This might be Merck's insert. There's a formal name for a drug company's statement like this. Anyone know what it is?
This is as far as I got before my attention span waned. I'll post the rest later.
TABLETS STROMECTOL® (Ivermectin)
DESCRIPTION
STROMECTOL® (Ivermectin) is a semisynthetic, anthelmintic agent for oral administration. Ivermectin is derived from the avermectins, a class of highly active broad-spectrum, anti-parasitic agents isolated from the fermentation products of Streptomyces avermitilis. Ivermectin is a mixture containing at least 90% 5-O-demethyl-22,23-dihydroavermectin A1a and less than 10% 5-O-demethyl-25-de(1-methylpropyl)- 22,23-dihydro-25-(1-methylethyl)avermectin A1a, generally referred to as 22,23-dihydroavermectin B1a and B1b, or H2B1a and H2B1b, respectively. The respective empirical formulas are C48H74O14 and C47H72O14, with molecular weights of 875.10 and 861.07, respectively. The structural formulas are: <image Image description:
Ivermectin is a white to yellowish-white, nonhygroscopic, crystalline powder with a melting point of about 155°C. It is insoluble in water but is freely soluble in methanol and soluble in 95% ethanol. STROMECTOL is available in 3-mg tablets containing the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, magnesium stearate, butylated hydroxyanisole, and citric acid powder (anhydrous).
CLINICAL PHARMACOLOGY
Pharmacokinetics Following oral administration of ivermectin, plasma concentrations are approximately proportional to the dose. In two studies, after single 12-mg doses of STROMECTOL in fasting healthy volunteers (representing a mean dose of 165 mcg/kg), the mean peak plasma concentrations of the major component (H2B1a) were 46.6 (±21.9) (range: 16.4-101.1) and 30.6 (±15.6) (range: 13.9-68.4) ng/mL, respectively, at approximately 4 hours after dosing. Ivermectin is metabolized in the liver, and ivermectin and/or its metabolites are excreted almost exclusively in the feces over an estimated 12 days, with less than 1% of the administered dose excreted in the urine. The plasma half-life of ivermectin in man is approximately 18 hours following oral administration.
The safety and pharmacokinetic properties of ivermectin were further assessed in a multiple-dose clinical pharmacokinetic study involving healthy volunteers. Subjects received oral doses of 30 to 120 mg (333 to 2000 mcg/kg) ivermectin in a fasted state or 30 mg (333 to 600 mcg/kg) ivermectin following a standard high-fat (48.6 g of fat) meal. Administration of 30 mg ivermectin following a high-fat meal resulted in an approximate 2.5-fold increase in bioavailability relative to administration of 30 mg ivermectin in the fasted state.
In vitro studies using human liver microsomes and recombinant CYP450 enzymes have shown that ivermectin is primarily metabolized by CYP3A4. Depending on the in vitro method used, CYP2D6 and CYP2E1 were also shown to be involved in the metabolism of ivermectin but to a significantly lower extent compared to CYP3A4. The findings of in vitro studies using human liver microsomes suggest that clinically relevant concentrations of ivermectin do not significantly inhibit the metabolizing activities of CYP3A4, CYP2D6, CYP2C9, CYP1A2, and CYP2E1.
Microbiology Ivermectin is a member of the avermectin class of broad-spectrum antiparasitic agents which have a unique mode of action. Compounds of the class bind selectively and with high affinity to glutamate-gated chloride ion channels which occur in invertebrate nerve and muscle cells. This leads to an increase in the permeability of the cell membrane to chloride ions with hyperpolarization of the nerve or muscle cell, resulting in paralysis and death of the parasite. Compounds of this class may also interact with other ligand-gated chloride channels, such as those gated by the neurotransmitter gamma-aminobutyric acid (GABA).
The selective activity of compounds of this class is attributable to the facts that some mammals do not have glutamate-gated chloride channels and that the avermectins have a low affinity for mammalian ligand-gated chloride channels. In addition, ivermectin does not readily cross the blood-brain barrier in humans.
SHIT my formatting was lost by my code that breaks up too-long posts into < 10,000 character chucks. :(
I'll fix it tomorrow. The formatting and the code.
Ivermectin is active against various life-cycle stages of many but not all nematodes. It is active against the tissue microfilariae of Onchocerca volvulus but not against the adult form. Its activity against Strongyloides stercoralis is limited to the intestinal stages. Clinical Studies Strongyloidiasis Two controlled clinical studies using albendazole as the comparative agent were carried out in international sites where albendazole is approved for the treatment of strongyloidiasis of the gastrointestinal tract, and three controlled studies were carried out in the U.S. and internationally using thiabendazole as the comparative agent. Efficacy, as measured by cure rate, was defined as the absence of larvae in at least two follow-up stool examinations 3 to 4 weeks post-therapy. Based on this criterion, efficacy was significantly greater for STROMECTOL (a single dose of 170 to 200 mcg/kg) than for albendazole (200 mg b.i.d. for 3 days). <image 2 In one study conducted in France, a non-endemic area where there was no possibility of reinfection, several patients were observed to have recrudescence of Strongyloides larvae in their stool as long as 106 days following ivermectin therapy. Therefore, at least three stool examinations should be conducted over the three months following treatment to ensure eradication. If recrudescence of larvae is observed, retreatment with ivermectin is indicated. Concentration techniques (such as using a Baermann apparatus) should be employed when performing these stool examinations, as the number of Strongyloides larvae per gram of feces may be very low. Onchocerciasis The evaluation of STROMECTOL in the treatment of onchocerciasis is based on the results of clinical studies involving 1278 patients. In a double-blind, placebo-controlled study involving adult patients with moderate to severe onchocercal infection, patients who received a single dose of 150 mcg/kg STROMECTOL experienced an 83.2% and 99.5% decrease in skin microfilariae count (geometric mean) 3 days and 3 months after the dose, respectively. A marked reduction of 90% was maintained for up to 12 months after the single dose. As with other microfilaricidal drugs, there was an increase in the microfilariae count in the anterior chamber of the eye at day 3 after treatment in some patients. However, at 3 and 6 months after the dose, a significantly greater percentage of patients treated with 3 STROMECTOL had decreases in microfilariae count in the anterior chamber than patients treated with placebo. In a separate open study involving pediatric patients ages 6 to 13 (n=103; weight range: 17-41 kg), similar decreases in skin microfilariae counts were observed for up to 12 months after dosing. INDICATIONS AND USAGE STROMECTOL is indicated for the treatment of the following infections: * Strongyloidiasis of the intestinal tract. STROMECTOL is indicated for the treatment of intestinal (i.e., nondisseminated) strongyloidiasis due to the nematode parasite Strongyloides stercoralis. This indication is based on clinical studies of both comparative and open-label designs, in which 64-100% of infected patients were cured following a single 200-mcg/kg dose of ivermectin. (See CLINICAL PHARMACOLOGY, Clinical Studies.) * Onchocerciasis. STROMECTOL is indicated for the treatment of onchocerciasis due to the nematode parasite Onchocerca volvulus. This indication is based on randomized, double-blind, placebo-controlled and comparative studies conducted in 1427 patients in onchocerciasis-endemic areas of West Africa. The comparative studies used diethylcarbamazine citrate (DEC-C). NOTE: STROMECTOL has no activity against adult Onchocerca volvulus parasites. The adult parasites reside in subcutaneous nodules which are infrequently palpable. Surgical excision of these nodules (nodulectomy) may be considered in the management of patients with onchocerciasis, since this procedure will eliminate the microfilariae-producing adult parasites. CONTRAINDICATIONS STROMECTOL is contraindicated in patients who are hypersensitive to any component of this product. WARNINGS Historical data have shown that microfilaricidal drugs, such as diethylcarbamazine citrate (DEC-C), might cause cutaneous and/or systemic reactions of varying severity (the Mazzotti reaction) and ophthalmological reactions in patients with onchocerciasis. These reactions are probably due to allergic and inflammatory responses to the death of microfilariae. Patients treated with STROMECTOL for onchocerciasis may experience these reactions in addition to clinical adverse reactions possibly, probably, or definitely related to the drug itself. (See ADVERSE REACTIONS, Onchocerciasis.) The treatment of severe Mazzotti reactions has not been subjected to controlled clinical trials. Oral hydration, recumbency, intravenous normal saline, and/or parenteral corticosteroids have been used to treat postural hypotension. Antihistamines and/or aspirin have been used for most mild to moderate cases.
PRECAUTIONS General After treatment with microfilaricidal drugs, patients with hyperreactive onchodermatitis (sowda) may be more likely than others to experience severe adverse reactions, especially edema and aggravation of onchodermatitis. Rarely, patients with onchocerciasis who are also heavily infected with Loa loa may develop a serious or even fatal encephalopathy either spontaneously or following treatment with an effective microfilaricide. In these patients, the following adverse experiences have also been reported: pain (including neck and back pain), red eye, conjunctival hemorrhage, dyspnea, urinary and/or fecal incontinence, difficulty in standing/walking, mental status changes, confusion, lethargy, stupor, seizures, or coma. This syndrome has been seen very rarely following the use of ivermectin. In individuals who warrant treatment with ivermectin for any reason and have had significant exposure to Loa loa-endemic areas of West or Central Africa, pretreatment assessment for loiasis and careful post-treatment follow-up should be implemented. Information for Patients STROMECTOL should be taken on an empty stomach with water. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.) Strongyloidiasis: The patient should be reminded of the need for repeated stool examinations to document clearance of infection with Strongyloides stercoralis. Onchocerciasis: The patient should be reminded that treatment with STROMECTOL does not kill the adult Onchocerca parasites, and therefore repeated follow-up and retreatment is usually required. Drug Interactions Post-marketing reports of increased INR (International Normalized Ratio) have been rarely reported when ivermectin was co-administered with warfarin. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of ivermectin. Ivermectin was not genotoxic in vitro in the Ames microbial mutagenicity assay of Salmonella typhimurium strains TA1535, TA1537, TA98, and TA100 with and without rat liver enzyme activation, the Mouse Lymphoma Cell Line L5178Y (cytotoxicity and mutagenicity) assays, or the unscheduled DNA synthesis assay in human fibroblasts. Ivermectin had no adverse effects on the fertility in rats in studies at repeated doses of up to 3 times the maximum recommended human dose of 200 mcg/kg (on a mg/m2/day basis). Pregnancy, Teratogenic Effects Ivermectin has been shown to be teratogenic in mice, rats, and rabbits when given in repeated doses of 0.2, 8.1, and 4.5 times the maximum recommended human dose, respectively (on a mg/m2/day basis). Teratogenicity was characterized in the three species tested by cleft palate; clubbed forepaws were additionally observed in rabbits. These developmental effects were found only at or near doses that were maternotoxic to the pregnant female. Therefore, ivermectin does not appear to be selectively fetotoxic to the developing fetus. There are, however, no adequate and well-controlled studies in pregnant women. Ivermectin should not be used during pregnancy since safety in pregnancy has not been established. Nursing Mothers STROMECTOL is excreted in human milk in low concentrations. Treatment of mothers who intend to breast-feed should only be undertaken when the risk of delayed treatment to the mother outweighs the possible risk to the newborn.
[-] TrumpLyftAlles | 1 points | Oct 02 2020 06:41:11
This might be Merck's insert. There's a formal name for a drug company's statement like this. Anyone know what it is?
This is as far as I got before my attention span waned. I'll post the rest later.
TABLETS STROMECTOL® (Ivermectin)
DESCRIPTION
STROMECTOL® (Ivermectin) is a semisynthetic, anthelmintic agent for oral administration. Ivermectin is derived from the avermectins, a class of highly active broad-spectrum, anti-parasitic agents isolated from the fermentation products of Streptomyces avermitilis. Ivermectin is a mixture containing at least 90% 5-O-demethyl-22,23-dihydroavermectin A1a and less than 10% 5-O-demethyl-25-de(1-methylpropyl)- 22,23-dihydro-25-(1-methylethyl)avermectin A1a, generally referred to as 22,23-dihydroavermectin B1a and B1b, or H2B1a and H2B1b, respectively. The respective empirical formulas are C48H74O14 and C47H72O14, with molecular weights of 875.10 and 861.07, respectively. The structural formulas are: <image Image description:
Ivermectin is a white to yellowish-white, nonhygroscopic, crystalline powder with a melting point of about 155°C. It is insoluble in water but is freely soluble in methanol and soluble in 95% ethanol. STROMECTOL is available in 3-mg tablets containing the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, magnesium stearate, butylated hydroxyanisole, and citric acid powder (anhydrous).
CLINICAL PHARMACOLOGY
Pharmacokinetics Following oral administration of ivermectin, plasma concentrations are approximately proportional to the dose. In two studies, after single 12-mg doses of STROMECTOL in fasting healthy volunteers (representing a mean dose of 165 mcg/kg), the mean peak plasma concentrations of the major component (H2B1a) were 46.6 (±21.9) (range: 16.4-101.1) and 30.6 (±15.6) (range: 13.9-68.4) ng/mL, respectively, at approximately 4 hours after dosing. Ivermectin is metabolized in the liver, and ivermectin and/or its metabolites are excreted almost exclusively in the feces over an estimated 12 days, with less than 1% of the administered dose excreted in the urine. The plasma half-life of ivermectin in man is approximately 18 hours following oral administration.
The safety and pharmacokinetic properties of ivermectin were further assessed in a multiple-dose clinical pharmacokinetic study involving healthy volunteers. Subjects received oral doses of 30 to 120 mg (333 to 2000 mcg/kg) ivermectin in a fasted state or 30 mg (333 to 600 mcg/kg) ivermectin following a standard high-fat (48.6 g of fat) meal. Administration of 30 mg ivermectin following a high-fat meal resulted in an approximate 2.5-fold increase in bioavailability relative to administration of 30 mg ivermectin in the fasted state.
In vitro studies using human liver microsomes and recombinant CYP450 enzymes have shown that ivermectin is primarily metabolized by CYP3A4. Depending on the in vitro method used, CYP2D6 and CYP2E1 were also shown to be involved in the metabolism of ivermectin but to a significantly lower extent compared to CYP3A4. The findings of in vitro studies using human liver microsomes suggest that clinically relevant concentrations of ivermectin do not significantly inhibit the metabolizing activities of CYP3A4, CYP2D6, CYP2C9, CYP1A2, and CYP2E1.
Microbiology Ivermectin is a member of the avermectin class of broad-spectrum antiparasitic agents which have a unique mode of action. Compounds of the class bind selectively and with high affinity to glutamate-gated chloride ion channels which occur in invertebrate nerve and muscle cells. This leads to an increase in the permeability of the cell membrane to chloride ions with hyperpolarization of the nerve or muscle cell, resulting in paralysis and death of the parasite. Compounds of this class may also interact with other ligand-gated chloride channels, such as those gated by the neurotransmitter gamma-aminobutyric acid (GABA).
The selective activity of compounds of this class is attributable to the facts that some mammals do not have glutamate-gated chloride channels and that the avermectins have a low affinity for mammalian ligand-gated chloride channels. In addition, ivermectin does not readily cross the blood-brain barrier in humans.
[Continued for length in the reply]
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[-] TrumpLyftAlles | 1 points | Oct 02 2020 06:42:38
SHIT my formatting was lost by my code that breaks up too-long posts into < 10,000 character chucks. :(
I'll fix it tomorrow. The formatting and the code.
Ivermectin is active against various life-cycle stages of many but not all nematodes. It is active against the tissue microfilariae of Onchocerca volvulus but not against the adult form. Its activity against Strongyloides stercoralis is limited to the intestinal stages. Clinical Studies Strongyloidiasis Two controlled clinical studies using albendazole as the comparative agent were carried out in international sites where albendazole is approved for the treatment of strongyloidiasis of the gastrointestinal tract, and three controlled studies were carried out in the U.S. and internationally using thiabendazole as the comparative agent. Efficacy, as measured by cure rate, was defined as the absence of larvae in at least two follow-up stool examinations 3 to 4 weeks post-therapy. Based on this criterion, efficacy was significantly greater for STROMECTOL (a single dose of 170 to 200 mcg/kg) than for albendazole (200 mg b.i.d. for 3 days). <image 2 In one study conducted in France, a non-endemic area where there was no possibility of reinfection, several patients were observed to have recrudescence of Strongyloides larvae in their stool as long as 106 days following ivermectin therapy. Therefore, at least three stool examinations should be conducted over the three months following treatment to ensure eradication. If recrudescence of larvae is observed, retreatment with ivermectin is indicated. Concentration techniques (such as using a Baermann apparatus) should be employed when performing these stool examinations, as the number of Strongyloides larvae per gram of feces may be very low. Onchocerciasis The evaluation of STROMECTOL in the treatment of onchocerciasis is based on the results of clinical studies involving 1278 patients. In a double-blind, placebo-controlled study involving adult patients with moderate to severe onchocercal infection, patients who received a single dose of 150 mcg/kg STROMECTOL experienced an 83.2% and 99.5% decrease in skin microfilariae count (geometric mean) 3 days and 3 months after the dose, respectively. A marked reduction of 90% was maintained for up to 12 months after the single dose. As with other microfilaricidal drugs, there was an increase in the microfilariae count in the anterior chamber of the eye at day 3 after treatment in some patients. However, at 3 and 6 months after the dose, a significantly greater percentage of patients treated with 3 STROMECTOL had decreases in microfilariae count in the anterior chamber than patients treated with placebo. In a separate open study involving pediatric patients ages 6 to 13 (n=103; weight range: 17-41 kg), similar decreases in skin microfilariae counts were observed for up to 12 months after dosing. INDICATIONS AND USAGE STROMECTOL is indicated for the treatment of the following infections: * Strongyloidiasis of the intestinal tract. STROMECTOL is indicated for the treatment of intestinal (i.e., nondisseminated) strongyloidiasis due to the nematode parasite Strongyloides stercoralis. This indication is based on clinical studies of both comparative and open-label designs, in which 64-100% of infected patients were cured following a single 200-mcg/kg dose of ivermectin. (See CLINICAL PHARMACOLOGY, Clinical Studies.) * Onchocerciasis. STROMECTOL is indicated for the treatment of onchocerciasis due to the nematode parasite Onchocerca volvulus. This indication is based on randomized, double-blind, placebo-controlled and comparative studies conducted in 1427 patients in onchocerciasis-endemic areas of West Africa. The comparative studies used diethylcarbamazine citrate (DEC-C). NOTE: STROMECTOL has no activity against adult Onchocerca volvulus parasites. The adult parasites reside in subcutaneous nodules which are infrequently palpable. Surgical excision of these nodules (nodulectomy) may be considered in the management of patients with onchocerciasis, since this procedure will eliminate the microfilariae-producing adult parasites. CONTRAINDICATIONS STROMECTOL is contraindicated in patients who are hypersensitive to any component of this product. WARNINGS Historical data have shown that microfilaricidal drugs, such as diethylcarbamazine citrate (DEC-C), might cause cutaneous and/or systemic reactions of varying severity (the Mazzotti reaction) and ophthalmological reactions in patients with onchocerciasis. These reactions are probably due to allergic and inflammatory responses to the death of microfilariae. Patients treated with STROMECTOL for onchocerciasis may experience these reactions in addition to clinical adverse reactions possibly, probably, or definitely related to the drug itself. (See ADVERSE REACTIONS, Onchocerciasis.) The treatment of severe Mazzotti reactions has not been subjected to controlled clinical trials. Oral hydration, recumbency, intravenous normal saline, and/or parenteral corticosteroids have been used to treat postural hypotension. Antihistamines and/or aspirin have been used for most mild to moderate cases.
PRECAUTIONS General After treatment with microfilaricidal drugs, patients with hyperreactive onchodermatitis (sowda) may be more likely than others to experience severe adverse reactions, especially edema and aggravation of onchodermatitis. Rarely, patients with onchocerciasis who are also heavily infected with Loa loa may develop a serious or even fatal encephalopathy either spontaneously or following treatment with an effective microfilaricide. In these patients, the following adverse experiences have also been reported: pain (including neck and back pain), red eye, conjunctival hemorrhage, dyspnea, urinary and/or fecal incontinence, difficulty in standing/walking, mental status changes, confusion, lethargy, stupor, seizures, or coma. This syndrome has been seen very rarely following the use of ivermectin. In individuals who warrant treatment with ivermectin for any reason and have had significant exposure to Loa loa-endemic areas of West or Central Africa, pretreatment assessment for loiasis and careful post-treatment follow-up should be implemented. Information for Patients STROMECTOL should be taken on an empty stomach with water. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.) Strongyloidiasis: The patient should be reminded of the need for repeated stool examinations to document clearance of infection with Strongyloides stercoralis. Onchocerciasis: The patient should be reminded that treatment with STROMECTOL does not kill the adult Onchocerca parasites, and therefore repeated follow-up and retreatment is usually required. Drug Interactions Post-marketing reports of increased INR (International Normalized Ratio) have been rarely reported when ivermectin was co-administered with warfarin. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of ivermectin. Ivermectin was not genotoxic in vitro in the Ames microbial mutagenicity assay of Salmonella typhimurium strains TA1535, TA1537, TA98, and TA100 with and without rat liver enzyme activation, the Mouse Lymphoma Cell Line L5178Y (cytotoxicity and mutagenicity) assays, or the unscheduled DNA synthesis assay in human fibroblasts. Ivermectin had no adverse effects on the fertility in rats in studies at repeated doses of up to 3 times the maximum recommended human dose of 200 mcg/kg (on a mg/m2/day basis). Pregnancy, Teratogenic Effects Ivermectin has been shown to be teratogenic in mice, rats, and rabbits when given in repeated doses of 0.2, 8.1, and 4.5 times the maximum recommended human dose, respectively (on a mg/m2/day basis). Teratogenicity was characterized in the three species tested by cleft palate; clubbed forepaws were additionally observed in rabbits. These developmental effects were found only at or near doses that were maternotoxic to the pregnant female. Therefore, ivermectin does not appear to be selectively fetotoxic to the developing fetus. There are, however, no adequate and well-controlled studies in pregnant women. Ivermectin should not be used during pregnancy since safety in pregnancy has not been established. Nursing Mothers STROMECTOL is excreted in human milk in low concentrations. Treatment of mothers who intend to breast-feed should only be undertaken when the risk of delayed treatment to the mother outweighs the possible risk to the newborn.
[Continued for length in the reply]
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