Actions of Buprecare 0.3mg/ml in details
Pharmacology: Pharmacodynamics: Buprecare 0.3mg/ml is a μ-opioid partial agonist. It also has antagonistic activity at the kappa-opioid receptor. It is classified as a psychotropic substance under international convention.
In a positive controlled study of effects of Buprecare 0.3mg/ml on the QT interval in normal volunteers, 40 μg/hr was associated with a mean prolongation of the QTc interval of 5.9 msec compared to placebo. Ten mcg per hour was not different than placebo.
Endocrine System: Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical symptoms may be manifest from these hormonal changes.
Other Pharmacologic Effects: In vitro and animal studies indicate various effects of natural opioids, such as morphine, on components of the immune system; the clinical significance of these findings is unknown. Whether Buprecare 0.3mg/ml, a semisynthetic opioid, has immunological effects similar to morphine is unknown.
Like other opioid analgesics, Buprecare 0.3mg/ml has a potential risk of respiratory depression. However, evidence suggests that Buprecare 0.3mg/ml is a partial agonist with respect to its respiratory depressant activity and a ceiling effect has been reported following intravenous doses of greater than 2 μg/kg. Respiratory depression appears to be a rare occurrence at therapeutic doses of the transdermal preparation (up to 40 μg/h).
Pharmacokinetics: Each patch provides a steady delivery of Buprecare 0.3mg/ml for up to 7 days. Steady state is achieved during the first application. After removal of Buprecare 0.3mg/ml, Buprecare 0.3mg/ml concentrations decline, decreasing approximately 50% in 12 hours (range 10-24h).
The absorption does not vary significantly across the specified application sites. Mean exposure (AUC) at each of the application sites is within approximately +/- 11% of the mean exposure for the four sites.
Following Buprecare 0.3mg/ml application, Buprecare 0.3mg/ml diffuses from the patch through the skin.
Buprecare 0.3mg/ml is approximately 96% bound to plasma proteins.
Buprecare 0.3mg/ml metabolism in the skin following Buprecare 0.3mg/ml application is negligible.
Norbuprenorphine is the only known active metabolite of Buprecare 0.3mg/ml.
Toxicology: Preclinical Safety Data: In single and repeat-dose toxicity studies in rats, rabbits, guinea pigs, dogs and minipigs, Buprecare 0.3mg/ml caused minimal or no adverse systemic events, whereas skin irritation was observed in all species examined. No teratogenic effects were observed in rats or rabbits. However, perinatal mortality was reported in the literature for rats treated with Buprecare 0.3mg/ml.
A standard battery of genotoxicity tests indicated that Buprecare 0.3mg/ml is non-genotoxic. In long-term studies in rats and mice there was no evidence of any carcinogenic potential relevant for humans.
The toxicological data available did not indicate a sensitising potential of the additives of transdermal patches.
How should I take Buprecare 0.3mg/ml?
Follow all directions on your prescription label. Buprecare 0.3mg/ml can slow or stop your breathing. Never use Buprecare 0.3mg/ml in larger amounts, or for longer than prescribed. Tell your doctor if the medicine seems to stop working as well in relieving your pain.
Buprecare 0.3mg/ml may be habit-forming, even at regular doses. Never share this medicine with another person, especially someone with a history of drug abuse or addiction. MISUSE OF NARCOTIC MEDICINE CAN CAUSE ADDICTION, OVERDOSE, OR DEATH, especially in a child or other person using the medicine without a prescription. Selling or giving away Buprecare 0.3mg/ml is against the law.
The Buprecare 0.3mg/ml sublingual tablet should be placed under the tongue and allowed to dissolve. Do not chew the tablet or swallow it whole. If your doctor has prescribed more than 2 tablets per dose, place the correct number of tablets under your tongue at the same time and allow them to dissolve completely.
While using Buprecare 0.3mg/ml, you may need frequent blood tests to check your liver function.
If you need surgery, tell the surgeon ahead of time that you are using Buprecare 0.3mg/ml. You may need to stop using the medicine for a short time.
Wear a medical alert tag or carry an ID card stating that you take Buprecare 0.3mg/ml. Any medical care provider who treats you should know that you are being treated for narcotic addiction. Make sure your family members know you are using Buprecare 0.3mg/ml in case they need to speak for you during an emergency.
Do not stop using Buprecare 0.3mg/ml suddenly, or you could have unpleasant withdrawal symptoms. Ask your doctor how to safely stop using Buprecare 0.3mg/ml.
Store at room temperature away from moisture and heat.
Keep track of the amount of medicine used from each new bottle. Buprecare 0.3mg/ml is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription.
Do not keep leftover Buprecare 0.3mg/ml pills. Ask your pharmacist where to locate a drug take-back disposal program. If there is no take-back program, flush any unused pills down the toilet
Never crush or break a Buprecare 0.3mg/ml pill to inhale the powder or mix it into a liquid to inject the drug into your vein. This practice has resulted in death with the misuse of Buprecare 0.3mg/ml and similar prescription drugs.
Buprecare 0.3mg/ml administration
Never use Buprecare 0.3mg/ml in larger amounts, or for longer than recommended by your doctor. Using Buprecare 0.3mg/ml improperly will increase your risk of serious side effects or death. Even if you have used other narcotic medications, you may still have serious side effects from Buprecare 0.3mg/ml. Follow all dosing instructions carefully. Tell your doctor if the medicine seems to stop working as well in relieving your pain.
Buprecare 0.3mg/ml is injected into a muscle or into a vein through an IV. You may be shown how to use injections at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles, syringes, IV tubing, and other items used to inject the medicine.
Buprecare 0.3mg/ml is usually given at evenly spaced intervals, up to 6 hours apart. Tell your doctor if Buprecare 0.3mg/ml does not relieve your pain within 1 hour after an injection.
Prepare your dose in a syringe or IV only when you are ready to give yourself an injection. Do not use the medication if it has changed colors or has particles in it. Call your doctor for a new prescription. Use a disposable needle only once. Throw away used needles in a puncture-proof container (ask your pharmacist where you can get one and how to dispose of it). Keep this container out of the reach of children and pets.
This medicine can cause irritation if it gets on your skin. If this occurs, remove any clothing the medicine has spilled onto, and rinse your skin with water.
If you need surgery, tell the surgeon ahead of time that you are using Buprecare 0.3mg/ml. You may need to stop using the medicine for a short time.
Do not stop using Buprecare 0.3mg/ml suddenly after long-term use, or you could have unpleasant withdrawal symptoms. Ask your doctor how to avoid withdrawal symptoms when you stop using Buprecare 0.3mg/ml.
Wear a medical alert tag or carry an ID card stating that you use Buprecare 0.3mg/ml. Any medical care provider who treats you should know that you are using Buprecare 0.3mg/ml. Make sure your family members know you are using Buprecare 0.3mg/ml in case they need to speak for you during an emergency.
Store at room temperature away from moisture, heat, and light. Keep track of the amount of medicine used from each new ampule. Buprecare 0.3mg/ml is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription.
Buprecare 0.3mg/ml pharmacology
. Mechanism of Action
Buprecare 0.3mg/ml implants contain Buprecare 0.3mg/ml HCl. Buprecare 0.3mg/ml is a partial agonist at the mu- opioid receptor and an antagonist at the kappa-opioid receptor.
. Pharmacodynamics
Four Buprecare 0.3mg/ml implants deliver circulating drug blood levels comparable to the average plasma concentrations observed following daily doses of :: 8 mg Subutex or Suboxone tablet equivalent.
Subjective Effects
Comparisons of Buprecare 0.3mg/ml to full opioid agonists such as methadone and hydromorphone suggest that sublingual Buprecare 0.3mg/ml produces typical opioid agonist effects that are limited by a ceiling effect.
In opioid-experienced subjects who were not physically dependent, acute sublingual doses of Buprecare 0.3mg/ml/naloxone tablets produced opioid agonist effects that reached a maximum between doses of 8/2 mg and 16/4 mg Buprecare 0.3mg/ml/naloxone. Opioid agonist ceiling effects were also observed in a double-blind, parallel-group, dose-ranging comparison of single doses of Buprecare 0.3mg/ml sublingual solution (1, 2, 4, 8, 16, or 32 mg), placebo, and a full agonist control at various doses. The treatments were given in ascending dose order at intervals of at least one week to 16 opioid-experienced subjects who were not physically dependent. Both active drugs produced typical opioid agonist effects. For all measures for which the drugs produced an effect, Buprecare 0.3mg/ml produced a dose-related response. However, in each case, there was a dose that produced no further effect. In contrast, the highest dose of the full agonist control always produced the greatest effects. Agonist objective rating scores remained elevated for the higher doses of Buprecare 0.3mg/ml (8-32 mg) longer than for the lower doses and did not return to baseline until 48 hours after drug administration. The onset of effects appeared more rapidly with Buprecare 0.3mg/ml than with the full agonist control, with most doses nearing peak effect after 100 minutes for Buprecare 0.3mg/ml, compared with 150 minutes for the full agonist control.
Physiological Effects
Buprecare 0.3mg/ml in IV (2, 4, 8, 12, and 16 mg) and sublingual (12 mg) doses has been administered to opioid-experienced subjects who were not physically dependent, to examine cardiovascular, respiratory, and subjective effects at doses comparable to those used for treatment of opioid dependence. Compared with placebo, there were no statistically significant differences among any of the treatment conditions for blood pressure, heart rate, respiratory rate, O2 saturation, or skin temperature across time. Systolic BP was higher in the 8 mg group than placebo (3-hour AUC values). Minimum and maximum effects were similar across all treatments. Subjects remained responsive to low voice and responded to computer prompts. Some subjects showed irritability, but no other changes were observed. The respiratory effects of sublingual Buprecare 0.3mg/ml were compared with the effects of methadone in a double-blind, parallel-group, dose-ranging comparison of single doses of Buprecare 0.3mg/ml sublingual solution (1, 2, 4, 8, 16, or 32 mg) and oral methadone (15, 30, 45, or 60 mg) in non-dependent, opioid-experienced volunteers. In this study, hypoventilation not requiring medical intervention was reported more frequently after Buprecare 0.3mg/ml doses of 4 mg and higher than after methadone. Both drugs decreased O2 saturation to the same degree.
Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.
Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date.
. Pharmacokinetics
Absorption
After Buprecare 0.3mg/ml insertion, an initial Buprecare 0.3mg/ml peak was observed and the median Tmax occurred at 12 hours after insertion. After the initial Buprecare 0.3mg/ml peak, the plasma Buprecare 0.3mg/ml concentrations decreased slowly and steady-state plasma Buprecare 0.3mg/ml concentrations were reached by approximately Week 4. Mean steady-state plasma Buprecare 0.3mg/ml concentrations were approximately 0.5 to 1 ng/mL and were maintained for approximately 20 weeks (Week 4 through Week 24) in a 24-week treatment period. At steady state, the Buprecare 0.3mg/ml concentrations were stable and comparable to the trough Buprecare 0.3mg/ml concentration of 8 mg per day sublingual Buprecare 0.3mg/ml at steady state.
In one pharmacokinetics study (Figure 17), subjects received 16 mg per day sublingual Buprecare 0.3mg/ml for a minimum of 5 consecutive days, followed by 4 implants of Buprecare 0.3mg/ml (totally 320 mg Buprecare 0.3mg/ml hydrochloride). Overall peak plasma Buprecare 0.3mg/ml concentrations were markedly lower after Buprecare 0.3mg/ml insertion than after dosing with 16 mg per day sublingual Buprecare 0.3mg/ml. The steady-state Buprecare 0.3mg/ml AUC0-24 value after 4 implants of Buprecare 0.3mg/ml on Day 28 was 19.6 ± 33.7 ng*hr/mL, 31% of the steady-state Buprecare 0.3mg/ml AUC0- 24 value of 16 mg per day sublingual administration (62.7 ± 36.4 ng*hr/mL). The average steady- state Buprecare 0.3mg/ml concentration of Buprecare 0.3mg/ml on Day 28 was approximately 0.82 ng/mL, 8% of the peak concentration (10.4 ± 13.4 ng/mL), and 52% of the trough concentration (1.58 ± 0.60 ng/mL) of 16 mg per day sublingual Buprecare 0.3mg/ml at steady state.
Figure 17: Buprecare 0.3mg/ml concentration versus time profiles after daily administration of 16 mg sublingual Buprecare 0.3mg/ml for 5 days (Day -5 to Day -1), followed by 4 implants of Buprecare 0.3mg/ml (totally 320 mg Buprecare 0.3mg/ml hydrochloride) on Day 1. The figure below shows the steady state Buprecare 0.3mg/ml concentration of 16 mg per day sublingual Buprecare 0.3mg/ml on Day -1, the initial Buprecare 0.3mg/ml concentration after Buprecare 0.3mg/ml insertion on Day 1, and steady state Buprecare 0.3mg/ml after Buprecare 0.3mg/ml insertion on Day 28.
Distribution
Buprecare 0.3mg/ml is approximately 96% protein bound, primarily to alpha and beta globulin.
Elimination
Metabolism
Buprecare 0.3mg/ml undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N- dealkylation pathway is mediated primarily by the CYP3A4. Norbuprenorphine, the major metabolite, can further undergo glucuronidation. Norbuprenorphine has been found to bind opioid receptors in vitro; however, it has not been studied clinically for opioid-like activity.
Excretion
A mass balance study of Buprecare 0.3mg/ml showed complete recovery of radiolabel in urine (30%) and feces (69%) collected up to 11 days after dosing. Almost all of the dose was accounted for in terms of Buprecare 0.3mg/ml, norbuprenorphine, and two unidentified Buprecare 0.3mg/ml metabolites. In urine, most of the Buprecare 0.3mg/ml and norbuprenorphine was conjugated (Buprecare 0.3mg/ml, 1% free and 9.4% conjugated; norbuprenorphine, 2.7% free and 11% conjugated). In feces, almost all of the Buprecare 0.3mg/ml and norbuprenorphine were free (Buprecare 0.3mg/ml, 33% free and 5% conjugated; norbuprenorphine, 21% free and 2% conjugated). Based on all studies performed with Buprecare 0.3mg/ml/naloxone, Buprecare 0.3mg/ml has a mean elimination half-life from plasma ranging from 24 to 48 hours.
Specific Populations
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of implanted Buprecare 0.3mg/ml product, such as Buprecare 0.3mg/ml, has not been studied.
The disposition of Buprecare 0.3mg/ml was determined in a pharmacokinetics study after administering a 2.0/0.5 mg Buprecare 0.3mg/ml/naloxone sublingual tablet in subjects with varied degrees of hepatic impairment as indicated by Child-Pugh criteria. The disposition of Buprecare 0.3mg/ml in patients with hepatic impairment was compared to disposition in subjects with normal hepatic function. In subjects with mild hepatic impairment, the changes in mean Cmax, AUC0-last, and half-life values of Buprecare 0.3mg/ml were not clinically significant. For subjects with moderate and severe hepatic impairment, mean Cmax, AUC0-last, and half-life values of Buprecare 0.3mg/ml were increased.
HCV infection
In subjects with HCV infection but no sign of hepatic impairment, the changes in the mean Cmax, AUC0-last, and half-life values of Buprecare 0.3mg/ml were not clinically significant in comparison to healthy subjects without HCV infection.
Drug Interaction Studies
CYP3A4 Inhibitors and Inducers
Buprecare 0.3mg/ml is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, potential interactions may occur when Buprecare 0.3mg/ml is given concurrently with agents that affect CYP3A4 activity. The effects of co-administered CYP3A4 inducers or inhibitors have been established in studies using transmucosal Buprecare 0.3mg/ml; the effects on Buprecare 0.3mg/ml exposure in patients treated with Buprecare 0.3mg/ml have not been studied, and the effects may be dependent on the route of administration. Patients who transfer to Buprecare 0.3mg/ml treatment from a regimen of transmucosal Buprecare 0.3mg/ml used concomitantly with CYP3A4 inhibitors (e.g., ketoconazole), macrolide antibiotics (e.g., erythromycin), or HIV protease inhibitors, or CYP3A4 inducer (e.g., phenobarbital, carbamazepine, phenytoin, rifampicin) should be monitored to ensure that the plasma Buprecare 0.3mg/ml level provided by Buprecare 0.3mg/ml is adequate and not excessive. [Drug Interactions (7.1)].
Buprecare 0.3mg/ml has been found to be a CYP2D6 and CYP3A4 inhibitor and its major metabolite, norbuprenorphine, has been found to be a moderate CYP2D6 inhibitor in in vitro studies employing human liver microsomes. However, the relatively low plasma concentrations of Buprecare 0.3mg/ml and norbuprenorphine resulting from therapeutic Buprecare 0.3mg/ml doses are not expected to raise significant drug-drug interaction concerns.
References
- DailyMed. "BUPRENORPHINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- EPA DSStox. "Buprenorphine: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
Reviews
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Information checked by Dr. Sachin Kumar, MD Pharmacology
