (RAR) alpha, beta and gamma with less affinity and is unable to bind to retinoid X receptors (RXR) and the retinoic acid cellular receptor (CRABP).
There are studies which show similar activity to systemic actions when administered topically. Inhibition of sebum production by topical isotretinoin has been demonstrated in the ears and flank organs of the Syrian hamster. Application of isotretinoin to the ear for 15 days led to a 50% reduction in sebaceous gland size, and application to the flank organ resulted in a 40% reduction. Topical application of isotretinoin has also been shown to have an effect on the epidermal differentiation of rhino mouse skin. Reduction in the size of the utriculi or superficial cysts leading to normal looking follicles was a predominant feature of isotretinoin treatment and has been used to quantify the antikeratinising effects of isotretinoin.
Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat meal. ABSORICA is bioequivalent to Accutane® (isotretinoin) capsule when both drugs are taken with a high-fat meal. ABSORICA is more bioavailable than Accutane® (isotretinoin) capsules when both drugs are taken fasted; the AUC0-t of ABSORICA is approximately 83% greater than that of Accutane®. ABSORICA is therefore not interchangeable with generic products of Accutane®.
A single dose two-way crossover pharmacokinetic trial was conducted in 14 healthy adult male subjects comparing ABSORICA 40 mg (1 x 40 mg capsules), dosed under fasted and fed conditions. Under fed conditions after a high-fat meal, it was observed that the mean AUC0-t and Cmax were approximately 50% and 26% higher, than that observed under fasting conditions (Table 2). The observed elimination half-life (T½) was slightly lower in the fed state versus fasted. The time to peak concentration (Tmax) increased with food and this may be related to a longer absorption phase.
Table 2: Pharmacokinetic parameters of ABSORICA mean (%CV) following administration of 40 mg strength, N=14
| ABSORICA (1 x 40 mg capsules) | AUC0-t (ng x hr/mL) | Cmax (ng/mL) | Tmax (hr) | T½ (hr) |
| Fed | 6095 (26 %) | 395 (39 %) | 6.4 (47 %) | 22 (25 %) |
| Fasted | 4055 (20 %) | 314 (26 %) | 2.9 (34 %) | 24 (28 %) |
Published clinical literature has shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin.
DistributionIsotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.
MetabolismFollowing oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin.
After a single 40 mg oral dose of ABSORICA to 57 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions.
All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown.
In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces.
EliminationFollowing oral administration of an 80 mg dose of 14C-isotretinoin as a liquid suspension, 14C-activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%).
After a single 40 mg (2 x 20 mg) oral dose of ABSORICA to 57 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (T½) of isotretinoin and 4-oxo-isotretinoin under fed states were 18 hours and 38 hours, respectively.
Special Patient PopulationsThe pharmacokinetics of isotretinoin were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients ( ≥ 18 years) who received isotretinoin for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo-isotretinoin was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. There were no statistically significant differences in the pharmacokinetics of isotretinoin between pediatric and adult patients.
AbsorptionDue to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 x 40 mg capsules) of Actaven (isotretinoin) under fasted and fed conditions. Both peak plasma concentration (Cmax) and the total exposure (AUC) of isotretinoin were more than doubled following a standardized high-fat meal when compared with Actaven (isotretinoin) given under fasted conditions (see Table 2). The observed elimination half-life was unchanged. This lack of change in half-life suggests that food increases the bioavailability of isotretinoin without altering its disposition. The time to peak concentration (Tmax) was also increased with food and may be related to a longer absorption phase. Therefore, Actaven (isotretinoin) capsules should always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical studies have shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin.
Table 2 : Pharmacokinetic Parameters of Isotretinoin Mean (%CV), N=74
| Actaven 2 x 40 mg Capsules | AUC0-∞ (ng×hr/mL) | Cmax (ng/mL) | Tmax (hr) | t½ (hr) |
| Fed* | 10,004 (22%) | 862 (22%) | 5.3 (77%) | 21 (39%) |
| Fasted | 3,703 (46%) | 301 (63%) | 3.2 (56%) | 21 (30%) |
| *Eating a standardized high-fat meal |
Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.
MetabolismFollowing oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxotretinoin). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin.
After a single 80 mg oral dose of Actaven (isotretinoin) to 74 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions.
All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotretinoin to adult cystic acne patients ( ≥ 18 years), the exposure of patients to 4-oxo-isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin.
In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces.
EliminationFollowing oral administration of an 80 mg dose of 14C-isotretinoin as a liquid suspension, 14Cactivity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of Actaven (isotretinoin) to 74 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (t½) of isotretinoin and 4-oxo-isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43 in patients with cystic acne.
Absorption
The absorption of isotretinoin from the gastro-intestinal tract is variable and dose-linear over the therapeutic range. The absolute bioavailability of isotretinoin has not been determined, since the compound is not available as an intravenous preparation for human use, but extrapolation from dog studies would suggest a fairly low and variable systemic bioavailability. When isotretinoin is taken with food, the bioavailability is doubled relative to fasting conditions.
Distribution
Isotretinoin is extensively bound to plasma proteins, mainly albumin (99.9 %). The volume of distribution of isotretinoin in man has not been determined since isotretinoin is not available as an intravenous preparation for human use. In humans little information is available on the distribution of isotretinoin into tissue. Concentrations of isotretinoin in the epidermis are only half of those in serum. Plasma concentrations of isotretinoin are about 1.7 times those of whole blood due to poor penetration of isotretinoin into red blood cells.
Biotransformation
After oral administration of isotretinoin, three major metabolites have been identified in plasma: 4-oxo-isotretinoin, tretinoin, (all-trans retinoic acid), and 4-oxo-tretinoin. These metabolites have shown biological activity in several in vitro tests. 4-oxo-isotretinoin has been shown in a clinical study to be a significant contributor to the activity of isotretinoin (reduction in sebum excretion rate despite no effect on plasma levels of isotretinoin and tretinoin). Other minor metabolites includes glucuronide conjugates. The major metabolite is 4-oxo-isotretinoin with plasma concentrations at steady state, that are 2.5 times higher than those of the parent compound.
Isotretinoin and tretinoin (all-trans retinoic acid) are reversibly metabolised (interconverted), and the metabolism of tretinoin is therefore linked with that of isotretinoin. It has been estimated that 20-30 % of an isotretinoin dose is metabolised by isomerisation.
Enterohepatic circulation may play a significant role in the pharmacokinetics of isotretinoin in man. In vitro metabolism studies have demonstrated that several CYP enzymes are involved in the metabolism of isotretinoin to 4-oxo-isotretinoin and tretinoin. No single isoform appears to have a predominant role. Isotretinoin and its metabolites do not significantly affect CYP activity.
Elimination
After oral administration of radiolabelled isotretinoin approximately equal fractions of the dose were recovered in urine and faeces. Following oral administration of isotretinoin, the terminal elimination half-life of unchanged drug in patients with acne has a mean value of 19 hours. The terminal elimination half-life of 4-oxo-isotretinoin is longer, with a mean value of 29 hours.
Isotretinoin is a physiological retinoid and endogenous retinoid concentrations are reached within approximately two weeks following the end of isotretinoin therapy.
Hepatic impairment
Since isotretinoin is contraindicated in patients with hepatic impairment, limited information on the kinetics of isotretinoin is available in this patient population.
Renal impairment
Renal failure does not significantly reduce the plasma clearance of isotretinoin or 4-oxo-isotretinoin.
Absorption
The absorption of Actaven from the gastro-intestinal tract is variable and dose-linear over the therapeutic range. The absolute bioavailability of Actaven has not been determined, since the compound is not available as an intravenous preparation for human use, but extrapolation from dog studies would suggest a fairly low and variable systemic bioavailability. When Actaven is taken with food, the bioavailability is doubled relative to fasting conditions.
Distribution
Actaven is extensively bound to plasma proteins, mainly albumin (99.9%). The volume of distribution of Actaven in man has not been determined since Actaven is not available as an intravenous preparation for human use. In humans little information is available on the distribution of Actaven into tissue. Concentrations of Actaven in the epidermis are only half of those in serum. Plasma concentrations of Actaven are about 1.7 times those of whole blood due to poor penetration of Actaven into red blood cells.
Biotransformation
After oral administration of Actaven, three major metabolites have been identified in plasma: 4-oxo-Actaven, tretinoin (all-trans retinoic acid), and 4-oxo-tretinoin. These metabolites have shown biological activity in several in vitro tests. 4-oxo-Actaven has been shown in a clinical study to be a significant contributor to the activity of Actaven (reduction in sebum excretion rate despite no effect on plasma levels of Actaven and tretinoin). Other minor metabolites include glucuronide conjugates. The major metabolite is 4-oxo-Actaven with plasma concentrations at steady state, that are 2.5 times higher than those of the parent compound.
Actaven and tretinoin (all-trans retinoic acid) are reversibly metabolised (interconverted), and the metabolism of tretinoin is therefore linked with that of Actaven. It has been estimated that 20-30% of an Actaven dose is metabolised by isomerisation.
Enterohepatic circulation may play a significant role in the pharmacokinetics of Actaven in man. In vitro metabolism studies have demonstrated that several CYP enzymes are involved in the metabolism of Actaven to 4-oxo-Actaven and tretinoin. No single isoform appears to have a predominant role. Actaven and its metabolites do not significantly affect CYP activity.
Elimination
After oral administration of radiolabelled Actaven approximately equal fractions of the dose were recovered in urine and faeces. Following oral administration of Actaven, the terminal elimination half-life of unchanged drug in patients with acne has a mean value of 19 hours. The terminal elimination half-life of 4-oxo-Actaven is longer, with a mean value of 29 hours.
Actaven is a physiological retinoid and endogenous retinoid concentrations are reached within approximately two weeks following the end of Actaven therapy.
Hepatic impairment
Since Actaven is contraindicated in patients with hepatic impairment, limited information on the kinetics of Actaven is available in this patient population.
Renal impairment
Renal failure does not significantly reduce the plasma clearance of Actaven or 4-oxo-Actaven.
Absorption
Following isotretinoin 0.05% gel application to acne patients at a daily dose of 20g (equivalent to 10 mg of isotretinoin) to the face, chest and back for 30 days, plasma concentrations of isotretinoin and tretinoin were not measurable (< 20 ng/mL)
Distribution
Systemic (oral) isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.
Metabolism
In vivo studies in humans showed that the three major metabolites identified in human plasma following systemic (oral) administration of isotretinoin were 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). In vitro studies indicated that all of these metabolites had retinoid activity.
In vitro studies indicate that the major enzymes responsible for isotretinoin metabolism are cytochrome P450 isoenzymes 2C8, 2C9, 3A4 and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates and excreted in urine and faeces.
Elimination
Following systemic (oral) administration of an 80 mg dose of 14C-isotretinoin, radioactivity in the blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately eliminated in the faeces and urine in similar amounts (total of 65% to 83%).
Return any unused Actaven capsules to the Pharmacist.
No special instructions.
There are no special instructions for use or handling of Actaven Gel.
