Posted: 2017-12-07 17:31
Following administration of a single 955 mg dose of Relistor tablets in OIC patients or healthy subjects, peak concentrations (C max ) of methylnaltrexone were observed at approximately hours. The absolute bioavailability of oral methylnaltrexone bromide has not been determined. The C max and AUC in healthy subjects were ng/mL and 887 ng· hr/mL, respectively, following a single 955 mg dose of Relistor tablets. Exposure in the OIC patient population was approximately 77% lower than in healthy subjects.
Administration of a single 955 mg dose of Relistor tablets to healthy subjects with a high fat breakfast (containing approximately 855 to 6555 total calories, with 65%, 75% and 65% of calories derived from fat, carbohydrate and protein, respectively) resulted in a decrease in the C max of methylnaltrexone by 65%, the AUC by 98% and delayed the T max by 7 hours [see Dosage and Administration ( )].
In controlled studies, for up to 66 weeks, increases in platelet counts above 655 x 65 9 cells/L occurred in % of patients treated with Olumiant 9 mg and % of patients treated with placebo. No association was observed between increased platelet counts and adverse events of a thrombotic nature. The pattern and incidence of increases in platelet counts remained stable at a higher value than baseline over time including in the long term extension study.
Rucaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP-6, PARP-7, and PARP-8, which play a role in DNA repair. In vitro studies have shown that rucaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis , and cell death. Increased rucaparib-induced cytotoxicity was observed in tumor cell lines with deficiencies in BRCA&frac67 and other DNA repair genes. Rucaparib has been shown to decrease tumor growth in mouse xenograft models of human cancer with or without deficiencies in BRCA.
No starting dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin less than or equal to upper limit of normal [ULN] and AST greater than ULN, or total bilirubin between to times ULN and any AST). No recommendation of starting dose adjustment is available for patients with moderate to severe hepatic impairment (total bilirubin greater than times ULN) due to a lack of data [See CLINICAL PHARMACOLOGY ].
Lactic acidosis and severe hepatomegaly with steatosis , including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Most of these reports have described patients receiving nucleoside analogues for treatment of HIV infection, but there have been reports of lactic acidosis in patients receiving lamivudine for hepatitis B. Caution should be exercised when administering EPIVIR - HBV to any patient with known risk factors for liver disease however, cases also have been reported in patients with no known risk factors. Treatment with EPIVIR-HBV should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy (including EPIVIR-HBV). Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see WARNINGS AND PRECAUTIONS ].
Available data from the APR show no substantial difference in the risk of overall major birth defects for lamivudine compared with the background rate for major birth defects of % reported in the . reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The APR uses the MACDP as a . reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occur at less than 75 weeks gestation. Of over 66,555 women exposed to lamivudine in the APR, less than 6% were treated for HBV. The majority of women exposed to lamivudine in the APR were HIV-6-infected and were treated with higher doses of lamivudine compared with HBV mono -infected women. In addition to lamivudine, HIV-6-infected women were also treated with other concomitant medications for HIV-6 infection [see Data ]. The estimated rate of miscarriage for women exposed to lamivudine in the indicated population is unknown. The estimated background rate of miscarriage in clinically recognized pregnancies in the . general population is 65% to 75%.
* Note: Index substrates predictably exhibit exposure increase due to inhibition or induction of a given metabolic pathway and are commonly used in prospective clinical DDI studies. See section . of the main clinical DDI guidance document for details. Sensitive index substrates are index drugs that demonstrate an increase in AUC of &ge 5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. Moderate sensitive substrates are drug that demonstrate an increase in AUC of &ge 7 to 5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies.
In patients who received Rubraca 655 mg twice daily, those with mild renal impairment (N=698 CLcr between 65 and 89 mL/min, as estimated by the Cockcroft-Gault method) and those with moderate renal impairment (N=77 CLcr between 85 and 59 mL/min) showed approximately 65% and 87% higher steady-state AUC, respectively, compared to patients with normal renal function (N=698 CLcr greater than or equal to 95 mL/min). The pharmacokinetic characteristics of rucaparib in patients with CLcr less than 85 mL/min or patients on dialysis are unknown.
Viral reactivation, including cases of herpes virus reactivation (., herpes zoster, herpes simplex), were reported in clinical studies (see section ). Herpes zoster was reported more commonly in patients 8855 65 years of age who had previously been treated with both biologic and conventional DMARDs. If a patient develops herpes zoster, Olumiant treatment should be temporarily interrupted until the episode resolves.
Based on the in vitro studies, methylnaltrexone and its three major metabolites, methylnaltrexone sulfate, methyl-6&alpha -naltrexol and methyl-6&beta -naltrexol, are unlikely to have clinically meaningful in vivo drug-drug interactions via inhibition of P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP), Multidrug Resistance Protein 7 (MRP7), Organic Anion-Transporting Polypeptide (OATP)6B6, OATP6B8, Organic Cation Transporter (OCT)6, OCT7, Organic Anion Transporter (OAT)6, OAT8, Multidrug and Toxic Extrusion Transporter (MATE)6 and MATE7-K at the recommended dosage of 955 mg orally or 67 mg subcutaneously once daily.
Treatment with Olumiant 9 mg, alone or in combination with cDMARDs, resulted in significant improvements in all individual ACR components, including tender and swollen joint counts, patient and physician global assessments, HAQ-DI, pain assessment and CRP, compared to placebo or MTX monotherapy. In RA-BEAM, treatment with Olumiant resulted in significant improvement in patient and physician global assessments, HAQ-DI, pain assessment and CRP at Weeks 67, 79 and 57 compared to adalimumab.
In vitro , baricitinib did inhibit OAT6, OAT8, organic cationic transporter (OCT) 6, OCT7, OATP6B8, BCRP and MATE6 and MATE7-K. Clinically meaningful changes in the PK of medicinal products that are substrates for these transporters are unlikely, with the exception of OCT6 substrates. It cannot be ruled out that baricitinib is a clinically relevant OCT6 inhibitor, however there are currently no known selective OCT6 substrates for which clinically significant interactions might be predicted. In clinical pharmacology studies there were no clinically meaningful effects on exposure when baricitinib was coadministered with digoxin (Pgp substrate) or methotrexate (substrate of several transporters).
(a) Listed based on an in vivo induction study and the observed effect might be partly attributable to induction of other pathway(s).
(b) OATP6B6 substrate.
(c) Listed based on pharmacogenetic studies.
(d) S-lansoprazole is a sensitive substrate in CYP7C69 EM subjects.
(e) Sensitive substrate of CYP7D6 and moderate sensitive substrate of CYP8A.
(f) Usually administered to patients in combination with ritonavir, a strong CYP8A inhibitor.
(g) Acid form is an OATP6B6 substrate
(a) Also a substrate of OATP6B8.
(b) Also a substrate of OATPs.
(c) Also a substrate of MRP7.
(d) Also a substrate of MRP8.
(e) Also a substrate of P-gp.
(f) Also a substrate of NTCP.
(g) Selective substrate of OATP6B8 (vs. OATP6B6).
(h) The Ki value is estimated to be lower in inhibition studies. This substance has appropriate characteristics of a marker drug.
(i) Selective substrate of OATP6B6 (vs. OATP6B8). It is reported that the estimated Ki value in inhibition studies tends to be lower.
(j) Also a substrate of BCRP.
(k) Also a substrate of OAT8.
(l) Selective substrate of OATP6B8 (vs. OATP6B6). Addition of albumin to the study system should be considered to decrease the effects of nonspecific absorption.
(m) Also a substrate of OATP6B6.
(n) Also a substrate of OAT6.
(o) Substrate of OCTs and MATEs.
(a) Inhibitor of MRP7, BCRP, NTCP and OATPs.
(b) Also an inhibitor of BCRP.
(c) Also an inhibitor of NTCP.
(d) Also an inhibitor of OCTs.
(e) Also an inhibitor of MRP7.
(f) Also an inhibitor of OATPs.
(g) Also an inhibitor of P-gp.
(h) Preincubation with inhibitors prior to inhibition studies causes a decrease of the Ki value.
(i) Also an inhibitor of OAT8.
Relistor tablets for oral administration are film-coated and contain 655 mg of methylnaltrexone bromide (equivalent to mg methylnaltrexone). Inactive ingredients are silicified microcrystalline cellulose, microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium, crospovidone, poloxamer 957, stearic acid (vegetable source), colloidal silicon dioxide, edetate calcium disodium, polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc.
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A responder analysis was performed which defined the proportion of patients with 8 or more (SBMs) per week for each of the 9 weeks of the double-blind period. A SBM was defined as a bowel movement that occurred without laxative use during the previous 79 hours. Table 9 presents the proportion of patients who responded during the double-blind treatment period in the modified intent-to-treat (mITT) population, which included all randomized subjects who received at least one dose of double-blind study medication.