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Author: Admin | 2025-04-28
Dose reaches the systemic circulation. Both dose-normalized Cmax and dose-normalized AUC0-48hr values of morphine after a single dose administration of morphine sulfate in healthy volunteers are less than those for morphine oral solution or an extended-release tablet formulation (Table 2). When morphine sulfate extended-release capsules were given twice daily to 24 patients with chronic pain due to malignancy, steady-state was achieved in about two days. At steady-state, morphine sulfate extended-release capsules have a significantly lower Cmax and a higher Cmin than equivalent doses of oral morphine solution given every 4 hrs and an extended-release tablet given twice daily. When given once daily to 24 patients with malignancy, morphine sulfate extended-release capsules have a similar Cmax and higher Cmin at steady-state when compared to an extended-release morphine tablets, given twice daily at an equivalent total daily dosage (see Table 2). The single-dose pharmacokinetics of morphine sulfate extended-release capsules are linear over the dosage range of 30 mg to 100 mg. Table 2: Mean pharmacokinetic parameters (% coefficient variation) resulting from a fasting single dose study in normal volunteers and a multiple-dose study in patients with cancer pain. Regimen/Dosage FormAUC*,† (ng∙h/mL)Cmax† (ng/mL)Tmax (h)Cmin† (ng/mL)Fluctuation‡ * For single dose AUC = AUC0-48h, for multiple dose AUC = AUC0-24h at steady-state † For single dose parameter normalized to 100 mg, for multiple dose parameter normalized to 100 mg per 24 hours ‡ Steady-state fluctuation in plasma concentrations = Cmax–Cmin/Cmin Single Dose (n=24) Morphine Sulfate Extended-Release Capsules271.0(19.4)15.6(24.4)8.6(41.1)N/AN/A Extended-Release Tablet304.3(19.1)30.5(32.1)2.5(52.6)N/AN/A Morphine Solution362.4(42.6)64.4(38.2)0.9(55.8)N/AN/A Multiple Dose (n=24) Morphine Sulfate Extended-Release Capsules Once Daily500.9(38.6)37.3(37.7)10.3(32.2)9.9(52.3)3.0(45.5) Extended-Release Tablet Twice Daily457.3(40.2)36.9(42.0)4.4(53.0)7.6(60.3)4.1(51.5) Food Effect: While concurrent administration of food slows the rate of absorption of morphine sulfate extended-release capsules, the extent of absorption is not affected, and morphine sulfate extended-release capsules can be administered without regard to meals. Distribution Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. The volume of distribution of morphine is approximately 3 L/kg to 4 L/kg. Morphine is 30% to 35% reversibly bound to plasma proteins. Although the primary site of action of morphine is in the CNS, only small quantities pass the blood-brain barrier. Morphine also crosses the placental membranes [see Use in Specific Populations (8.1)] and has been found in breast milk [see Use in Specific Populations (8.2)]. Elimination Metabolism Major pathways of morphine metabolism include glucuronidation in the liver to produce metabolites including morphine-3-glucuronide, M3G (about 50%) and morphine-6-glucuronide, M6G (about 5% to 15%) and sulfation in the liver to produce morphine-3-etheral sulfate. A small fraction (less than 5%) of morphine is demethylated. M3G has no significant contribution to the analgesic activity. Although M6G does not readily cross the blood-brain barrier, it has been shown to have opioid
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