Maxmarvil

Maxmarvil

Manufacturer:

Yuyu

Distributor:

AA Medical
Full Prescribing Info
Contents
Alendronate sodium, calcitriol.
Description
Each film-coated tablet contains alendronate sodium 6.53 mg (equivalent to alendronic acid 5 mg) and calcitriol 0.5 mcg.
Action
Pharmacology: Pharmacodynamics: Sodium Alendronate: Alendronate is a nitrogen-containing bisphosphonate that inhibits osteoclastic bone resorption. It has no direct effect on bone formation. The mode of action postulates incorporation of alendronate present preferentially on the bone resorption surfaces into the cytoplasm of the osteoclast. The activity of osteoclasts is thereby inhibited. After bone resorption stops, bone formation proceeds on the surfaces containing alendronate, which is then incorporated within the matrix where it is no longer pharmacologically active.
The primary pharmacology of alendronate has been investigated in various animal models. Alendronate was administered intermittently, twice weekly (1.8 or 18 mcg/kg SC), to ovariectomised rats in a 1-year treatment study and every 2 weeks (0.05 or 0.25 mg/kg IV) to ovariectomised baboons in a 2-year prevention study. Alendronate prevented or reversed the bone changes produced in the estrogen deficient animals. The changes eg, increased bone turnover, increase in cancellous bone remodeling, decreased bone mineral density (BMD) and bone loss were similar as observed in humans following ovariectomy or menopause.
In other animal models of human bone diseases, alendronate was shown to inhibit bone resorption regardless of cause.
In the long-term study in dogs (36 months at oral doses ranging from 0.25-1 mg/kg/day), alendronate treatment had no deleterious effect on bone quality, bone strength or bone dynamics.
Calcitriol: Various animal pharmacodynamic studies show that the action of calcitriol on bone is mediated via the vitamin D receptor (VDR). Because vitamin D3 serves as a prohormone with the little intrinsic biological activity towards VDR, most animal studies have been performed using the fully active hormone 1,25-(OH)2D3. In ovariectomised rats, 1,25-(OH)2D3 increased serum calcium and prevented the ovariectomy-induced lumbar bone loss.
Published data on pharmacodynamic effects of the 1,25-(OH)2D3 in knockout mice lacking either VDR or the 1α-hydroxylase enzyme confirm the known targets for the active vitamin D3 metabolites. For the 1α-hydroxylase, but not the VDR, knock mice, all bone and cartilage phenotypes were rescued through administration of 1,25-(OH)2D3 suggesting that 1,25-(OH)2D3 is the essential metabolite responsible for most biological effects.
Optimum Ratio Study: In order to derive each optimum concentration ratio of calcitriol and alendronate in combination enabling the bone turnover rate and the serum calcium concentration to be maintained normally while suppressing development of osteoporosis to the maximum extent after menopause by administering calcitriol and alendronate in combination, 1 of calcitriol and alendronate was or both of them were orally administered at 3 different proportions in combination (combination administration group 1, 2 and 3) to female mice for 2 months after ovariectomy was conducted on them. (See Table 1.)

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In all of combination administration groups 1, 2 and 3, the development degree of trabecular bone of tibia was maintained at the same level as in the alendronate-alone administration group. Also, in all of combination administration groups 1, 2 and 3, the serum calcium concentration was maintained at the normal level, which was a good effect. However, in combination administration group 1, the excretory amount of calcium through urine was greatly increased. In combination administration group 3, the excretory amount of calcium through urine was increased, and at the same time, the alkaline phosphatase activity, an osteogenic index was decreased, while in combination administration group 2, the excretory amount of calcium through urine was not increased and the alkaline phosphatase activity was not suppressed.
In comprehensive view of the previously mentioned results, in combination administration group 2 using each concentration ratio of calcitriol and alendronate (calcitriol 0.1 mcg/kg + alendronate 1 mg/kg) in combination, development of osteoporosis was effectively suppressed and the osteogenic velocity was not suppressed, and also, the serum calcium concentration and the excretory amount of calcium through urine were maintained at the normal level. Therefore, it is thought that such concentration ratios are the optimum concentration ratios for development of a pharmaceutical combination.
Mechanism of Action: Sodium Alendronate: Animal studies have indicated the following mode of action. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Studies in mice on the localization of radioactive [3H]alendronate in bone showed about 10-fold higher uptake on osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days after [3H]alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover (ie, the number of sites at which bone is remodelled). In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass.
Calcitriol: Vitamin D3 is produced in the skin by photochemical conversion of 7-dehydrocholesterol to previtamin D3 by ultraviolet light. This is followed by non-enzymatic isomerization to vitamin D3. In the absence of adequate sunlight exposure, vitamin D3 is an essential dietary nutrient. Vitamin D3 in skin and dietary vitamin D3 (absorbed into chylomicrons) is converted to 25-hydroxyvitamin D3 in the liver. Conversion to the active calcium-mobilizing hormone 1,25-dihydroxyvitamin D3 (calcitriol) in the kidney is stimulated by both parathyroid hormone and hypophosphatemia. The principal action of 1,25-dihydroxyvitamin D3 is to increase intestinal absorption of both calcium and phosphate as well as regulate serum calcium, renal calcium and phosphate excretion, bone formation and bone resorption.
Vitamin D is required for normal bone formation. Vitamin D insufficiency develops when both sunlight exposure and dietary intake are inadequate. Insufficiency is associated with negative calcium balance, increased parathyroid hormone levels, bone loss and increased risk of skeletal fracture. In severe cases, deficiency results in more severe hyperparathyroidism, hypophosphatemia, proximal muscle weakness, bone pain and osteomalacia.
Clinical Studies: The randomized, double-blind, parallel group, comparative, multicenter study was conducted in Korea in 217 postmenopausal women with osteoporosis. Patients were randomized to 2 treatment groups and received once daily over 24 weeks.
Treatments: The subject were allocated randomly to 1 of the following 2 treatment groups: Test Group: Maxmarvil tablets (alendronate 5 mg + calcitriol 0.5 mcg) + Alfacalcidol placebo tablets.
Reference Group: Maxmarvil placebo tablets + Alfacalcidol tablets.
None of the patients were vitamin-D-deficient, as assessed by serum 25-hydroxyvitamin D [25(OH)D], nor had they received any drugs affecting bone metabolism before enrollment. Bone mineral densities of L1-L4 and the femur were measured by dual-energy x-ray absorptiometry (DXA) at the initial assessment and after 6 months of treatment.
Serum biochemical assays, including serum calcium, 24-hr urinary calcium excretion, and bone turnover markers [both bone-specific alkaline phosphatase (bsALP) and urine N-telopeptide (NTx)], were performed at the baseline, and after 3 and 6 months of treatment.
Efficacy Results: Primary efficacy endpoint was lumbar spine BMD. The BMD of the lumbar spine increased up to 2.42±5.1% from the baseline after 6 months (p<0.05). On the other hand, the change in BMD in the alfacalcidol group was 0.28±5.01% after 6 months. (See Table 2.)

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The secondary efficacy endpoint was femoral BMD, levels of bsALP and NTx. There was no significant difference in femoral BMD between the 2 groups. The levels of bsALP and NTx were significantly lower in the Maxmarvil group than in the alfacalcidol group [-22.04±39.16% vs -11.42±27.54% (p=0.0219) and -25.46±52.68% vs 1.24±61.5% (p=0.007), respectively]. (See Tables 3 and 4.)

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Conclusion on Efficacy: Study demonstrates that a combination of calcitriol and alendronate is quite effective in preventing bone loss, with the advantage of lesser hypercalciuric effect of calcitriol in the postmenopausal osteoporotic women.
Pharmacokinetics: Absorption: Sodium Alendronate: As with other bisphosphonates, the oral absorption of alendronate in animals is limited under fasting conditions and negligible in the presence of food. The fasting oral bioavailability of alendronate was estimated as 0.9% in rat, 1.8% in dog and 1.7% in monkey. Oral administration to rats in the presence of food decreases bioavailability about 6- to 7-fold.
Since alendronate is highly polar and charged at physiological pH, absorption across the gastrointestinal tract has been proposed to occur primarily by the paracellular, rather than transcellular route. Alendronate is better absorbed from segments of the GIT with larger surface areas ie, the jejunum > duodenum > ileum.
Calcitriol: Calcitriol is rapidly absorbed from the intestine. Peak serum concentrations (above basal values) were reached within 3-6 hrs following oral administration of single doses of calcitriol 0.25-1 mcg. Following a single oral dose of 0.5 mcg, mean serum concentrations of calcitriol rose from a baseline value of 40±4.4 (SD) pg/mL to 60±4.4 pg/mL at 2 hrs, and declined to 53±6.9 at 4 hrs, 50±7 at 8 hrs, 44±4.6 at 12 hrs and 41.5±5.1 at 24 hrs.
Distribution: Sodium Alendronate: The plasma protein binding (means±SD) determined by ultrafiltration at alendronate concentrations of 0.2-10 mcg/mL (rat, human) and 0.5-5 mcg/mL (dog, monkey) is species-dependent: High to rat plasma proteins (94.76±0.29%), but not to dog (24.6±3%), monkey (68.9±3.8%) or human (72.3±3.7%). At a low concentration range of 0.2-0.5 mcg/mL, the unbound fraction was about 3% for the rat, 23% for the human, 27% for the monkey and 74% for the dog.
Systemically available alendronate disappears very rapidly from plasma, and it is either taken up by bone tissues or excreted by the kidneys. The uptake of alendronate by bone tissues was species-dependent, likely due to plasma flow rate to bone tissues as well as intrinsic bone uptake, and dose-dependent.
Calcitriol: Calcitriol is approximately 99.9% bound in blood. Calcitriol and other vitamin D metabolites are transported in blood, by an α-globulin vitamin D binding protein. There is evidence that maternal calcitriol may enter the fetal circulation. Calcitriol is transferred into human milk at low levels (ie, 2.2±0.1 pg/mL).
Metabolism: Sodium Alendronate: Alendronate is not metabolized in rat and dogs, a finding reported also for other bisphosphonates.
Calcitriol: In vivo and in vitro studies indicate the presence of 2 pathways of metabolism for calcitriol. The 1st pathway involves the 24-hydroxylase as the 1st step in catabolism of calcitriol. There is definite evidence of 24-hydroxylase activity in the kidney; this enzyme is also present in many target tissues which possess the vitamin D receptor eg, the intestine. The end-product of this pathway is a side chain shortened metabolite, calcitroic acid. The 2nd pathway involves the conversion of calcitriol via the stepwise hydroxylation of carbon-26 and carbon-23, and cyclization to yield ultimately 1α, 25R(OH)2-26, 23S-lactone D3. The lactone appears to be the major metabolite circulating in humans, with mean serum concentrations of 131±17 pg/mL. In addition, several other metabolites of calcitriol have been identified: 1α, 25(OH)2-24-oxo-D3; 1α, 23,25(OH)3-24-oxo-D3; 1α, 24R,25(OH)3D3; 1α, 25S,26(OH)3D3; 1α, 25(OH)2-23-oxo-D3; 1α, 25R,26(OH)3-23-oxo-D3; 1α, (OH)24,25,26,27-tetranor-COOH-D3.
Excretion: Sodium Alendronate: Renal excretion is the only route of elimination of alendronate and urinary recovery is quite similar among species. Following IV administration (0.8-1 mg/kg) to rats, dogs and monkeys, approximately 30-40% of the dose was excreted in the urine in 24 hrs, mostly in the first 3-4 hrs. Only a very small fraction, <0.4% of the dose was recovered in rat feces in 24 hrs. Detailed studies in rat revealed that alendronate is actively secreted by an uncharacterized renal transport system, but not by anionic or cationic renal transport systems. Because alendronate is not metabolized and no biliary excretion, compound not excreted in 24 hr post-dose is believed to be sequestered in the skeleton. Once taken up by the bone, the elimination of alendronate from the bone tissue into the circulation to be then eliminated renally is slow, ranging from 200 days in rats to 3 years in dogs.
Calcitriol: Enterohepatic recycling and biliary excretion of calcitriol occur. The metabolites of calcitriol are excreted primarily in feces. Following IV administration of radiolabeled calcitriol in normal subjects, approximately 27% and 7% of the radioactivity appeared in the feces and urine, respectively, within 24 hrs. When a 1 mcg oral dose of radiolabeled calcitriol was administered to normal subjects, approximately 10% of the total radioactivity appeared in urine within 24 hrs. Cumulative excretion of radioactivity on the 6th day following IV administration of radiolabeled calcitriol averaged 16% in urine and 49% in feces. The elimination half-life of calcitriol in serum after single oral doses is about 5-8 hrs in normal subjects.
Toxicology: Carcinogenesis, Mutagenesis & Impairment of Fertility: Sodium Alendronate: Harderian gland (a retroorbital gland not present in humans) adenomas were increased in high-dose female mice (p=0.003) in a 92-week carcinogenicity study at doses of alendronate of 1, 3, and 10 mg/kg/day (males) or 1, 2, and 5 mg/kg/day (females). These doses are equivalent to 0.5-4 times the 10 mg human dose based on surface area (mg/m2). Parafollicular cell (thyroid) adenomas were increased in high-dose male rats (p=0.003) in a 2-year carcinogenicity study at doses of 1 and 3.75 mg/kg body weight. These doses are equivalent to 1 and 3 times the 10 mg human dose based on surface area.
Alendronate was not genotoxic in the in vitro microbial mutagenesis assay with and without metabolic activation, in an in vitro mammalian cell mutagenesis assay, in an in vitro alkaline elution assay in rat hepatocytes, and in an in vivo chromosomal aberration assay in mice. In an in vitro chromosomal aberration assay in Chinese hamster ovary cells, however, alendronate was weakly positive at concentrations 5 mM in the presence of cytotoxicity.
Alendronate had no effect on fertility (male or female) in rats at oral doses up to 5 mg/kg/day (4 times the 10-mg human dose based on surface area).
Calcitriol: Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of calcitriol. Calcitriol is not mutagenic in vitro in the Ames test, nor is it genotoxic in vivo in the mouse micronucleus test. No significant effects of calcitriol on fertility and/or general reproductive performances were observed in a segment I study in rats at doses of up to 0.3 mcg/kg (approximately 3 times the maximum recommended dose based on body surface area).
Animal Toxicology and/or Pharmacology: The relative inhibitory activities on bone resorption and mineralization of alendronate and etidronate were compared in the Schenk assay, which is based on histological examination of the epiphyses of growing rats. In this assay, the lowest dose of alendronate that interfered with bone mineralization (leading to osteomalacia) was 6000-fold the antiresorptive dose. The corresponding ratio for etidronate was 1:1. These data suggest that alendronate administered in therapeutic doses is highly unlikely to induce osteomalacia.
Indications/Uses
Osteoporosis.
Dosage/Direction for Use
Recommended Dose: 1 tab once daily.
Administration: Maxmarvil must be taken at least ½ hr before the 1st food, beverage or medication of the day with plain water only. Other beverages (including mineral water), food and some medications are likely to reduce the absorption of Maxmarvil. Taking Maxmarvil with food, beverages (other than plain water) or other medications will lessen the effect of Maxmarvil by decreasing its absorption into the body.
Overdosage
Significant lethality after single oral doses was seen in female rats and mice at 552 mg/kg (3256 mg/m2) and 966 mg/kg (2898 mg/m2), respectively. In males, these values were slightly higher, 626 and 1280 mg/kg, respectively. There was no lethality in dogs at oral doses up to 200 mg/kg (4000 mg/m2).
Symptoms: Adverse effects of calcitriol are, in general, similar to those encountered with excessive vitamin D intake. High intake of calcium and phosphate concomitant with Maxmarvil may lead to similar abnormalities. High levels of calcium in the dialysate bath may contribute to hypercalcemia.
The acute symptoms of vitamin D intoxication include anorexia, headache, vomiting or constipation. The chronic symptoms include weakness, weight loss, dysesthesia, polyuria, pyrexia with polydipsia, dehydration, apathism and hypercalcemia. Widespread calcification of soft tissues, including heart, kidneys and lungs can occur.
Treatment: No specific information is available on the treatment of overdosage with Maxmarvil. Hypocalcemia, hypophosphatemia and upper GI adverse events eg, upset stomach, heartburn, esophagitis, gastritis, or ulcer may result from oral overdosage. Milk or antacids should be given to bind alendronate. Due to the risk of esophageal irritation, vomiting should not be induced and the patient should remain fully upright.
Dialysis would not be beneficial.
General treatment of hypercalcemia.
The treatment of accidental overdosage should consist of general supportive measures. Induction of emesis, gastric lavage or administration of liquid paraffin may be of benefit in preventing further absorption. Serum calcium level should be obtained. Should, however, persistent and markedly elevated serum calcium levels occur, use drugs eg, phosphates and corticosteroids to induce and appropriate forced diuresis.
Contraindications
Hypersensitivity to alendronate, calcitriol or any of the ingredients of Maxmarvil; abnormalities of the esophagus which delay esophageal emptying eg, stricture or achalasia; hypocalcemia; hypercalcemia relevant diseases; evidence of vitamin D toxicity.
Warnings
Maxmarvil, like other bisphosphonates, may cause local irritation of the upper gastrointestinal mucosa. Esophageal adverse effects eg, esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with Maxmarvil. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue Maxmarvil and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
The risk of severe esophageal adverse effects appears to be greater in patients who lie down after taking Maxmarvil and/or who fail to swallow it with the recommended amount of water, and/or who continue to take Maxmarvil after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient. In patients that cannot comply with dosing instructions due to mental disability, therapy with Maxmarvil should be used under appropriate supervision.
Because possible irritant effects of Maxmarvil on the upper GI mucosa and a potential for worsening of the underlying disease, caution should be used when Maxmarvil is given to patients with active upper GI problems (eg, dysphagia, esophageal diseases, gastritis, duodenitis or ulcers).
Special Precautions
General: While no increased risk was observed in extensive clinical trials, there have been rare (post-marketing) reports of gastric and duodenal ulcers, some severe and with complications.
Maxmarvil is not recommended for patients with renal insufficiency [creatinine clearance (CrCl) <35 mL/min].
Causes of osteoporosis other than estrogen deficiency and aging should be considered.
Hypocalcemia must be corrected before initiating therapy with Maxmarvil. Other disturbances of mineral metabolism (eg, vitamin D deficiency) should also be effectively treated.
Presumably due to the effects of Maxmarvil on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur, especially in patients with Paget's disease, in whom the pre-treatment rate of bone turnover may be greatly elevated. Adequate calcium and vitamin D intake should be ensured to provide for these enhanced needs.
Information for Patients: Patients should be instructed that the expected benefits of Maxmarvil may only be obtained when each tablet is swallowed with plain water the first thing upon rising for the day at least 30 min before the first food, beverage or other medications of the day. Even dosing with orange juice or coffee has been shown to markedly reduce the absorption of Maxmarvil.
To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, patients should be instructed to swallow Maxmarvil with a full glass of water (170-230 mL) and not to lie down for at least 30 min and until after the 1st food of the day.
Patients should not chew or suck on the tablet because of a potential for oropharyngeal ulceration. Patients should be specifically instructed not to take Maxmarvil at bedtime or before rising for the day. Patients should be informed that failure to follow these instructions may increase the risk of esophageal problems. Patients should be instructed that if they have developed symptoms of esophageal disease (eg, difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn), the patient should stop taking Maxmarvil and consult a physician.
Patients should be instructed to take supplemental calcium and vitamin D if daily dietary intake is inadequate. Weight-bearing exercise should be considered along with the modification of certain behavioral factors eg, excessive cigarette smoking and/or alcohol consumption, if these factors exist.
Physicians should instruct patients to read the patient package insert before starting therapy with Maxmarvil and to re-read it each time the prescription is renewed.
Calcitriol can affect an occurrence of hypercalcemia. Excessive calcium intake eg, increased intake of dairy products can lead to hypercalcemia. The patients and their parents or spouse should be carefully informed about the adherence to instructed diet and symptoms of hypercalcemia. If serum calcium level is >1 mg/dL above the upper limit of the normal range, 9-11 mg/dL or serum creatinine is >120 micromol/L, Maxmarvil should be immediately discontinued until normocalcemia ensues.
Immobile patients after surgery are particularly prone to hypercalcemia.
Calcitriol induces an increase in serum phosphate level, which is good for hypophosphatemia. But calcitriol may lead to ectopic calcification in patients with impaired renal function. Both appropriate oral phosphate-binders and a low phosphate diet should be used to control serum phosphate levels (2-5 mg/100 mL or 0.65-1.62 mmol/L) in patients undergoing dialysis. The patients with vitamin D resistant rickets (familial hypophosphatemia) should be administered phosphate orally. But Maxmarvil should be used with caution because calcitriol may lead to stimulate intestinal phosphorus absorption. Serum calcium, phosphorus, magnesium, alkaline phosphatase, and 24-hr urinary calcium and phosphate should be determined periodically. Therefore, early in treatment during dosage adjustment, serum calcium levels should be determined at least twice weekly.
Since calcitriol is the most potent metabolite of vitamin D, vitamin D and its derivatives should be withheld during treatment of Maxmarvil.
When switching from ergocalciferol to calcitriol, it may take several months to recover baseline level of serum ergocalciferol.
Patients with normal renal function taking Maxmarvil should be given adequate fluid to avoid dehydration.
Renal Insufficiency: No dosage adjustment is necessary for patients with mild to moderate renal insufficiency (CrCl 35-60 mL/min). Maxmarvil is not recommended for patients with more severe renal insufficiency (CrCl <35 mL/min) due to lack of experience.
Use in Men: Safety and effectiveness in male osteoporosis have not been established.
Laboratory Test Findings: In double-blind, multicenter, controlled studies, asymptomatic, mild, and transient decreases in serum calcium and phosphate were observed in approximately 18% and 10%, respectively, of patients taking Maxmarvil versus approximately 12% and 3% of those taking placebo. However, the incidences of decreases in serum calcium to <8 mg/dL (2 microM) and serum phosphate to 2 mg/dL (0.65 microM) were similar in both treatment groups.
Effects on the Ability to Drive or Operate Machinery: Calcitriol appears to be safe considering its characteristics of adverse reaction with no such activities.
Use in pregnancy: Reproduction studies in rats showed decreased post-implantation survival at 2 mg/kg/day of alendronate and decreased body weight gain in normal pups at 1 mg/kg/day of alendronate. Sites of incomplete fetal ossification were statistically and significantly increased in rats beginning at 10 mg/kg/day of alendronate in vertebral (cervical, thoracic and lumbar), skull and sternebral bones. The previously mentioned doses ranged from 1 time (1 mg/kg) to 9 times (10 mg/kg) the 10-mg human dose based on surface area (mg/m2). No similar fetal effects were seen when pregnant rabbits were treated at doses up to 35 mg/kg/day of alendronate [50 times the 10-mg human dose based on surface area (mg/m2)].
Both total and ionized calcium decreased in pregnant rats at 15 mg/kg/day of alendronate (13 times the 10-mg human dose based on surface area) resulting in delays and failures of delivery. Protracted parturition due to maternal hypocalcemia occurred in rats at doses as low as 0.5 mg/kg/day of alendronate (0.5 times the recommended human dose) when rats were treated from before mating through gestation. Maternotoxicity (late pregnancy deaths) occurred in the female rats treated with alendronate 15 mg/kg/day for varying periods of time ranging from treatment only during pre-mating to treatment only during early, middle or late gestation; these deaths were lessened but not eliminated by cessation of treatment. Calcium supplementation either in the drinking water or by mini-pump could not ameliorate the hypocalcemia or prevent maternal and neonatal deaths due to delays in delivery; calcium supplementation IV prevented maternal, but not fetal deaths.
There are no studies in pregnant women. Maxmarvil should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.
Calcitriol given orally at lethal dose has been reported to induce aortic stenosis in rabbits. No teratogenic evidence with high intake of vitamin D was observed in human. However, calcitriol should be used during pregnancy only if the potential benefit justifies the potential risk to fetus.
Use in lactation: Alendronate was secreted in the milk of rats after an IV dose. It is not known whether alendronate is excreted in human milk. Maxmarvil has not been studied in nursing women and should not be given to them.
Calcitriol is believed to be excreted in human milk. A decision should be made whether to discontinue nursing or to discontinue Maxmarvil, taking into account the importance of Maxmarvil to the mother and potential for hypercalcemia in nursing infants. Thus, serum calcium level of nursing mother and infant should be determined when Maxmarvil is administered to a nursing woman.
Use in children: Safety and effectiveness in pediatric patients have not been established.
Use in the elderly: Of the patients receiving Maxmarvil in the 2 large osteoporosis studies, 45% were ≥65 years. No overall differences in efficacy or safety were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out.
Use In Pregnancy & Lactation
Use in pregnancy: Reproduction studies in rats showed decreased post-implantation survival at 2 mg/kg/day of alendronate and decreased body weight gain in normal pups at 1 mg/kg/day of alendronate. Sites of incomplete fetal ossification were statistically and significantly increased in rats beginning at 10 mg/kg/day of alendronate in vertebral (cervical, thoracic and lumbar), skull and sternebral bones. The previously mentioned doses ranged from 1 time (1 mg/kg) to 9 times (10 mg/kg) the 10-mg human dose based on surface area (mg/m2). No similar fetal effects were seen when pregnant rabbits were treated at doses up to 35 mg/kg/day of alendronate [50 times the 10-mg human dose based on surface area (mg/m2)].
Both total and ionized calcium decreased in pregnant rats at 15 mg/kg/day of alendronate (13 times the 10-mg human dose based on surface area) resulting in delays and failures of delivery. Protracted parturition due to maternal hypocalcemia occurred in rats at doses as low as 0.5 mg/kg/day of alendronate (0.5 times the recommended human dose) when rats were treated from before mating through gestation. Maternotoxicity (late pregnancy deaths) occurred in the female rats treated with alendronate 15 mg/kg/day for varying periods of time ranging from treatment only during pre-mating to treatment only during early, middle or late gestation; these deaths were lessened but not eliminated by cessation of treatment. Calcium supplementation either in the drinking water or by mini-pump could not ameliorate the hypocalcemia or prevent maternal and neonatal deaths due to delays in delivery; calcium supplementation IV prevented maternal, but not fetal deaths.
There are no studies in pregnant women. Maxmarvil should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.
Calcitriol given orally at lethal dose has been reported to induce aortic stenosis in rabbits. No teratogenic evidence with high intake of vitamin D was observed in human. However, calcitriol should be used during pregnancy only if the potential benefit justifies the potential risk to fetus.
Use in lactation: Alendronate was secreted in the milk of rats after an IV dose. It is not known whether alendronate is excreted in human milk. Maxmarvil has not been studied in nursing women and should not be given to them.
Calcitriol is believed to be excreted in human milk. A decision should be made whether to discontinue nursing or to discontinue Maxmarvil, taking into account the importance of Maxmarvil to the mother and potential for hypercalcemia in nursing infants. Thus, serum calcium level of nursing mother and infant should be determined when Maxmarvil is administered to a nursing woman.
Adverse Reactions
The adverse experiences from these studies considered by the investigators as possibly, probably or definitely drug related in ≥1% of 268 patients treated with Maxmarvil and Alfacalcidol are presented in the table as follows. (See Table 5.)

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In clinical studies, adverse experiences associated with alendronate usually were mild, and generally did not require discontinuation of therapy. Alendronate has been evaluated for safety in approximately 8000 postmenopausal women in clinical studies.
In 2 large, 3-year, placebo-controlled, double-blind, multicenter studies (United States and multinational), discontinuation of therapy due to any clinical adverse experience occurred in 4.1% of 196 patients treated with alendronate 10 mg/day and 6% of 397 patients treated with placebo. Adverse experiences reported by the investigators as possibly, probably or definitely drug related in ≥1% of patients treated with either alendronate 10 mg/day or placebo are presented in the table as follows. (See Table 6.)

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Rarely, rash and erythema have occurred. One (1) patient treated with alendronate (10 mg/day), who had a history of peptic ulcer disease and gastrectomy, and who was taking concomitant aspirin developed an anastomotic ulcer with mild hemorrhage, which was considered drug-related. Aspirin and alendronate were discontinued and the patient recovered. The adverse experience profile was similar with 401 patients treated with 5- or 20-mg doses of alendronate. In the vertebral fracture study of the fracture intervention trial, discontinuation of therapy due to any clinical adverse experience occurred in 7.6% of 1022 patients treated with Maxmarvil 5 mg/day for 2 years and 10 mg/day for the 3rd year and 9.4% of 1005 patients treated with placebo. Similarly, discontinuations due to upper GI adverse experiences were comparable: Alendronate 2.6%; placebo 2.6%. The overall adverse experience profile was similar to that seen in other studies with alendronate 5 or 10 mg/day.
Post-Marketing Experience: The following adverse reactions have been reported in post-marketing use of alendronate: Body as a Whole: Hypersensitivity reactions including urticaria and, rarely, angioedema. Transient symptoms of myalgia, malaise, asthenia and rarely, fever have been reported with alendronate, typically in association with initiation of treatment. Rarely, symptomatic hypocalcemia has occurred, generally in association with predisposing conditions. Rarely, peripheral edema.
Gastrointestinal: Esophagitis; esophageal erosions, esophageal ulcers, rarely esophageal stricture or perforation, and oropharyngeal ulceration. Gastric or duodenal ulcers, some severe and with complications have also been reported.
Localized osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection with delayed healing, has been reported rarely.
Musculoskeletal: Bone, joint and/or muscle pain, occasionally severe, and rarely incapacitating; joint swelling; low-energy femoral shaft and subtrochanteric fractures.
Nervous System: Dizziness and vertigo.
Skin: Rash (occasionally with photosensitivity), pruritus, alopecia, rarely severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis.
Special Senses: Rarely uveitis, scleritis or episcleritis.
Maxmarvil has not reported adverse reactions in usual dosage.
Maxmarvil is effective in vitamin D activity in the body. Therefore, adverse effects are similar to those encountered with excessive vitamin D intake. Acute reactions include anorexia, headache, vomiting and constipation. The relatively short biological half-life of calcitriol permits rapid elimination of the compound when treatment is stopped or when dosage is reduced, and normalization of serum calcium levels may be observed within a few days, this rate of reversal of biological effects is more rapid than when other vitamin D derivatives are used. Chronic Reactions: Weakness, weight loss, dysesthesia, polyuria, pyrexia with polydipsia, dehydration or apathia.
In 15-year clinical studies on all the indications for calcitriol, there were few adverse reaction reports. Hypercalcemia and hyperphosphatemia together may lead to soft tissue calcification. Radiographic evaluation may be useful in detection of this condition.
In patients with normal renal function, chronic hypercalcemia may occur associated with an elevation of serum creatinine.
Maxmarvil may cause hypersensitivity to sensitive patients.
Drug Interactions
Estrogen: Concomitant use of hormone replacement therapy and Maxmarvil in the treatment of osteoporosis in postmenopausal women is not recommended because of lack of clinical experience.
Calcium Supplements/Antacids: It is likely that calcium supplements, antacids, and some oral medications will interfere with absorption of Maxmarvil. Therefore, patients must wait at least ½ hr after taking Maxmarvil before taking any other drug.
Aspirin: In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving concomitant therapy with doses of Maxmarvil >10 mg/day and aspirin-containing compounds.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Maxmarvil may be administered to patients taking NSAIDs. In a 3-year, controlled, clinical study (n=2027) during which a majority of patients received concomitant NSAIDs, the incidence of upper gastrointestinal adverse events was similar in patients taking alendronate 5 or 10 mg compared to those taking placebo. However, since NSAIDs use is associated with gastrointestinal irritation, caution should be used during concomitant use with Maxmarvil.
Since calcitriol is the most potent metabolite of vitamin D available, pharmacologic doses of vitamin D and its derivatives should be withheld during Maxmarvil treatment to avoid possible additive effects or hypercalcemia.
Patients should be informed about adherence to diet and calcium supplementation and avoidance of the use of excessive calcium intake.
The concomitant use of thiazide diuretics and calcitriol can increase hypercalcemia.
The optimal dose of calcitriol must be carefully given to patients on digitalis, because hypercalcemia in such patients may precipitate cardiac arrhythmias.
Vitamin D metabolites which enhance calcium absorption are the antagonists of corticosteroids which inhibit calcium absorption.
Magnesium-containing antacid and calcitriol should not be used concomitantly to patients undergoing chronic renal dialysis, because such use may lead to hypermagnesemia.
The known sites of action of calcitriol are intestine, bone and kidney. Calcitriol has been shown to stimulate phosphorus transport. A phosphate-binding compound should be used to control serum phosphate level (normal: 2-5 mg/100 mL or 0.65-1.62 mmol/L).
Patients with vitamin D resistant rickets (familial hypophosphatemia) should be administered phosphate orally. But calcitriol should be used with caution, because calcitriol may lead to stimulate intestinal phosphorus absorption.
Concurrent administration of enzyme-inducing drugs eg, phenytoin and phenobarbital may increase the clearance of calcitriol. Thus, an increase in calcitriol dosage may be necessary.
Cholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins; as such, it may impair intestinal absorption of calcitriol.
Storage
Store in a well-closed container below 25°C.
ATC Classification
M05BB03 - alendronic acid and colecalciferol ; Belongs to the class bisphosphonates, combinations. Used in the treatment of bone diseases.
Presentation/Packing
Enteric FC tab (white, circular, enteric) 3 x 10's.
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