Pharmacology: Pharmacodynamics: Mechanism of Action: Administered orally, Netlook has a marked effect in severe forms of acne, which have proved insufficiently responsive to previous treatment. The mechanism of action of Netlook 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 dose-related suppression of sebaceous gland activity and a histologically demonstrated reduction in the size of the sebaceous glands. Furthermore, a dermal anti-inflammatory effect of Netlook has been established.
Pharmacokinetics: Time-related blood concentrations can be predicted on the basis of linear pharmacokinetics.
Absorption: Peak plasma concentrations (Cmax) of approximately 200-300 ng/mL have been achieved in healthy volunteers 3-4 hrs time to reach maximum plasma concentration (tmax) after administration of Netlook 40 mg.
Taking Netlook with food increases bioavailability up to 2-fold relative to fasting conditions, probably as a result of easier absorption of this highly lipophilic medication. Furthermore, there is an overall decrease in fluctuations in systemic availability when Netlook is ingested with food.
Distribution: Netlook is extensively bound to plasma proteins (99.9%) with the result that the free active fraction of the substance is <0.1% of the total over a wide range of therapeutic concentrations. Albumin appears to be the major binding protein.
The volume of distribution of Netlook is not known in humans since it is not available as an IV preparation.
Metabolism: Three (3) major metabolites have been identified in plasma: 4-oxo-Netlook, tretinoin (all-trans retinoic acid) and 4-oxo-tretinoin, which is rapidly formed following oral administration achieving peak concentrations of 100-140 ng/mL at about 2 hrs after administration of Netlook 40 mg. Other metabolites have been detected but are not completely identified, which also includes glucuronide conjugates.
Netlook metabolites have shown biological activity in several in vitro tests. Thus, the observed clinical profile in patients could be the result of the pharmacological activity of Netlook and its metabolites.
Since Netlook and tretinoin (all-trans retinoic acid) are reversibly metabolised (interconverted), the metabolism of tretinoin is linked with that of Netlook. It has been estimated that 20-30% of an Netlook dose is metabolised by isomerization.
Netlook also isomerises in vivo via an alternative metabolic pathway to tretinoin (all-trans retinoic acid). Glucuronidation of the metabolites has not been conclusively demonstrated in humans but is strongly suggested by animal studies. Investigations in humans and dogs point to an enterohepatic recirculation of Netlook, which would contribute to the observed interindividual variability in plasma concentrations.
In vitro metabolism studies have demonstrated that several CYP enzymes are involved in the metabolism of Netlook to 4-oxo-Netlook and tretinoin. No single isoform appears to have a predominant role. CYP2C8, CYP2C9, CYP2B6 and possibly CYP3A4 appear to have the greatest contributions in the metabolism of Netlook to 4-oxo-Netlook. CYP2C9, CYP2B6 and possibly CYP2C8, CYP3A4, CYP2A6 and CYP2E1 contribute to the metabolism of Netlook. CYP26 is also known to metabolise retinoids.
Elimination: Netlook appears to be eliminated almost exclusively by hepatic metabolism and biliary excretion.
Following oral administration of Netlook, the elimination half-life (t½) of unchanged substance has ranged from 7-39 hrs (mean approximately 20 hrs) in both healthy volunteers and patients with cystic acne.
The mean elimination t½ of the 4-oxo-metabolite in patients with cystic acne is slightly longer (25 hrs, range: 17-50 hrs) than that of the parent substance.
Netlook is a physiological retinoid and endogenous retinoid concentrations are reached within approximately 2 weeks following the end of Netlook therapy.
Special Populations: Since Netlook is contraindicated in patients with hepatic impairment, there is no information on the pharmacokinetics of the substance in this population.
Patients with Renal Impairment: In patients with severe renal insufficiency, treatment should be started at a lower dose (eg, 10 mg/day) and afterwards individually adjusted according to tolerability.
Netlook comes with a patient information form and medication guide. It is very important that you read and understand this information. Be sure to carefully follow these instructions and ask your doctor if you have any questions.
Women of reproductive age must sign up for a pregnancy risk program called iPLEDGE™ in order to receive their Netlook prescription each month. You can sign up on the internet (www.ipledge.com) or by telephone (1-866-495-0654). Be sure to ask your doctor if you have any questions about this program. It is very important that you understand and follow all of the requirements. You will not get another prescription unless you follow the instructions for the program.
Netlook must not be taken by women of reproductive age unless two effective forms of contraception (birth control) have been used for at least 1 month before the beginning of treatment. Contraception must be continued during the period of treatment, which is up to 20 weeks, and for 1 month after Netlook is stopped. Be sure you have discussed this information with your doctor.
If you are a woman who is able to have children, you must have 2 pregnancy tests before beginning treatment with Netlook to make sure you are not pregnant. The second pregnancy test must be taken at least 19 days after the first test and during the first 5 days of the menstrual period immediately prior to beginning treatment. In addition, you must have a pregnancy test each month while you are taking Netlook and one month after treatment is completed.
Swallow the capsule whole with a full glass (8 ounces) of water or other liquid. Netlook(R) and its generic products should be taken with food. Netlook(TM) may be taken with or without food. Do not crush, break, or chew the capsule.
It is very important that you take Netlook only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.
It is very important that you not share Netlook with anyone else because of the risk of birth defects and other serious side effects.
Netlook™ oral capsules should not be substituted with other forms of Netlook (e.g., Netlook®). Different brands may not work the same way. If you refill your medicine and it looks different, check with your pharmacist.
The dose of Netlook will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Netlook. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
If you miss a dose of Netlook, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Each prescription of Netlook must be filled within 7 days of the date it was prescribed by your doctor. You will receive no more than a 30-day supply of Netlook at one time.
Always take Netlook with a full glass of water to prevent the capsule from melting in your esophagus (food pipe), causing irritation. Do not chew or suck on the capsule. Swallow it as quickly as possible.
Take Netlook with food or milk.
Take this medication for the entire length of time prescribed by your doctor. Your acne may seem to get worse at first, but should then begin to improve.
To be sure this medication is not causing harmful effects, your blood may need to be tested often. Your liver function may also need to be tested. Visit your doctor regularly.
Never share this medicine with another person, even if they have the same symptoms you have.
Store at room temperature away from moisture, heat, and light.
Netlook is a retinoid, which when administered in pharmacologic dosages of 0.5 to 1 mg/kg/day, inhibits sebaceous gland function and keratinization. Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with Netlook and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation. The exact mechanism of action of Netlook is unknown.
The pharmacodynamics of Netlook are unknown.
Due to its high lipophilicity, oral absorption of Netlook is enhanced when given with a high-fat meal. Netlook is bioequivalent to Netlook® (Netlook) capsule when both drugs are taken with a high-fat meal. Netlook is more bioavailable than Netlook® (Netlook) capsules when both drugs are taken fasted; the AUC0-t of Netlook is approximately 83% greater than that of Netlook®. Netlook is therefore not interchangeable with generic products of Netlook®.
A single dose two-way crossover pharmacokinetic trial was conducted in 14 healthy adult male subjects comparing Netlook 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 (T1/2) 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.
Netlook¶ (1 x 40 mg capsules)
(ng x hr/mL)
6095 (26 %)
395 (39 %)
6.4 (47 %)
22 (25 %)
4055 (20 %)
314 (26 %)
2.9 (34 %)
24 (28 %)
Published clinical literature has shown that there is no difference in the pharmacokinetics of Netlook between patients with nodular acne and healthy subjects with normal skin.
Netlook is more than 99.9% bound to plasma proteins, primarily albumin.
Following oral administration of Netlook, at least three metabolites have been identified in human plasma: 4-oxo-Netlook, 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. Netlook is also irreversibly oxidized to 4-oxo-Netlook, which forms its geometric isomer 4-oxo-tretinoin.
After a single 40 mg oral dose of Netlook 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 Netlook. However, the clinical significance of these models is unknown.
In vitro studies indicate that the primary P450 isoforms involved in Netlook metabolism are 2C8, 2C9, 3A4, and 2B6. Netlook and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces.
Following oral administration of an 80 mg dose of 14C-Netlook as a liquid suspension, 14C-activity in blood declined with a half-life of 90 hours. The metabolites of Netlook 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 Netlook to 57 healthy adult subjects under fed conditions, the mean ± SD elimination half-lives (T1/2) of Netlook and 4-oxo-Netlook under fed states were 18 hours and 38 hours, respectively.
Special Patient Populations
The pharmacokinetics of Netlook were evaluated after single and multiple doses in 38 pediatric patients (12 to 15 years) and 19 adult patients (≥18 years) who received Netlook for the treatment of severe recalcitrant nodular acne. In both age groups, 4-oxo-Netlook was the major metabolite; tretinoin and 4-oxo-tretinoin were also observed. There were no statistically significant differences in the pharmacokinetics of Netlook between pediatric and adult patients.
|With a meal||2||40.0%|
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Information checked by Dr. Sachin Kumar, MD Pharmacology