Included as part of the PRECAUTIONS section.
Buprenorphine can be abused in a manner similar to other
opioids, legal or illicit. Prescribe and dispense buprenorphine with
appropriate precautions to minimize risk of misuse, abuse, or diversion, and
ensure appropriate protection from theft, including in the home. Clinical
monitoring appropriate to the patient's level of stability is essential.
Multiple refills should not be prescribed early in treatment or without
appropriate patient follow-up visits [see Drug Abuse and Dependence].
Buprenorphine, particularly when taken by the IV route,
in combination with benzodiazepines or other CNS depressants (including
alcohol), has been associated with significant respiratory depression and
death. Many, but not all, post-marketing reports regarding coma and death
associated with the concomitant use of buprenorphine and benzodiazepines
involved misuse by self-injection. Deaths have also been reported in
association with concomitant administration of buprenorphine with other
depressants such as alcohol or other CNS depressant drugs. Patients should be
warned of the potential danger of self-administration of benzodiazepines or
other depressants while under treatment with buprenorphine and naloxone
sublingual tablets [see DRUG INTERACTIONS].
In the case of overdose, the primary management should
be the re-establishment of adequate ventilation with mechanical assistance of
respiration, if required. Naloxone may be of value for the management of buprenorphine
overdose. Higher than normal doses and repeated administration may be
Buprenorphine and naloxone sublingual tablets should be
used with caution in patients with compromised respiratory function (e.g.,
chronic obstructive pulmonaiy disease, cor pulmonale, decreased respiratory
reserve, hypoxia, hypercapnia, or pre-existing respiratory depression).
Patients receiving buprenorphine in the presence of
opioid analgesics, general anesthetics, benzodiazepines, phenothiazines, other
tranquilizers, sedative/hypnotics, or other CNS depressants (including alcohol)
may exhibit increased CNS depression. Consider dose reduction of CNS
depressants, buprenorphine and naloxone sublingual tablets, or both in
situations of concomitant prescription [see DRUG INTERACTIONS].
Unintentional Pediatric Exposure
Buprenorphine can cause severe, possibly fatal,
respiratory depression in children who are accidentally exposed to it. Store
buprenorphine-containing medications safely out of the sight and reach of
children and destroy any unused medication appropriately [see Disposal of
Unused Buprenorphine and Naloxone Sublingual Tablets].
Buprenorphine is a partial agonist at the mu-opioid
receptor and chronic administration produces physical dependence of the opioid
type, characterized by withdrawal signs and symptoms upon abrupt
discontinuation or rapid taper. The withdrawal syndrome is typically milder
than seen with full agonists and may be delayed in onset. Buprenorphine can be
abused in a manner similarto other opioids. This should be considered when prescribing
or dispensing buprenorphine in situations when the clinician is concerned about
an increased risk of misuse, abuse, or diversion [see Drug Abuse and
Hepatitis, Hepatic Events
Cases of cytolytic hepatitis and hepatitis with jaundice
have been observed in individuals receiving buprenorphine in clinical trials
and through post-marketing adverse event reports. The spectrum of abnormalities
ranges from transient asymptomatic elevations in hepatic transaminases to case
reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and
hepatic encephalopathy. In many cases, the presence of pre-existing liver
enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant
usage of other potentially hepatotoxic drugs, and ongoing injecting drug use
may have played a causative or contributory role. In other cases, insufficient
data were available to determine the etiology of the abnormality. Withdrawal of
buprenorphine has resulted in amelioration of acute hepatitis in some cases; however,
in other cases no dose reduction was necessaiy. The possibility exists that
buprenorphine had a causative or contributory role in the development of the
hepatic abnormality in some cases. Liver function tests, prior to initiation of
treatment is recommended to establish a baseline. Periodic monitoring of liver function
during treatment is also recommended. A biological and etiological evaluation
is recommended when a hepatic event is suspected. Depending on the case,
buprenorphine and naloxone sublingual tablets may need to be carefully discontinued
to prevent withdrawal signs and symptoms and a return by the patient to illicit
drug use, and strict monitoring of the patient should be initiated.
Cases of hypersensitivity to buprenorphine and naloxone
containing products have been reported both in clinical trials and in the
post-marketing experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic
shock have been reported. The most common signs and symptoms include rashes,
hives, and pruritus. A history of hypersensitivity to buprenorphine or naloxone
is a contraindication to the use of buprenorphine and naloxone sublingual
Precipitation Of Opioid Withdrawal Signs And Symptoms
Because it contains naloxone, buprenorphine and naloxone
sublingual tablets are highly likely to produce marked and intense withdrawal
signs and symptoms if misused parenterally by individuals dependent on full opioid
agonists such as heroin, morphine, or methadone. Because of the partial agonist
properties of buprenorphine, buprenorphine and naloxone sublingual tablets may
precipitate opioid withdrawal signs and symptoms in such persons if
administered sublingually before the agonist effects of the opioid have
Neonatal withdrawal has been reported in the infants of
women treated with buprenorphine during pregnancy. From post-marketing reports,
the time to onset of neonatal withdrawal signs ranged from Day 1 to Day 8 of
life with most cases occurring on Day 1. Adverse events associated with the
neonatal withdrawal syndrome included hypertonia, neonatal tremor, neonatal
agitation, and myoclonus, and there have been reports of convulsions, apnea,
respiratory depression, and bradycardia.
Use In Opioid Naive Patients
There have been reported deaths of opioid naive
individuals who received a 2 mg dose of buprenorphine as a sublingual tablet
for analgesia. Buprenorphine and naloxone sublingual tablets are not
appropriate as an analgesic.
Use In Patients With Impaired Hepatic Function
Buprenorphine/naloxone products are not recommended in
patients with severe hepatic impairment and may not be appropriate for patients
with moderate hepatic impairment. The doses of buprenorphine and naloxone in
this fixed-dose combination product cannot be individually titrated, and
hepatic impairment results in a reduced clearance of naloxone to a much greater
extent than buprenorphine. Therefore, patients with severe hepatic impairment will
be exposed to substantially higher levels of naloxone than patients with normal
hepatic function. This may interfere with buprenorphine's efficacy throughout
treatment. In patients with moderate hepatic impairment, the differential
reduction of naloxone clearance compared to buprenorphine clearance is not as
great as in subjects with severe hepatic impairment. Therefore, buprenorphine/naloxone
products may be used with caution for maintenance treatment in patients with moderate
hepatic impairment who have initiated treatment on a buprenorphine product
without naloxone. However, patients should be carefully monitored and
consideration given to the possibility of naloxone interfering with
buprenorphine's efficacy [see Use in Specific Populations].
Impairment Of Ability To Drive Or Operate Machinery
Buprenorphine and naloxone sublingual tablets may impair
the mental or physical abilities required for the performance of potentially
dangerous tasks such as driving a car or operating machinery, especially during
treatment induction and dose adjustment. Patients should be cautioned about
driving or operating hazardous machinery until they are reasonably certain that
buprenorphine and naloxone sublingual tablets therapy does not adversely affect
his or her ability to engage in such activities.
Like other opioids, buprenorphine and naloxone sublingual
tablets may produce orthostatic hypotension in ambulatory patients.
Elevation Of Cerebrospinal Fluid Pressure
Buprenorphine, like other opioids, may elevate
cerebrospinal fluid pressure and should be used with caution in patients with
head injury, intracranial lesions, and other circumstances when cerebrospinal
pressure may be increased. Buprenorphine can produce miosis and changes in the
level of consciousness that may interfere with patient evaluation.
Elevation Of Intracholedochal Pressure
Buprenorphine has been shown to increase intracholedochal
pressure, as do other opioids, and thus should be administered with caution to
patients with dysfunction of the biliary tract.
Effects In Acute Abdominal Conditions
As with other opioids, buprenorphine may obscure the
diagnosis or clinical course of patients with acute abdominal conditions.
Buprenorphine and naloxone sublingual tablets should be
administered with caution in debilitated patients and those with myxedema or
hypothyroidism, adrenal cortical insufficiency (e.g., Addison's disease); CNS
depression or coma; toxic psychoses; prostatic hypertrophy or urethral
stricture; acute alcoholism; delirium tremens; or kyphoscoliosis.
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide)
Before initiating treatment with buprenoiphine and
naloxone sublingual tablets, explain the points listed below to caregivers and
patients. Instruct patients to read the Medication Guide each time
buprenorphine and naloxone sublingual tablets are dispensed because new information
may be available.
- Patients should be warned that it is extremely dangerous
to self-administer non-prescribed benzodiazepines or other CNS depressants
(including alcohol) while taking buprenorphine and naloxone sublingual tablets.
Patients prescribed benzodiazepines or other CNS depressants should be
cautioned to use them only as directed by their physician [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
- Patients should be advised that buprenorphine and
naloxone sublingual tablets contain an opioid that can be a target for people who
abuse prescription medications or street drugs. Patients should be cautioned to
keep their tablets in a safe place, and to protect them from theft.
- Patients should be instructed to keep buprenorphine and naloxone
sublingual tablets in a secure place, out of the sight and reach of children.
Accidental or deliberate ingestion by a child may cause respiratory depression
that can result in death. Patients should be advised that if a child is exposed
to buprenorphine and naloxone sublingual tablets, medical attention should be
- Patients should be advised never to give buprenorphine
and naloxone sublingual tablets to anyone else, even if he or she has the same
signs and symptoms. It may cause harm or death.
- Patients should be advised that selling or giving away
this medication is against the law.
- Patients should be cautioned that buprenorphine and
naloxone sublingual tablets may impair the mental or physical abilities
required forthe performance of potentially dangerous tasks such as driving or
operating machinery. Caution should be taken especially during drug induction
and dose adjustment and until individuals are reasonably certain that
buprenorphine therapy does not adversely affect their ability to engage in such
activities [see WARNINGS AND PRECAUTIONS].
- Patients should be advised not to change the dosage of
buprenorphine and naloxone sublingual tablets without consulting their
- Patients should be advised to take buprenorphine and
naloxone sublingual tablets once a day.
- Patients should be informed that buprenorphine and
naloxone sublingual tablets can cause drug dependence and that withdrawal signs
and symptoms may occur when the medication is discontinued.
- Patients seeking to discontinue treatment with
buprenorphine for opioid dependence should be advised to work closely with
their physician on a tapering schedule and should be apprised of the potential
to relapse to illicit drug use associated with discontinuation of opioid agonist/partial
agonist medicationassisted treatment.
- Patients should be cautioned that, like other opioids,
buprenorphine and naloxone sublingual tablets may produce orthostatic
hypotension in ambulatory individuals [see WARNINGS AND PRECAUTIONS].
- Patients should inform their physician if any other
prescription medications, over-the-counter medications, or herbal preparations
are prescribed or currently being used [see DRUG INTERACTIONS].
- Women of childbearing potential, who become pregnant or
are planning to become pregnant, should be advised to consult their physician
regarding the possible effects of using buprenorphine and naloxone sublingual
tablets during pregnancy [see Use in Specific Populations].
- Patients should be warned that buprenorphine passes into
breast milk. Breast-feeding is not advised in mothers treated with
buprenorphine products [see Use in Specific Populations].
- Patients should inform their family members that, in the
event of emergency, the treating physician or emergency room staff should be
informed that the patient is physically dependent on an opioid and that the
patient is being treated with buprenorphine and naloxone sublingual tablets.
- Refer to the Medication Guide for additional information
regarding the counseling information.
Disposal of Unused Buprenorphine and Naloxone
Unused buprenorphine and naloxone sublingual tablets
should be disposed of as soon as they are no longer needed. Unused tablets
should be flushed down the toilet.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
A carcinogenicity study of buprenorphine/naloxone (4:1
ratio of the free bases) was performed in Alderley Park rats.
Buprenorphine/naloxone was administered in the diet at doses of approximately
7,31, and 123 mg/kg/day for 104 weeks (estimated exposure was approximately
4,18, and 44 times the recommended human sublingual dose of 16 mg/4 mg
buprenorphine/naloxone based on buprenorphine AUC comparisons). A statistically
significant increase in Leydig cell adenomas was observed in all dose groups.
No other drugrelated tumors were noted.
Carcinogenicity studies of buprenorphine were conducted
in Sprague-Dawley ratsand CD-1 mice. Buprenorphine was administered in the diet
to rats at doses of 0.6, 5.5, and 56 mg/kg/day (estimated exposure was approximately
0.4,3, and 35 times the recommended human daily sublingual dose of 16 mg on a
mg/m² basis) for 27 months. As in the buprenorphine/naloxone carcinogenicity
study in rat, statistically significant doserelated increases in Leydig cell
tumors occurred. In an 86-week study in CD-1 mice, buprenorphine was not carcinogenic
at dietary doses up to 100 mg/kg/day (estimated exposure was approximately 30
times the recommended human daily sublingual dose of 16 mg on a mg/m² basis).
The 4:1 combination of buprenorphine and naloxone was not
mutagenic in a bacterial mutation assay (Ames test) using four strains of S.
typhimurium and two strains of E coli. The combination was not clastogenic
in an in vitro cytogenetic assay in human lymphocytes or in an IV micronucleus
test in the rat.
Buprenorphine was studied in a series of tests utilizing
gene, chromosome, and DNA interactions in both prokaryotic and eukaryotic
systems. Results were negative in yeast (S. cerevisiae) for recombinant,
gene convertant, or forward mutations; negative in Bacillus subtillis “;rec”
assay, negative for clastogenicity in CHO cells, Chinese hamster bone marrow
and spermatogonia cells, and negative in the mouse lymphoma L5178Y assay.
Results were equivocal in the Ames test: negative in
studies in two laboratories, but positive for frame shift mutation at a high
dose (5 mg/plate) in a third study. Results were positive in the Green-Tweets
(Â£ coli) survival test, positive in a DNA synthesis inhibition (DSI) test with
testicular tissue from mice, for both in vivo and in vitro incorporation of
pHJthymidine, and positive in unscheduled DNA synthesis (UDS) test using testicular
cells from mice.
Impairment Of Fertility
Dietary administration of buprenorphine in the rat at
dose levels of 500 ppm or greater (equivalent to approximately 47 mg/kg/day or
greater; estimated exposure approximately 28 times the recommended human daily
sublingual dose of 16 mg on a mg/m² basis) produced a reduction in fertility
demonstrated by reduced female conception rates. A dietary dose of 100 ppm
(equivalent to approximately 10 mg/kg/day; estimated exposure approximately 6
times the recommended human daily sublingual dose of 16 mg on a mg/m² basis) had
no adverse effect on fertility.
Use In specific Populations
Pregnancy Category C.
There are no adequate and well-controlled studies of
buprenorphine and naloxone sublingual tablets or buprenorphine/naloxone in
pregnant women. Limited published data on use of buprenorphine, the active ingredient
in buprenorphine and naloxone sublingual tablets, in pregnancy, have not shown
an increased risk of major malformations. All pregnancies, regardless of drug
exposure, have a background risk of 2-4% for major birth defects, and 15-20%
for pregnancy loss. Reproductive and developmental studies in rats and rabbits
identified adverse events at clinically relevant doses. Pre-and postnatal
development studies in rats demonstrated dystocia, increased neonatal deaths,
and developmental delays. No clear teratogenic effects were seen with a range
of doses equivalent to or greater than the human dose. However, in a few
studies, some events such as acephalus, omphalocele, and skeletal abnormalities
were observed but these findings were not clearly treatment-related.
Embryofetal death was also observed in both rats and rabbits. Buprenorphine and
naloxone sublingual tablets should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Disease-Associated Maternal And Embryo-Fetal Risk
Opioid dependence in pregnancy is associated with adverse
obstetrical outcomes such as low birth weight, preterm birth, and fetal death.
Fetal/Neonatal Adverse Reactions
Neonatal abstinence syndrome may occur in newborn infants
of mothers who were on buprenorphine maintenance treatment. Observe newborns
for poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and
manage accordingly [see WARNINGS AND PRECAUTIONS].
Labor Or Delivery
As with all opioids, use of buprenorphine prior to
delivery may result in respiratory depression in the newborn. Closely monitor
neonates for signs of respiratory depression. An opioid antagonist such as
naloxone should be available for reversal of opioid induced respiratory
depression in the neonate.
Studies have been conducted to evaluate neonatal outcomes
in women exposed to buprenorphine during pregnancy. Limited published data on
malformations from trials, observational studies, case series, and case reports
on buprenorphine use in pregnancy have not shown an increased risk of major
malformations. Based on these studies the incidence of neonatal abstinence
syndrome is not clear and there does not appear to be a dose-response
Effects on embryo-fetal developmentwere studied in
Sprague-Dawley rats and Russian white rabbits following oral (1:1) and
intramuscular (IM) (3:2) administration of mixtures of buprenorphine and naloxone.
Following oral administration to rats and rabbits, no teratogenic effects were
observed at buprenorphine doses up to 250 mg/kg/day and 40 mg/kg/day,
respectively (estimated exposure approximately 150 times and 50 times,
respectively, the recommended human daily sublingual dose of 16 mg on a mg/m²
basis). No definitive drug-related teratogenic effects were observed in rats
and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20
times and 35 times, respectively, the recommended human daily dose of 16 mg on
a mg/m² basis). Acephalus was observed in one rabbit fetus from the low-dose
group and omphalocele was observed in two rabbit fetuses from the same litter
in the mid-dose group; no findings were observed in fetuses from the high-dose
group. Following oral administration of buprenorphine to rats, dose-related postimplantation
losses, evidenced by increases in the numbers of early resorptions with
consequent reductions in the numbers of fetuses, were observed at doses of 10
mg/kg/day or greater (estimated exposure approximately 6 times the recommended
human daily sublingual dose of 16 mg on a mg/m² basis). In the rabbit,
increased post-implantation losses occurred at an oral dose of 40 mg/kg/day. Following
IM administration in the rat and the rabbit, post-implantation losses, as
evidenced by decreases in live fetuses and increases in resorptions, occurred
at 30 mg/kg/day.
Buprenorphine was not teratogenic in rats or rabbits
after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was
approximately 3 and 6times, respectively, the recommended human daily
sublingual dose of 16 mg on a mg/m² basis), after IV doses up to 0.8 mg/kg/day
(estimated exposure was approximately 0.5 times and equal to, respectively, the
recommended human daily sublingual dose of 16 mg on a mg/m² basis), or after
oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95
times the recommended human daily sublingual dose of 16 mg on a mg/m² basis)
and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the
recommended human daily sublingual dose of 16 mg on a mg/m² basis). Significant
increases in skeletal abnormalities (e.g., extra thoracic vertebra or
thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day
and up (estimated exposure was approximately 0.6 times the recommended human
daily sublingual dose of 16 mg on a mg/m² basis), but were not observed at oral
doses up to 160 mg/kg/day. Increases in skeletal abnormalities in rabbits after
IM administration of 5 mg/kg/day (estimated exposure was approximately 6 times
the recommended human daily sublingual dose of 16 mg on a mg/m² basis) or oral
administration of 1 mg/kg/day or greater (estimated exposure was approximately
equal to the recommended human daily sublingual dose of 16 mg on a mg/m² basis)
were not statistically significant.
In rabbits, buprenorphine produced statistically
significant pre-implantation losses at oral doses of 1 mg/kg/day orgreaterand
post-implantation losses that were statistically significantat IV doses of 0.2
mg/kg/day or greater (estimated exposure approximately 0.3 times the
recommended human daily sublingual dose of 16 mg on a mg/m² basis).
Dystocia was noted in pregnant rats treated
intramuscularly with buprenorphine 5 mg/kg/day (approximately 3 times the
recommended human daily sublingual dose of 16 mg on a mg/m² basis). Fertility,
peri-, and post-natal development studies with buprenorphine in rats indicated
increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up
(approximately 0.5 times the recommended human daily sublingual dose of 16 mg
on a mg/m² basis), after IM doses of 0.5 mg/kg/day and up (approximately 0.3
times the recommended human daily sublingual dose of 16 mg on a mg/m² basis), and
after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the recommended
human daily sublingual dose of 16 mg on a mg/m² basis). An apparent lack of
milk production during these studies likely contributed to the decreased pup
viability and lactation indices. Delays in the occurrence of righting reflex
and startle response were noted in rat pups at an oral dose of 80 mg/kg/day
(approximately 50 times the recommended human daily sublingual dose of 16 mg on
a mg/m² basis).
Based on two studies in 13 lactating women, buprenorphine
and its metabolite norbuprenorphine are present in low levels in human milk and
infant urine, and available data have not shown adverse reactions in breastfed infants.
There are no data on the combination product buprenorphine/naloxone in
breastfeeding, however oral absorption of naloxone is minimal. Caution should
be exercised when buprenorphine and naloxone sublingual tablets are
administered to a nursing woman. The developmental and health benefits of
breastfeeding should be considered along with the mother's clinical need for
buprenorphine and naloxone sublingual tablets and any potential adverse effects
on the breastfed child from the drug or from the underlying maternal condition.
Advise the nursing mother taking buprenorphine and
naloxone sublingual tablets to monitor the infant for increased drowsiness and
Based on limited data from a study of 6 lactating women who
were taking a median oral dose of buprenorphine of 0.29 mg/kg/day 5-8 days
after delivery, breast milk contained a median infant dose of 0.42 mcg/kg/day
of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, which are equal to
0.2% and 0.12% of the maternal weight-adjusted dose.
Based on limited data from a study of 7 lactating women who
were taking a median oral dose of buprenorphine of 7 mg/day an average of 1.12
months after delivery, the mean milk concentrations of buprenorphine and norbuprenorphine
were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the limited data from
this study, and assuming milk consumption of 150 mL/kg/day, an exclusively
breastfed infant would receive an estimated mean of 0.55 mcg/kg/day of
buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, which are 0.38% and 0.18%
of the maternal weight-adjusted dose.
No adverse reactions were observed in the infants in
these two studies.
The safety and effectiveness of buprenorphine and
naloxone sublingual tablets have not been established in pediatric patients.
This product is not appropriate for the treatment of neonatal abstinence
syndrome in neonates, because it contains naloxone, an opioid antagonist.
Clinical studies of buprenorphine and naloxone sublingual
tablets, buprenorphine and naloxone sublingual film, or buprenorphine
sublingual tablets did not include sufficient numbers of subjects aged 65 and
over to determine whether they responded differently than younger subjects.
Other reported clinical experience has not identified differences in responses
between the elderly and younger patients. In general, dose selection for an
elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug therapy.
The effect of hepatic impairment on the pharmacokinetics
of buprenorphine and naloxone has been evaluated in a pharmacokinetic study.
Both drugs are extensively metabolized in the liver. While no clinically
significant changes have been observed in subjects with mild hepatic
impairment: the plasma levels have been shown to be higher and half-life values
have been shown to be longer for both buprenorphine and naloxone in subjects with
moderate and severe hepatic impairment. The magnitude of the effects on
naloxone are greater than that on buprenorphine in both moderately and severely
impaired subjects. The difference in magnitude of the effects on naloxone and
buprenorphine are greater in subjects with severe hepatic impairment than in
subjects with moderate hepatic impairment, and therefore the clinical impact of
these effects is likely to be greater in patients with severe hepatic
impairment than in patients with moderate hepatic impairment.
Buprenorphine/naloxone products should be avoided in patients with severe
hepatic impairment and may not be appropriate for patients with moderate
hepatic impairment [see WARNINGS AND PRECAUTIONS, and CLINICAL
No differences in buprenorphine pharmacokinetics were observed
between 9 dialysis-dependent and 6 normal patients following IV administration
of 0.3 mg buprenorphine. The effects of renal failure on naloxone pharmacokinetics