Paraflex is particularly useful for relief of painful skeletal muscle spasm associated with such medical and orthopedic problems as arthritides; acute and chronic back pain; bursitis, fibrositis, or myositis; contusions; disc syndromes; lumbosacral strain; rheumatism and lumbago; sacroiliac strain; spondylitis; sprains and strains; tension headache; tendinitis and tenosynovitis; torticollis; and in premedication for electroshock therapy. Advantages: 1. Unsurpassed effectiveness as a skeletal muscle relaxant. 2. Rapid and consistent absorption from the gastrointestinal tract. 3. Prolonged effect-therapeutic blood levels for six hours. 4. No loss of effectiveness in long-term therapy. 5. Side effects are rarely a problem. Administration and dosage: For Skeletal Muscle Spasm: Children: One-half to two tablets (125 mg. to 500 mg.) three or four times a day depending upon age and weight. Adults: One tablet (250 mg.) three or four times a day. Initial dosage for severe muscle spasm should be two tablets (500 mg.) three or four times a day. If adequate response is not obtained with this dose, it may be increased to three tablets (750 mg.) three or four times a day. As improvement occurs the dosage may often be reduced. For Tension Headache: Two tablets (500 mg.) every four hours, for 12 to 24 hours, depending on clinical response. In Premedication for Electroshock Therapy: Four tablets (1000 mg.) about 10 hours before therapy and two to six tablets (500–1500 mg.) about 2 hours before treatment, the second dose varying according to weight of the patient and intensity of seizure expected. Side Effects: Side effects seldom occur. Occasional patients may note some mild gastrointestinal disturbances or central nervous system effects such as dizziness or malaise. Paraflex has produced no serious toxic reactions, blood dyscrasias, hepatitis, jaundice, or kidney damage. Precautions: Hypersensitivity reactions to Paraflex are uncommon. If pruritus or urticaria should develop, discontinue administration of the drug. Contraindications: None. How Supplied: Bottles of 50. PARAFON R PARAFON ® WITH CODEINE PARAFON WITH PREDNISOLONE (par' a fon) Composition: Parafon: Each scored, pink tablet contains Paraflex® Chlorzoxazone 1 125 mg. and Tylenol® Acetaminophen 300 mg. Parafon with Codeine: Each scored white tablet contains Codeine Phosphate 15 mg. (4 gr.) (Warning-May be habit forming), Paraflex Chlorzoxazone 125 mg., and Tylenol Acetaminophen 300 mg. Parafon with Prednisolone: Each scored buff tablet contains Paraflex Chlorzoxazone 125 mg., Tylenol Acetaminephen 300 mg., and Prednisolone 1.0 mg. Action and Uses: Parafon is effective in musculoskeletal disorders through (a) relief of pain by Tylenol, a nominating analgesic particularly useful in pain associated with musculoskeletal disorders and (b) relaxation of skeletal muscle spasm and stiffness by Paraflex, a well tolerated, centrally acting agent. Parafon is useful in low back disorders such as lumbago acute paravertebral spasm or sacroiliac strain; myositis; wry neck; tendinitis; bursitis; sprains; osteoarthritis; rheumatoid arthritis; traumatic hydrarthrosis; fibrositis; traumatic muscle injuries; and tension headache. Parafon with Codeine provides the supplemental analgesia of codeine phosphate when pain is severe. Parafon with Prednisolone provides treatment for the inflammation which is often associated with rheumatic and orthopedic musculoskeletal disorders. Administration and Dosage: Parafon For painful muscle spasm: Two tablets three or four times a day. 1 U.S. patent No. 2,895,877. For tension headache: Two tablets every four hours, for 12 to 24 hours, depending on clinical response. Parafon with Codeine For severely painful muscle spasm: One to two tablets three or four times a day. Parafon with Prednisolone For muscle spasm with inflammatory involvement: One to two tablets three or four times a day. Side Effects: Side effects seldom occur. For the occasional patient who notes mild nausea, the Parafons should be administered after meals or with food. Drowsiness or dizziness can usually be controlled by moderate reduction in dosage. Precautions: Hypersensitivity reactions to any of the Parafons are rare. If pruritus or urticaria should develop, discontinue administration. The precautions and contraindications that apply to all steroids should be kept in mind when prescribing Parafon with Prednisolone. How Supplied: Tablets Parafon: bottles of 50. Tablets Parafon with Codeine: bottles of 24-Class B Taxable Narcotic permissible on oral (verbal) prescription. Tablets Parafon with Prednisolone: bottles of 36. EXHIBIT 18-DESCRIPTIONS OF PARAFLEX PRODUCTS FROM 1963 PHYSICIAN'S DESK REFERENCE PARAFLEX CHLORZOXAZONE R Composition: Each scored, orange tablet contains Paraflex Chlorzoxazone' 250 mg. Action and Uses: Paraflex, an orally effective skeletal muscle relaxant, acts mainly on the spinal cord to inhibit transmission of nerve impulses through multisynaptic reflex arcs involved in the production of painful skeletal muscle spasm. The clinical effect is a reduction of muscle spasm with relief of pain and increased mobility of the involved muscles. Paraflex is particularly useful for relief of painful skeletal muscle spasm associated with such medical and orthopedic problems as arthritides; acute and chronic back pain; bursitis, fibrositis, or myositis; contusions; disc syndromes; lumbosacral strain; rheumatism and lumbago; sacroiliac strain; spondylitis; sprains and strains; tension headache; tendinitis and tenosynovitis; torticollis; and in premedication for electroshock therapy. Advantages: 1. Unsurpassed effectiveness as a skeletal muscle relaxant, 2. Rapid and consistent absorption from the gastrointestinal tract. 3. Prolonged effect-therapeutic blood levels for six hours. 4. No loss of effectiveness in long-term therapy. 5. Side effects are rarely a problem. Administration and dosage: For Skeletal Muscle Spasm: Children: One-half to two tables (125 mg. to 500 mg.) three or four times a day depending upon age and weight. Adults: One tablet (250 mg.) three or four times a day. Initial dosage for severe muscle spasm should be two tablets (500 mg.) three or four times a day. If adequate response is not obtained with this dose, it may be increased to three tablets (750 mg.) three or four times a day. As improvement occurs the dosage may often be reduced. For Tension Headache: Two tablets (500 mg.) every four hours, for 12 to 24 hours; depending on clinical response. In Premedication for Electroshock Therapy: Four tablets (1000 mg.) about 10 hours before therapy and two to six tablets (500 mg. to 1500 mg.) about 2 hours before treatment, the second dose varying according to weight of the patient and intensity of seizure expected. Side Effects: Paraflex is well tolerated and seldom produces undesirable side effects. Occasional patients may develop gastrointestinal disturbances; in rare instances Paraflex may have been associated with gastrointestinal bleeding. Drowsiness, dizziness, lightheadedness, malaise, or overstimulation may be noted in an occasional patient. Rarely, allergic-type rashes, petechiae, or ecchymoses may develop during treatment. Angioneurotic edema or anaphylactic reactions are extremely rare. There is no evidence that Paraflex will cause renal damage. 1 U.S. patent No. 2,895,877. Five patients have been reported in whom the administration of Paraflex or Paraflex-containing products was suspected of causing liver damage. One of these five patients had cancer of the head of the pancreas, another is suspected of having cancer with bony metastasis; in the remaining three patients it is not possible to state that the hepatitis was or was not drug-induced. Precautions: Paraflex should be used with caution in patients with known allergies. If urticaria, redness, or itching of the skin develops, the drug should be stopped. If any signs or symptoms suggestive of liver dysfunction are observed, Paraflex should be discontinued. How Supplied: Bottles of 50. PARAFON FORTER R Composition: Each scored, light green tablet contains Paraflex® Chlorzoxa. zone 1 250 mg. and Tylenol® Acetaminophen 300 mg. Action and Uses: Parafon Forte provides optimum relief of severely painful musculoskeletal spasm through the actions of (1) Paraflex, a muscle relaxant which acts at the level of the spinal cord and subcortical areas of the brain to inhibit multisynaptic reflex arcs involved in production of skeletal muscle spasm, and (2) Tylenol, a nonsalicylate analgesic especially effective in treating skeletal muscle pain. Indications: Parafon Forte is particularly useful for treatment of pain and skeletal muscle spasm associated with sprains, strains, and other traumatic muscle injuries; myalgias; low back pain; arthritides; fibrositis; torticollis; spondylitis; tension headache; and cervical root and disc syndromes. Advantages: Painful musculoskeletal spasm, with associated stiffness and limitation of motion, is most effectively treated with Parafon Forte because (1) Paraflex provides excellent skeletal muscle relaxation with continuing effectiveness in long-term therapy; prompt and prolonged effect because it is rapidly and consistently absorbed from the gastrointestinal tract, with therapeutic blood levels for six hours. (2) Tylenol is the preferred analgesic for treatment of skeletal muscle pain; a nonsalicylate analgesic that is not irritating to the gastrointestinal tract. (3) No tranquilizing or sedative effect is produced, so that the patient remains alert and able to perform functions such as driving automobiles or operating machinery. (4) Side effects rarely occur; both Paraflex and Tylenol are safe for prolonged use. Administration and Dosage: Two tablets of Parafon Forte four times a day. This dosage provides most patients with a full therapeutic dose of Paraflex plus a full analgesic dose of Tylenol. Side Effects: Parafon Forte is well tolerated and seldom produces undesirable side effects. For side effects due to chlorzoxazone, see Paraflex. Tylenol is an unusually safe and well tolerated analgesic. Precautions: See Paraflex. How Supplied: Bottles of 50. (Tablets imprinted "McNeil") EXHIBIT 19-DESCRIPTIONS OF PARAFLEX PRODUCTS FROM 1964 PHYSICIAN'S DESK REFERENCE PARAFLEX ® CHLORZOXAZONE R Composition: Each scored, orange tablet contains Paraflex chlorzoxazone1 250 mg. Action and Uses: Paraflex chlorzoxazone, an orally effective skeletal muscle relaxant, acts mainly on the spinal cord to inhibit transmission of nerve impulses through multisynaptic reflex areas involved in the production of painful skeletal muscle spasm. The clinical effect is a reduction of muscle spasm with relief of pain and increased mobility of the involved muscles. Paraflex chlorzoxazone is particularly useful for relief of painful skeletal muscle spasm associated with such medical and orthopedic problems as arthritides; acute and chronic back pain; bursitis, fibrositis, or myositis; contusions; disc syndromes; lumbosacral strain; rheumatism and lumbago; sacroiliac strain; spondylitis; sprains and strains; tension headache; tendinitis and tenosynovitis; torticollis; and in premedication for electroshock therapy. 1 U.S. patent No. 2,895.877. Advantages: 1. Unsurpassed effectiveness as a skeletal muscle relaxant. 2. Rapid and consistent absorption from the gastrointestinal tract. 3. Prolonged effect-therapeutic blood levels for six hours. 4. No loss of effectiveness in longterm therapy. 5. Side effects are rarely a problem. Administration and Dosage: For Skeletal Muscle Spasm: Children: One-half to two tablets (125 mg. to 500 mg.) three or four times a day depending upon age and weight. Adults: One tablet (250 mg.) three or four times a day. Initial dosage for severe muscle spasm should be two tablets (500 mg.) three or four times a day. If adequate response is not obtained with this dose, it may be increased to three tablets (750 mg.) three or four times a day. As improvement occurs the dosage may often be reduced. For Tension Headache: Two tablets (500 mg.) every four hours, for 12 to 24 hours, depending on clinical response. In Premedication for Electroshock Therapy: Four tablets (1000 mg.) about 10 hours before therapy and two to six tablets (500 mg. to 1500 mg.) about 2 hours before treatment, the second dose varying according to weight of the patient and intensity of seizure expected. Side Effects: Paraflex chlorzoxazone is well tolerated and seldom produces undesirable side effects. Occasional patients may develop gastrointestinal disturbances; in rare instances the drug may have been associated with gastrointestinal bleeding. Drowsiness, dizziness, lightheadedness, malaise, or overstimulation may be noted in an occasional patient. Rarely, allergic-type rashes, petechiae, or ecchymoses may develop during treatment. Angioneurotic edema or anaphylactic reactions are extremely rare. There is no evidence that the drug will cause renal damage. Nine patients have been reported in whom the administration of Paraflex chlorzoxazone or chlorzoxazone-containing products was suspected of causing liver damage. One of these patients had cancer of the head of the pancreas, another is suspected of having cancer with bony metastasis; in the remaining patients it is not possible to state that the hepatitis was or was not drug-induced. Precautions: Paraflex chlorzoxazone should be used with caution in patients with known allergies. If urticaria, redness, or itching of the skin develops, the drug should be stopped. If any signs or symptoms suggestive of liver dysfunction are observed, the drug should be discontinued. How supplied: Bottles of 50. PARAFON FORTE R Composition: Each scored, light green Tablet contains Paraflex® chlorzoxazone1 250 mg. and Tylenol ® acetaminophen 300 mg. Action and Uses: Parafon Forte provides optimum relief of severely painful musculoskeletal spasm through the actions of (1) Paraflex chlorzoxazone, a muscle relaxant which acts at the level of the spinal cord and subcortical areas of the brain to inhibit multisynaptic reflex arcs involved in production of skeletal muscle spasm, and (2) Tylenol acetaminophen, a nonsalicylate analgesic especially effective in treating skeletal muscle pain. Indications: Parafon Forte is particularly useful for treatment of pain and skeletal muscle spasm associated wtih sprains, strains, and other traumatic muscle injuries; myalgias; low back pain; arthritides; fibrositis; torticollis; spondylitis; tension headache; and cervical root and disc syndromes. Advantages: Painful musculoskeletal spasm, with associated stiffness and limitation of motion, is most effectively treated with Parafon Forte because (1) Paraflex chlorzoxazone provides excellent skeletal muscle relaxation with continuing effectiveness in long-term therapy; prompt and prolonged effect because it is rapidly and consistently absorbed from the gastrointestinal tract, with therapeutic blood levels for six hours. (2) Tylenol acetaminophen is the preferred analgesic for treatment of skeletal muscle pain; a nonsalicylate analgesic that is not irritating to the gastrointestinal tract. (3) No tranquilizing or sedative effect is produced, so that the patient remains alert and able to perform funetions such as driving automobiles or operating machinery. (4) Side effects rarely occur; both Paraflex chlorzoxazone and Tylenol acetaminophen are safe for prolonged use. 1 U.S. patent No. 2,895,877. Administration and Dosage: Two tablets of Parafon Forte four times a day. This dosage provides most patients with a full therapeutic dose of Paraflex chlorzoxazone plus a full analgesic dose of Tylenol acetaminophen. Side Effects: Parafon Forte is well tolerated and seldom produces undesirable side effects. For side effects due to chlorzoxazone, see Paraflex chlorzoxazone. Tylenol acetaminophen is an unusually safe and well tolerated analgesic. Precautions: See Paraflex chlorzoxazone. How Supplied: Bottles of 50. Mr. FOUNTAIN. It may be that in the process of examining these exhibits some of the material will be irrelevant, in which case it may not be necessary to include all of it in the record. Mr. LARRICK. Gentlemen, I will be quite happy to leave that entirely to the discretion of the committee. But when I had taken excerpts from someone's statement, I wanted the whole statement to be in. Mr. FOUNTAIN. It may not be necessary to include all of these last exhibits, but I do not know. I was simply making that observation. Mr. LARRICK. Quite right. And that, Mr. Chairman, concludes the statement you have been good enough to permit me to make. Mr. FOUNTAIN. Thank you very much, Mr. Larrick. Do you have any other statement you would care to make by way of supplement to the prepared statement before we begin our questioning? Mr. LARRICK. No; I have not. Mr. FOUNTAIN. You stated that approval of the original new drug application of Flexin as safe was an institutional decision on the part of FDA. I wonder if you would explain just what you mean by an institutional decision in this case? Mr. LARRICK. The record shows, Mr. Chairman and members of the committee, that the original application was considered by Dr. Barbara Moulton, who was a physician on our staff, was considered by Dr. Geoffrey Woodard, who was a pharmacologist on our staff; a chemist reviewed the portions of the application that pertained to the chemistry, and the final decision was reviewed by the head of the new drug branch. Mr. FOUNTAIN. That was the final decision upon the original application? Mr. LARRICK. Yes. Mr. FOUNTAIN. I believe this application was submitted on November 14, 1955; is that right? Mr. LARRICK. That is correct. Mr. FOUNTAIN. So by way of summary, are we right in concluding that an institutional decision means a decision in which a number of responsible people have participated for and on behalf of the Food and Drug Administration in the making of the final decision? Mr. LARRICK. That is right. And as I testified when I was here. before, we have very greatly formalized the procedures by which institutional decisions will invariably be made. Mrs. DWYER. Mr. Chairman? Mr. FOUNTAIN. Mrs. Dwyer. Mrs. DWYER. You mentioned FDA making institutional decisions. Were these decisions made on information submitted by McNeil or on the basis of FDA's own investigation? Mr. LARRICK. It was made on the basis of information submitted by McNeil, as the statute provides. 37-272-64-pt. 2--16 |