Actions of Bupain in details
Pharmacology: Pharmacodynamics: Bupain 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 Bupain 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 Bupain, a semisynthetic opioid, has immunological effects similar to morphine is unknown.
Like other opioid analgesics, Bupain has a potential risk of respiratory depression. However, evidence suggests that Bupain 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 Bupain for up to 7 days. Steady state is achieved during the first application. After removal of Bupain, Bupain 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 Bupain application, Bupain diffuses from the patch through the skin.
Bupain is approximately 96% bound to plasma proteins.
Bupain metabolism in the skin following Bupain application is negligible.
Norbuprenorphine is the only known active metabolite of Bupain.
Toxicology: Preclinical Safety Data: In single and repeat-dose toxicity studies in rats, rabbits, guinea pigs, dogs and minipigs, Bupain 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 Bupain.
A standard battery of genotoxicity tests indicated that Bupain 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 Bupain?
Follow all directions on your prescription label. Bupain can slow or stop your breathing. Never use Bupain in larger amounts, or for longer than prescribed. Tell your doctor if the medicine seems to stop working as well in relieving your pain.
Bupain 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 Bupain is against the law.
The Bupain 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 Bupain, 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 Bupain. 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 Bupain. 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 Bupain in case they need to speak for you during an emergency.
Do not stop using Bupain suddenly, or you could have unpleasant withdrawal symptoms. Ask your doctor how to safely stop using Bupain.
Store at room temperature away from moisture and heat.
Keep track of the amount of medicine used from each new bottle. Bupain 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 Bupain 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 Bupain 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 Bupain and similar prescription drugs.
Bupain administration
Never use Bupain in larger amounts, or for longer than recommended by your doctor. Using Bupain 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 Bupain. Follow all dosing instructions carefully. Tell your doctor if the medicine seems to stop working as well in relieving your pain.
Bupain 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.
Bupain is usually given at evenly spaced intervals, up to 6 hours apart. Tell your doctor if Bupain 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 Bupain. You may need to stop using the medicine for a short time.
Do not stop using Bupain suddenly after long-term use, or you could have unpleasant withdrawal symptoms. Ask your doctor how to avoid withdrawal symptoms when you stop using Bupain.
Wear a medical alert tag or carry an ID card stating that you use Bupain. Any medical care provider who treats you should know that you are using Bupain. Make sure your family members know you are using Bupain 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. Bupain is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription.
Bupain pharmacology
. Mechanism of Action
Bupain implants contain Bupain HCl. Bupain is a partial agonist at the mu- opioid receptor and an antagonist at the kappa-opioid receptor.
. Pharmacodynamics
Four Bupain 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 Bupain to full opioid agonists such as methadone and hydromorphone suggest that sublingual Bupain 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 Bupain/naloxone tablets produced opioid agonist effects that reached a maximum between doses of 8/2 mg and 16/4 mg Bupain/naloxone. Opioid agonist ceiling effects were also observed in a double-blind, parallel-group, dose-ranging comparison of single doses of Bupain 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, Bupain 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 Bupain (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 Bupain than with the full agonist control, with most doses nearing peak effect after 100 minutes for Bupain, compared with 150 minutes for the full agonist control.
Physiological Effects
Bupain 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 Bupain were compared with the effects of methadone in a double-blind, parallel-group, dose-ranging comparison of single doses of Bupain 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 Bupain 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 Bupain insertion, an initial Bupain peak was observed and the median Tmax occurred at 12 hours after insertion. After the initial Bupain peak, the plasma Bupain concentrations decreased slowly and steady-state plasma Bupain concentrations were reached by approximately Week 4. Mean steady-state plasma Bupain 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 Bupain concentrations were stable and comparable to the trough Bupain concentration of 8 mg per day sublingual Bupain at steady state.
In one pharmacokinetics study (Figure 17), subjects received 16 mg per day sublingual Bupain for a minimum of 5 consecutive days, followed by 4 implants of Bupain (totally 320 mg Bupain hydrochloride). Overall peak plasma Bupain concentrations were markedly lower after Bupain insertion than after dosing with 16 mg per day sublingual Bupain. The steady-state Bupain AUC0-24 value after 4 implants of Bupain on Day 28 was 19.6 ± 33.7 ng*hr/mL, 31% of the steady-state Bupain AUC0- 24 value of 16 mg per day sublingual administration (62.7 ± 36.4 ng*hr/mL). The average steady- state Bupain concentration of Bupain 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 Bupain at steady state.
Figure 17: Bupain concentration versus time profiles after daily administration of 16 mg sublingual Bupain for 5 days (Day -5 to Day -1), followed by 4 implants of Bupain (totally 320 mg Bupain hydrochloride) on Day 1. The figure below shows the steady state Bupain concentration of 16 mg per day sublingual Bupain on Day -1, the initial Bupain concentration after Bupain insertion on Day 1, and steady state Bupain after Bupain insertion on Day 28.
Distribution
Bupain is approximately 96% protein bound, primarily to alpha and beta globulin.
Elimination
Metabolism
Bupain 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 Bupain 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 Bupain, norbuprenorphine, and two unidentified Bupain metabolites. In urine, most of the Bupain and norbuprenorphine was conjugated (Bupain, 1% free and 9.4% conjugated; norbuprenorphine, 2.7% free and 11% conjugated). In feces, almost all of the Bupain and norbuprenorphine were free (Bupain, 33% free and 5% conjugated; norbuprenorphine, 21% free and 2% conjugated). Based on all studies performed with Bupain/naloxone, Bupain 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 Bupain product, such as Bupain, has not been studied.
The disposition of Bupain was determined in a pharmacokinetics study after administering a 2.0/0.5 mg Bupain/naloxone sublingual tablet in subjects with varied degrees of hepatic impairment as indicated by Child-Pugh criteria. The disposition of Bupain 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 Bupain were not clinically significant. For subjects with moderate and severe hepatic impairment, mean Cmax, AUC0-last, and half-life values of Bupain 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 Bupain were not clinically significant in comparison to healthy subjects without HCV infection.
Drug Interaction Studies
CYP3A4 Inhibitors and Inducers
Bupain is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, potential interactions may occur when Bupain 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 Bupain; the effects on Bupain exposure in patients treated with Bupain have not been studied, and the effects may be dependent on the route of administration. Patients who transfer to Bupain treatment from a regimen of transmucosal Bupain 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 Bupain level provided by Bupain is adequate and not excessive. [Drug Interactions (7.1)].
Bupain 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 Bupain and norbuprenorphine resulting from therapeutic Bupain 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).
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Information checked by Dr. Sachin Kumar, MD Pharmacology
